(BQ) Part 1 book Metabolism at a slance has contents: Introduction to metabolic pathways, metabolism of glucose to provide energy, metabolism of glucose to glycogen, regulation of gluconeogenesis, regulation of krebs cycle, regulation of krebs cycle,... and other contents.
glycogen synthase α (1—> 4) glucose oligosaccharide (n +1 residues) UDP branching enzyme O α (1—> 4) glucose oligosaccharide primer (n residues) H HO glycogen C CH2OH O H H OH H H OH O – – O O P O P O CH2 O P i H phosphorylase (pyridoxal 5' P ) glycogen (n–1 residues) HO debranching enzyme (i) glycosyltransferase (ii) α (1— > 6) glucosidase pyrophosphatase PPi CH O C CH O H Pi H N OH H CH2OPO32– O H H H HO O uridine diphosphate glucose CH2OH O H HN H H HO H OH OH H H ATP OH H H OH HO OH glucose glucose 6-phosphatase Pi H H2O H i 2– OPO3CH2 H H OH CH2OPO32– ribose 5-phosphate Mg2+ (thiamine PP) transketolase HC O HCOH HCOH CH2OPO32– HCOH O O fructose 1,6-bisphosphate H 3C C glyceraldehyde 3-phosphate HCOH triose phosphate isomerase O malonyl-acetyl CoA-ACP transacylase (MAT) NADH+H+ H3C O C OPO32– H C OH D-3-hydroxybutyryl ACP SACP NADPH+H+ NADP+ H3C CH2 C4 HCOH CH2OPO32– 3-phosphoglycerate phosphoglycerate Mg2+ mutase – COO HCOPO32– CH2OH 2-phosphoglycerate C C SACP H enoyl ACP acetyl—KS acetoacetyl ACP O H phosphoglycerate kinase COO β-hydroxyacyl ACP dehydratase (DH) H2O HS-ACP – CH2 C SACP H3C C CH2OPO32– 1,3-bisphosphoglycerate ATP O H3C C cysteine-SH of KS (condensing enzyme) HCOH ADP β-ketoacyl ACP reductase (KR) NADP+ acetyl ACP Pi glyceraldehyde 3-phosphate dehydrogenase HS-ACP O glyceraldehyde 3-phosphate Fatty acid synthesis acetoacetyl ACP C4 NADPH+H+ CoASH CH2OPO32– O H3C C CH2 C SACP SCoA acetyl CoA NAD+ Cytosol CH2OPO32– fructose 6-phosphate HC Glycolysis xylulose 5-phosphate transaldolase CH2OPO32– CH2OPO32– dihydroxyacetone phosphate HCOH CH2OPO32– CH2OPO32– C O CH2OPO32– CHO HCOH HCOH HCOH sedoheptulose 7-phosphate HOCH glyceraldehyde 3-phosphate C CH2OH ribose 5-phosphate isomerase HCOH CH2OH O HCOH aldolase O HOCH HCOH erythrose 4-phosphate HC C O HCOH HCOH OH H ribulose phosphate 3-epimerase HOCH CH2OPO32– fructose 6-phosphate HO ribulose 5-phosphate CH2OH HCOH fructose 6-phosphate CH2OH O CH2OPO32– 6-phosphogluconate C O ADP H2O HCOH CH2OPO32– CHO CH2OPO32– ATP phosphofructokinase-1 Mg2+ P fructose 1,6-bisphosphatase HCOH HCOH CH2OH OH H 6-phosphogluconate dehydrogenase HCOH HCOH glucose 6-phosphate OH Endoplasmic reticulum OH lactonase HCOH OH HO H C O Mg2+ (thiamine PP) HOCH OH H H CH2OH CO2 transketolase C O H O OH NADPH H+ HOCH Pentose phosphate pathway CH2OH H OPO3CH2 HO O NADP+ HCOH 6-phosphogluconoδ-lactone glucose 1-phosphate OH 2– H H2O UTP phosphoglucose isomerase Pi OH OPO32– OH CH2OPO3 O H H H glucose 6-phosphate dehydrogenase OH COO– CH2OPO O32– O H UDP-glucose pyrophosphorylase H 2– ADP + H glucokinase hexokinase Mg2+ H NADPH H+ glucose 6-phosphate phosphoglucomutase CH2OH O H OH NADP+ hexanoyl ACP palmitoyl ACP enoyl ACP reductase (ER) H2O thioesterase (TE) O CH2 C acyl ACP SACP C8 C6 CO2 HS–KS CO2 CO2 C10 CO2 C12 CO2 C14 acyl carrier protein (ACP) C16 CO2 CO2 condensation condensation CoASH acyl-KS O O -O C CH2 C CoASH CoASH CoASH CoASH SACP CoASH CH3(CH2)14C O- palmitate HS-ACP malonyl ACP CoASH O translocation β-ketoacyl-ACP synthase (KS) (condensing enzyme) malonyl-acetyl CoA-ACP transacylase (MAT) CH2OH esterification CHOH l lC A CH OPO 2- O S C enoyl ACP + acetyl—KS NADPH+H ADP Glycolysis phosphoglycerate kinase ATP H3C CH2 – acetoacetyl ACP COO C4 HCOH 2– CH2OPO3 3-phosphoglycerate H2O COO C O H2C COO– oxaloacetate NADH+H+ COO ATP COO– COO CHOH HCOH H2C COO– malate CH3 lactate NAD+ – NADH+H+ – ADP4– NAD+ – COO HPO42– HPO42– – COO CHOH ADP3– H2C 6H+ C malate dehydrogenase COO– IV 2H+ H2O / O2 C III 4H+ H2O oxaloacetate succinate CoASH GTP O C SCoA succinyl CoA Pi HOC GDP nucleoside diphosphate kinase O (triacylglycerol) CH2OH ADP+Pi ATP CoASH H2O tripalmitin H2O glycerol CoASH citrate lyase 2P i palmitoyl CoA citrate palmitoylcarnitine glycerol phosphate shuttle outer CPT carnitine inner CPT O CH3(CH2)12 CH CH C 2 β Oxidation C12 FADH2 NADH+H+ CH2COO– OH FADH2 C4 HOCH COO– isocitrate CH2COO– CH2 NADH+H+ CO2 / O2 H2O NAD+ I 2H+ III Q outer membrane 4H+ + 4H C H2O O CH2 C SCoA H L-3-hydroxyacyl CoA L-3-hydroxyacyl CoA dehydrogenase NAD+ NADH+H+ + 2H CoASH thiolase O 2HPO4 H+ ATP4– FO HPO42– H+ O O F1 10H+ O CH3(CH2)12 C CH C SCoA 3-ketoacyl CoA CH3(CH2)12 C SCoA myristoyl CoA IV C intermembrane space CoASH thiolase ADP3– 4H+ FADH2 CH3COCH2COSCoA acetoacetyl CoA 3H+ O C COO– α-ketoglutarate NAD+ CoASH 4H+ SCoA NADH+H+ Respiratory chain NAD+ CH3(CH2)12 NADH+H+ HC COO– C enoyl CoA hydratase NADH+H+ C6 C H trans-Δ -enoyl CoA FADH2 [cis-aconitate] FAD FADH2 H O CH3(CH2)12 C FADH2 C8 SCoA palmitoyl CoA acyl CoA dehydrogenase 4H+ ADP3– ATP4– H3C C SCoA acetyl CoA ATGL & hormone sensitive lipase (adipose tissue) (3) palmitate long chain acyl CoA synthetase aconitase H2O CoASH ATP PP +AMP pyroi phosphatase NADH+H+ inner membrane ATP O ATP CHOH COO matrix translocase ADP C H2C COO– oxaloacetate NADH+H+ Mitochondrion CHOC(CH2)14CH3 CH2OH C10 H2C COO– α-ketoglutarate dehydrogenase CO2 NADH H+ ADP glycerol kinase (not in white adipose tissue) – isocitrate dehydrogenase Mg2+ CH2 O CH2OC(CH2)14CH3 O SCoA CH2COO– succinate dehydrogenase CH2COO– esterification CH2OPO32- acetyl CoA carboxylase (biotin) (8) acetyl CoA FAD CH2COO– CH3(CH2)14C O- CoASH glycerol 3-phosphate NADH+H+ Krebs cycle succinyl CoA synthetase CoASH CHOH malonyl CoA FADH2 H2O CH2COO– CoASH CH2O aconitase OOCCH fumarate FADH2 CoASH malonyl-acetyl CoA-ACP transacylase (MAT) malonyl-acetyl CoA-ACP transacylase (MAT) tricarboxylate carrier fumarase Q II malate dehydrogenase C SCoA CoASH CO2 palmitate C14 HCCOO– – SACP NADH+H+ citrate synthase CO2 CoASH acetyl CoA H2O CoASH acetyl CoA malate/ aspartate shuttle O H2C COO– malate 2H+ 4H+ NADH+H+ CO2 C16 HS-ACP CoASH O H3C 3H+ H+ H2C COOmalate COO pyruvate dehydrogenase CO2 ADP+Pi HCO3– H+ COO – NAD+ thiamine PP lipoate riboflavin (as FAD) pyruvate carboxylase (biotin) ADP3– 4H+ – pyruvate carrier ATP CH2 C HCO3–+ATP H+ NAD+ NADH CHOH malic enzyme pyruvate CoASH ADP4– NADPH H+ NADP+ CH3 C14 CH2OC(CH2)14CH3 C O dicarboxylate carrier -O C H++ADP+Pi CO2 COO lactate dehydrogenase O O O -O C CH C malonyl CoA pyruvate kinase Mg2+ K+ ADP O —SH of acyl carrier protein (ACP) CH2 phosphoenolpyruvate malate dehydrogenase NAD+ CO2 C12 O translocation CoASH – CO2 acyl-KS malonyl ACP COPO32– phosphoenolpyruvate carboxykinase HS–KS condensation enolase Mg2+ CO2 GDP C10 acyl carrier protein (ACP) condensation CH2OH 2-phosphoglycerate GTP SACP C8 CO2 HCOPO32– – CH2 C acyl ACP β-ketoacyl-ACP synthase (KS) (condensing enzyme) COO– H2O thioesterase (TE) O C6 CO2 phosphoglycerate Mg2+ mutase Cytosol hexanoyl ACP palmitoyl ACP enoyl ACP reductase (ER) + NADP α (1—> 4) glucose oligosaccharide (n+1 residues) UDP branching enzyme Regulatory enzyme Pi ATP NADP + dihydrobiopterin reductase 4-monooxygenase ADP Pi acetyl CoA phosphofructokinase-1 ADP dihydroxyacetone phosphate noradrenaline Cytosol S-adenosylmethionine S-adenosylmethyltransferase triose phosphate isomerase Glycolysis NAD + glyceraldehyde 3-phosphate dehydrogenase NADPH+H + alanine C6 aminotransferase phosphoenolpyruvate carboxykinase glutamate oxaloacetate aminotransferase isomerase fumarylacetoacetate fumarylacetoacetase pyruvate kinase NADPH+H + GDP CO2 NAD + NADH+H + ATP NAD + fumarate pyruvate lactate malate lactate dehydrogenase acetoacetate CO2 acetyl CoA Glyceroneogenesis ADP+P i citrate lyase ATP H2O pyruvate carrier ATP 4H+ H+ histidase 4-imidazolone5-propionate 4H+ H2 O + Pi Comple x IV C Comple x III H2O –O 2 4H+ + NADPH+H glutamate γ-semialdehyde dehydrogenase NAD + P 5-C synthetase NADP + aminotransferase spontaneous Outer membrane (P 5-C) FADH proline oxygenase NADPH+H NADP proline Pi NADH+H + H+ GTP ADP GDP Pi NADH+H 4H+ NAD + Comple x I H+ nucleoside diphosphate kinase 4H+ ATP Q C4 NADH+H + + –O2 ADP 3H 4H+ 2H+ H2O Pi CoASH thiolase 4H+ C ATP Comple x IV 2H+ Pi H+ 10H+ ornithine NH4 + CoASH thiolase FO Comple x III NADH+H+ 3-ketoacyl CoA myristoyl CoA (C14) + H+ L-3-hydroxyacyl CoA dehydrogenase acetoacetyl CoA 4H+ Respiratory chain ATP + FADH NADH +H+ NAD + F1 CoASH NAD+ Ketogenesis NH4+ glutamate translocase acetoacetate + reductase FAD Intermembrane space GDP L-3-hydroxyacyl CoA FADH NADH+H + 3-hydroxybutyrate CO2 α-ketoglutarate NAD + GTP Inner membrane + ADP+P i glutamate γ-semialdehyde succinyl CoA NADH+H + “Ketone bodies" NADH+H + CoASH Mitochondrion acetyl Co A H2O enoyl CoA hydratase FADH C6 NAD + α-ketoglutarate dehydrogenase C8 FAD acyl CoA dehydrogenase trans-Δ2-enoyl CoA FADH NADH+H + isocitrate CO2 succinate dehydrogenase succinate ATP NADH+H carnitine FADH2 NADH+H + hydroxymethyl glutaryl CoA (HMGCoA) H2O aconitase isocitrate dehydrogenase succinyl CoA synthetase FADH CoASH [ ci s -aconitate ] Krebs cycle fumarate N 5-formimino -THF glutamate acetyl CoA β-Oxidation C10 H2O aconitase H2O FAD glutamate formiminotransferase citrate citrate synthase H2O CoASH H2O Comple x II THF oxaloacetate NADH+H + F FADH Q (8) acetyl CoA acetyl CoA fumarase 2H+ C12 acetoacetyl CoA malate ADP 2H+ imidazolone propionase NH4 long chain acyl CoA synthetase palmitoyl CoA (C16) NADH+H + NAD + malate dehydrogenase 6H+ H O 3H+ H+ Pi NH4+ urocanate FIGLU F1 FO (3) palmitate ATP CoASH FADH – histidine PPi+AMP outer CPT C14 NADH+H + CO2 ATGL & hormone sensitive lipase (adipose tissue) inner CPT citrate pyruvate dehydrogenase ADP+P i HCO3 N 5,N 10 -methenyl-THF pyrophosphatase palmitoyl CoA CoASH tricarboxylate carrier NAD + CoASH pyruvate carboxylase ATP ATP folate cycle CoASH pyrophosphatase Pi H2O glycerol CoASH oxaloacetate NAD + tripalmitin lipolysis palmitoylcarnitine dicarboxylate carrier esterification (triacylglycerol) HCO3–+ATP carnitine acyltransferase I oxidized by extrahepatic tissues CO2 CoASH ATP acetyl CoA carboxylase malate dehydrogenase NADH+H + CoASH ADP NADP + malic enzyme CoASH glycerol kinase (not in white adipose tissue) malonyl CoA acetoacetyl CoA malate CO2 CO2 CO2 CoASH glycerol 3-phosphate malonyl CoA NADPH+H + + H +ADP+P i ADP GTP malate dehydrogenase thioesterase palmitate acyl carrier protein hydroxymethyl glutaryl CoA (HMGCoA) phosphoenolpyruvate NADH+H + H2O C16 CoASH NADP + enolase C14 ACP CoASH malonyl CoA-ACP transacylase HMGCoA reductase H2O C12 malonyl ACP many intermediates 2-phosphoglycerate C10 CO2 CoASH mevalonate α-ketoglutarate aspartate cholesterol C8 β-ketoacyl-ACP synthase CO2 (condensing enzyme) synthase CO2 (condensing enzyme) phosphoglycerate mutase glutamate 1,2 dioxygenase palmitoyl ACP acyl ACP acetoacetyl ACP C4 3-phosphoglycerate pyruvate enoyl ACP reductase NADP + β-ketoacyl-ACP phosphoglycerate kinase serine cysteineα-ketoglutarate Fatty acid synthesis dehydratase ACP ADP glycine homogentisate hydratase NAD + and NADP+ synthesis Pi ATP H2O transketolase enoyl ACP 1,3-bisphosphoglycerate 4-maleylacetoacetate (thiamine PP) transketolase β-hydroxyacyl ACP H2O cysteine–SH group of condensing enzyme glyceraldehyde 3-phosphate NADH+H + S-adenosyl homocysteine dioxygenase ribose 5-phosphate D-3-hydroxybutyryl ACP acetyl CoA-ACP transacylase CoASH aldolase CO2 xanthurenate (yellow) β-ketoacyl ACP reductase NADP + ACP fructose 1,6-bisphosphate H2O O2 NADPH+H + acetyl ACP 4-hydroxyphenylpyruvate (thiamine PP) glyceraldehyde 3-phosphate acetoacetyl ACP O2 O2 transaldolase glyceraldehyde 3-phosphate ATP fructose 1,6-bisphosphatase H2O adrenaline ribose 5-phosphate isomerase xylulose 5-phosphate fructose 6-phosphat 6-phosphate dopamine glutamate sedoheptulose 7-phosphate fructose 6-phosphate Pi Endoplasmic reticulum CO2 tyrosine aminotransferase ribulose phosphate 3-epimerase phosphoglucose isomerase glucose 6-phosphatase H2O α-ketoglutarate ribulose 5-phosphate 6-phosphogluconate dehydrogenase Pi L-DOPA tyrosine CO2 Pentose phosphate pathway (Hexose monophosphate Shunt) erythrose 4-phosphate glucose 6-phosphat 6-phosphate glucokinase hexokinase NADPH+H + phosphoglucomutase NADPH+H + dihydrobiopterin H2O debranching enzyme (i) glycosyltransferase (ii) α (1—> 6)glucosidase glucose tetrahydrobiopterin UTP 6-phosphogluconate lactonase transketolase Mg2+ (thiamine PP) glucose 1-phosphate glycogen (n–1 residues) O2 6-phosphogluconoΔ-lactone fructose 6-phosphate UDP-glucose pyrophosphorylase glycogen phosphorylase phenylalanine PPi NADP + H2O glucose 6-phosphate dehydrogenase uridine diphosphate glucose pyrophosphatase Pi NADPH+H + glucose 6-phosphate α (1—> 4) glucose oligosaccharide primer (n residues) glycogen NADP + glycogen synthase acetyl CoA carbamoyl phosphate synthetase I tryptophan ribulose phosphate 3-epimerase folate N-formylkynurenine xanthurenate (yellow) NAD + and NADP+ synthesis carbamoyl phosphate aspartate Folate cycle carbamoyl aspartate glycinamide ribonucleotide (GAR) ADP+Pi H2O dihydroorotate N 10-formyl THF N 10-formyl THF FMN FMNH2 THF H2O 2-aminomuconate semialdehyde formylglycinamide ribonucleotide (FGAR) H2O glutamine N 5, N 10-methenyl THF NADPH+H+ N , N methylene THF NH4+ PPi glutamate NADPH+H+ α-ketoadipate orotate ATP NADP+ 10 2-aminomuconate Fatty acid synthesis glutamate ADP+Pi ATP ADP+Pi formylglycinamidine ribonucleotide (FGAM) NADP+ OMP (orotidine monophosphate) ATP N 5-methyl THF CO2 ADP+Pi UMP (uridine monophosphate) AIR CO2 N5-methyl THF THF vitamin B12 palmitoyl ACP C8 C10 C12 C14 thioesterase homocysteine SAM ACP CO2 CoASH CO2 CO2 CO2 CoASH CoASH CoASH CO2 –CH yl meth CoASH palmitate glycerol 3-phosphate esterification ADP (triacylglycerol) ATP lipolysis H2O ATGL & hormone sensitive lipase (adipose tissue) CoASH PPi+AMP dCDP AICAR N 10-formyl THF dCMP THF N 5, N 10-methenyl THF threonine H2O UTP IMP dTMP GDP lysine vitamin B6 glycine CTP UTP cystathionine aminoadipate semialdehyde homoserine 2-aminoadipate α-ketobutyrate long chain acyl CoA synthetase dTDP GTP ATP dGTP dATP dTTP dCTP RNA isoleucine aminotransferase ATP ADP saccharopine cysteine (3) palmitate valine aminotransferase α-ketoadipate α-keto-β-methylvalerate leucine aminotransferase α-ketoisovalerate DNA aminotransferase α-ketoisocaproate outer CPT carnitine carnitine shuttle inner CPT NAD+ CoASH palmitoyl CoA (C16) NADH+H+ CO2 glutaryl CoA propionyl CoA acyl CoA dehydrogenase CoASH dehydrogenase NADH+H+ CO2 NAD+ CoASH dehydrogenase FAD carnitine shuttle NAD+ CoASH dehydrogenase CO2 CoASH NADH+H+ NAD+ dehydrogenase dehydrogenase NADH+H+ CO2 α-methylbutyryl CoA carnitine shuttle NAD+ CO2 NADH+H+ isovaleryl CoA isobutyryl CoA THF FADH2 trans-Δ2-enoyl CoA CO2 H2O enoyl CoA hydratase L-3-hydroxyacyl CoA NADH+H+ HCO3– NH4 + CoASH thiolase 2ATP CoASH acetyl CoA methylmalonate semialdehyde propionyl CoA citrulline Pi ornithine transcarbamoylase NAD+ L-3-hydroxyacyl CoA dehydrogenase 3-ketoacyl CoA acetyl CoA N 5, N 10 -methylene THF 2ADP+Pi carbamoyl phosphate Odd numbered fatty acids Urea cycle acetyl CoA D-methylmalonyl CoA acetyl CoA L-methylmalonyl CoA acetoacetate carbamoyl phosphate synthetase I mutase acetyl CoA dUMP DHF methyl group transferred to acceptor homocysteine glycerol CDP fumarate S-adenosylhomocysteine tripalmitin glycerol kinase (not in white adipose tissue) pyrophosphatase SAM methyl transferase UTP SAICAR FAICAR (S-adenosylmethionine) UDP ATP ADP+Pi Methionine salvage pathway H2O C16 CAIR aspartate UTP methionine homocysteine methyltransferase carbamoyl phosphate synthetase II 2ADP+Pi β-5-phosphoribosylamine glycine ATP THF 2-amino-3-carboxymuconate semialdehyde transketolase 2ATP glutamine-PRPP amidotransferase (tetrahydrofolate) 3-hydroxykynurenine (thiamine PP) glutamate NADP+ alanine 3-hydroxyanthranilate ribose 5-phosphate PRPP H2O glutamine NADPH+H+ kynurenine glutamine AMP DHF (dihydrofolate) formate bicarbonate ATP NADP+ ribose 5-phosphate isomerase xylulose 5-phosphate ribose 5-phosphate NADPH+H+ ribulose 5-phosphate aspartate ATP synthetase AMP+PPi argininosuccinate lyase fumarate arginine arginase ornithine urea Vitamin B12 succinyl CoA To the memory of Richard W Hanson (1935–2014), Case Western Reserve University, Ohio, USA This title is also available as an e‐book For more details, please see www.wiley.com/buy/9780470674710 or scan this QR code: Metabolism at a Glance J G Salway University of Surrey Guildford, UK FOURTH EDITION This edition first published 2017 © 2017 by John Wiley & Sons Ltd First published 1994 First Japanese edition 1994 First Complex Chinese edition 1996 First German edition 1997 Second edition 1999 Second Japanese edition 2000 Second German edition 2000 Spanish edition 2002 Third edition 2004 Korean edition 2006 Brazilian edition 2009 Portuguese edition 2009 Turkish edition 2012 Registered Office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Offices 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030‐5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley‐blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book It is sold on the understanding that the publisher is not engaged in rendering professional services If professional advice or other expert assistance is required, the services of a competent professional should be sought The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions Readers should consult with a specialist where appropriate The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom Library of Congress Cataloging‐in‐Publication Data Names: Salway, J G., author Title: Metabolism at a glance / J.G Salway Other titles: At a glance series (Oxford, England) Description: Fourth edition | Chichester, West Sussex ; Hoboken, NJ : John Wiley & Sons Inc., 2017 | Series: At a glance series | Includes bibliographical references and index Identifiers: LCCN 2016007782| ISBN 9780470674710 (pbk.) | ISBN 9781119277781 (Adobe PDF) Subjects: | MESH: Metabolism | Metabolic Diseases | Handbooks Classification: LCC QP171 | NLM QU 39 | DDC 616.3/9–dc23 LC record available at http://lccn.loc.gov/2016007782 A catalogue record for this book is available from the British Library Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books Cover image: © Caroline Mardon 2016 Set in 9.25/12.5pt Minion by SPi Global, Pondicherry, India 1 2017 Contents Preface ix Acknowledgements x Part 1 Energy metabolism Introduction to metabolic pathways Biosynthesis of ATP I: ATP, the molecule that powers metabolism Biosynthesis of ATP II: mitochondrial respiratory chain Oxidation of cytosolic NADH: the malate/aspartate shuttle and glycerol phosphate shuttle Metabolism of glucose to provide energy 10 Metabolism of one molecule of glucose yields 31 (or should it be 38?) molecules of ATP 12 Anaerobic metabolism of glucose and glycogen to yield energy as ATP 14 2,3‐Bisphosphoglycerate (2,3‐BPG) and the red blood cell 16 Metabolism of triacylglycerol to provide energy as ATP 18 Part 2 Carbohydrate metabolism 10 Metabolism of glucose to glycogen 20 11 Glycogen metabolism I 22 12 Glycogen metabolism II 24 13 Glycogen metabolism III: regulation of glycogen breakdown (glycogenolysis) 26 14 Glycogen metabolism IV: regulation of glycogen synthesis (glycogenesis) 28 15 Pentose phosphate pathway: the production of NADPH and reduced glutathione 30 16 Regulation of glycolysis: overview exemplified by glycolysis in cardiac muscle 32 17 Glycolysis in skeletal muscle: biochemistry of sport and exercise 34 18 Regulation of gluconeogenesis 36 19 Regulation of Krebs cycle 38 20 Mammals cannot synthesize glucose from fatty acids 40 21 Supermouse: overexpression of cytosolic PEPCK in skeletal muscle causes super‐athletic performance 42 22 Sorbitol, galactitol, glucuronate and xylitol 44 23 Fructose metabolism 46 24 Ethanol metabolism 48 Part 3 Fat metabolism 25 Pyruvate/malate cycle and the production of NADPH 50 26 Metabolism of glucose to fat (triacylglycerol) 52 27 Metabolism of glucose to fatty acids and triacylglycerol 54 28 Glycolysis and the pentose phosphate pathway collaborate in liver to make fat 56 29 Esterification of fatty acids to triacylglycerol in liver and white adipose tissue 58 30 Mobilization of fatty acids from adipose tissue I: regulation of lipolysis 60 31 Mobilization of fatty acids from adipose tissue II: triacylglycerol/fatty acid cycle 62 32 Glyceroneogenesis 64 33 Metabolism of protein to fat after feeding 66 34 Elongation and desaturation of fatty acids 68 35 Fatty acid oxidation and the carnitine shuttle 70 36 Ketone bodies 72 vii 37 Ketone body utilization 74 38 β-Oxidation of unsaturated fatty acids 76 39 Peroxisomal β‐oxidation 78 40 α‐ and β‐oxidation 80 41 ω-Oxidation 82 Part 4 Steroid metabolism 42 Cholesterol 84 43 Steroid hormones and bile salts 86 Part 5 Amino acid metabolism 44 Biosynthesis of the non‐essential amino acids 88 45 Catabolism of amino acids I 90 46 Catabolism of amino acids II 92 47 Metabolism of amino acids to glucose in starvation and during the period immediately after refeeding 94 48 Disorders of amino acid metabolism 96 49 Phenylalanine and tyrosine metabolism 98 50 Tryptophan metabolism: the biosynthesis of NAD+, serotonin and melatonin 100 51 Ornithine cycle for the production of urea: the ‘urea cycle’ 102 Part 6 Metabolic channelling 52 Metabolic channelling I: enzymes are organized to enable channelling of metabolic intermediates 104 53 Metabolic channelling II: fatty acid synthase 106 Part 7 Purines, pyrimidines and porphyrins 54 Amino acid metabolism, folate metabolism and the ‘1‐carbon pool’ I: purine biosynthesis 108 55 Amino acid metabolism, folate metabolism and the ‘1‐carbon pool’ II: pyrimidine biosynthesis 110 56 Krebs uric acid cycle for the disposal of nitrogenous waste 112 57 Porphyrin metabolism, haem and the bile pigments 114 Part 8 Integration of metabolic pathways and diabetes 58 Metabolic pathways in fasting liver and their disorder in Reye’s syndrome 116 59 Diabetes I: metabolic changes in diabetes 118 60 Diabetes II: types I and II diabetes, MODY and pancreatic β‐cell metabolism 120 61 Diabetes III: type diabetes and dysfunctional liver metabolism 122 Index 125 viii glycogen synthase α (1–> 4) glucose oligosaccharide (n+1 residues) UDP branching enzyme O α (1–> 4) glucose oligosaccharide primer (n residues) H glycogen phosphorylase r (pyridoxal 5' P) glycogen (n–1 residues) HO debranching enzyme (i) glycosyltransferase (ii) α (1–> 6)glucosidase CH HN O- O- C e pyrophosphatase Pi OH Mitochondrion O CH3 H PPi CH2OH O H H H O C CH O P O P O CH2 O N O O OH H H H H H uridine diphosphate glucose OH HO Pi COO- C CH2OH O H pyruvate CoASH NAD+ acetyl CoA NADH pyruvate OH UDP-glucose pyrophosphorylase r H UTP OPO32- OH H H OH ATP glucose 1-phosphate P phosphoglucomutase CH2OH O H OH HO H H OH OH OH H H glucose 2- OPO3C CH2 glucose 6-phosphatase Pi H OPO3C CH2 O H C H O Purine nucleotide cycle NH + synthetase 2Pi muscle contraction ASase deficiency fumarase ATP H 2O COOO + NADH+H malate dehydrogenase + NAD COO- CHOH NAD+ COO- NADH+H+ C HCOH H2C COOmalate lactate dehydrogenase CH3 lactate O ADP3ATP4 - HCO H+ 2HPO4 6H+ 2H+ IV 4H+ III 4H+ NADH+H+ COO- CHOH ADP3- C malate dehydrogenase H2C COO- COO- H O H2C citrate synthase CoASH / O2 CoASH malonyl-acetyl CoA-ACP ttransacylase tr ransacylase (MAT) CH2COO- succinyl CoA synthetase CoASH Mitochondrion GTP O C SCoA CO succinyl CoA Pi HPO42- H C O ADP+Pi A ATP CoASH H2O acetyl CoA H2C COOoxaloacetate Pi citrate citr trate llyase ly yase GTP4ADP3- GDP3- HPO 2- H+ nucleoside diphosphate kinase A ATP outer CPT O CH3(CH2)12 + NADH+H C12 FADH2 NADH+H+ βOxidation CH2COO- α-ketoglutarate dehydrogenase CH2 + NADH NAD CoASH H+ CH2 CH2 C acyl CoA dehydrogenase CO2 C4 O C COOα-ketoglutarate matrix 4H+ intermembrane space outer membrane I / O2 2H+ 2H+ 4H+ III + 4H + SCoA C H2O O CH2 C SCoA H L-3-hydroxyacyl CoA L-3-hydroxyacyl CoA dehydrogenase NAD+ CoASH thiolase H2O CH3(CH2)12 NADH+H+ O C CH2 C SCoA 3-ketoacyl CoA CoASH O CH3(CH2)12 C SCoA myristoyl CoA thiolase O F1 + HPO 2- H O H3C C SCoA acetyl CoA ATP4- FO IV C 4H FADH2 CH3COCH2COSCoA acetoacetyl CoA ADP3- Q C H trans-Δ -enoyl CoA NADH+H+ 3H+ NAD+ C OH CH3(CH2)12 FADH2 NADH+H+ Respiratory chain NADH+H+ Mg2+ C enoyl CoA hydratase FADH2 HOCH COOisocitrate FAD FADH2 H O CH3(CH2)12 FADH2 C6 SCoA palmitoyl CoA NADH+H+ NAD+ (3) palmitate carnitine inner CPT CH2COOHC COO- isocitrate dehydrogenase CoASH ATGL & hormone r sensitive v lipase (adipose tissue) long chain acyl CoA synthetase palmitoylcarnitine glycerol phosphate shuttle [cis-aconitate] inner membrane ATP4- (triacylglycerol) PPi+AMP pyrophosphatase palmitoyl CoA FADH NADH+H+ translocase tripalmitin H2O glycerol C8 + GDP O CHOH aconitase H O NADH CH2 succinate CHOC(CH2)14CH3 A ATP NADH+H+ COO- FAD CH2COOCH COO- ADP glycerol kinase (not in white adipose tissue) C10 citrate Krebs cycle succinate dehydrogenase O CH2OC(CH2)14CH3 glycerol 3-phosphate O CH2COOHOC COO- HCCOO- FADH2 esterification CH2OPO32- CH2OH acetyl CoA H2C O CH3(CH2)14C O- CoASH CHOH SCoA tricarboxylate carrier H2O -OOCCH fumarate CoASH CH2OH malonyl CoA malonyl-acetyl CoA-ACP ttransacylase tr ransacylase (MAT) ATP, NADH, acetyl CoA pyruvate, insulin,Ca2+ fumarase H2O CoASH CoASH CoASH palmitate C14 SCoA O oxaloacetate Q II C acetyl CoA CoASH aconitase 2H+ NAD+ malate 2H+ H2O C H3C COO- H+ HPO42- H2C COOmalate COO- malate dehydrogenase O + CO CH2OH + NADH+H+ C16 CO acetyl CoA carboxylase o (biotin) HCO3-+ATP A pyruvate dehydrogenase CO2 ADP+Pi 3H COO- malate/ aspartate shuttle NAD thiamine PP lipoate riboflavin (as FAD) + H + NAD NADH CHOH malic enzyme CH3 CoASH ATP 4H+ + H +ADP+Pi CO2 C14 CO 2 CH2OC(CH2)14CH3 pyruvate carrier pyruvate carboxylase (biotin) SACP O O -O C CH C malonyl CoA NADPH D DP NADP+ H+ pyruvate dicarboxylate carrier ATP4- —SH of acyl carrier protein (ACP) pyr y uvate v pyruvate kinase Mg2+ K+ A ATP COO- C12 CO HS-ACP O CH2 C CoASH CH2 phosphoenolpyruvate ADP translocation acyl-KS malonyl ACP COPO32- phosphoenolp phosphoenolpyruvate l yr y uvate v carboxykinase o H2C COOoxaloacetate Cytosol COO- CO2 GDP O -O C enolase 2+ Mg H2O GTP C10 C8 CO acyl carrier protein (ACP) condensation condensation HCOPO32- fumarate SACP HS–KS β-ketoacyl-ACP synthase (KS) (condensing enzyme) CH2OH 2-phosphoglycerate H O thioesterase (TE) O CH2 C acyl ACP CO2 mutase palmitoyl ACP enoyl ACP reductase (ER) C6 CO COO- malate C H3C CH2 hexanoyl ACP C4 SACP H enoyl ACP NADP+ acetoacetyl ACP C C NADPH+H+ CH2OPO323-phosphoglycerate adenylosuccinase (ASase) r 2+ phosphoglycerate ATP (for muscle contraction) adenylate kinase acetyl—KS HCOH AMP O H3C C phosphoglycerate r kinase Mg β-hydroxyacyl ACP dehydratase (DH) H COO- adenylosuccinate O CH2 C SACP H2O 1,3-bisphosphoglycerate ATP A + OH D-3-hydroxybutyryl ACP CH2OPO32- GDP Fatty acid synthesis reductase (KR) H3C C CoASH HCOH ADP O H malonyl-acetyl CoA-ACP transacylase (MAT) O C OPO32- AMP deaminase deficiency ADP NADP cysteine-SH of KS (condensing enzyme) Pi glyceralde r hyde 3-phosphate glyceraldehyde dehydrogenase + NADH+H IMP H2O O glyceraldehyde 3-phosphate NAD+ Pi acetoacetyl ACP SCoA Regulation H3C C 19.1 Diagram of pyruvate dehydrogenase by phosphorylation and dephosphorylation C4 NADPH+H+ acetyl CoA β-ketoacyl ACP CH2OPO32- dihydroxyacetone phosphate GTP aspartate CoA H3C C CH2 C SACP O HCOH ttr riose phosphate triose isomerase r CH2OH glutamate CH2COO- HOC COOH C COO- citrate CH2OPO32- HC O citrate synthase H2C COO- H O fructose 1,6-bisphosphate CH2OPO32C O oxaloacetate aldolase synthetase C SCoA OH HO OH glutamine + acetyl CoA COO- ADP 2- inactive pyruvate dehydrogenase O H3C A ATP phosphofr f uctokinase-1 phosphofructokinase-1 2+ Mg H2O NADH+H CO2 i HCO fructose 6-phosphate H P i H ADP+P CH2OH HO Ca2+ insulin (in adipocyte) ATP pyruvate carboxylase (biotin) OH OH ffructose fr uctose 1,6-bisphosphatase + NH4 OH glucose 6-phosphate O H H O Endoplasmic reticulum ATP OH phosphoglucose isomerase r Pi ADP + Pi H P active pyruvate dehydrogenase H H HO P PDH phosphatase CH2OPO32O ADP DP + H glucokinase hexokinase e Mg2+ A ATP H H P ADP PDH kinase 2H + + HPO42- H 10H+ 4H+ ATP4- ADP3- Chart 19.1 Regulation of Krebs cycle Part 2 Carbohydrate metabolism 39 Mammals cannot synthesize glucose from fatty acids 20 Chart 20.1 Two molecules of carbon dioxide are evolved when acetyl CoA is oxidized in Krebs (TCA) cycle CH2OH O H H H HO OH H H OH CH2OPO32O ADP H+ glucokinase hexokinase Mg2+ ATP H OH H HO H OH H OH glucose 6-phosphate phosphoglucose isomerase Pi 2- OPO3CH2 glucose 6-phosphatase Endoplasmic reticulum The chart illustrates why mammals cannot convert fatty acids to glucose Fatty acids are oxidized to acetyl CoA Because the pyruvate dehydrogenase and pyruvate kinase reactions are irreversible, acetyl CoA cannot simply be carboxylated to pyruvate and proceed to form glucose by reversal of glycolysis Instead, the two carbon atoms contained in the acetyl group of acetyl CoA enter Krebs cycle However, two carbon atoms are removed as carbon dioxide, as shown in the chart Hence, in animals, there can be no net synthesis of glucose from acetyl CoA Having emphasized this point, it should be noted that if fatty acids uniformly labelled with 14C are fed to mammals, some of the radioactive label does become incorporated into g lucose This is because the 14C‐fatty acid is catabolized to 14C‐acetyl CoA, which enters Krebs cycle The label is incorporated into citrate and may be retained in other intermediates of the cycle If 14C‐ malate is formed, it can leave the mitochondrion and the 14C label may be incorporated into glucose by gluconeogenesis NB: This incorporation of the 14C label from acetyl CoA into carbohydrate does not represent net synthesis because two carbon atoms have been lost as carbon dioxide in the process H OH glucose Pi Chart 20.1: in mammals, two molecules of carbon dioxide are evolved when acetyl CoA is oxidized in Krebs tricarboxylic acid (TCA) cycle Fatty acids cannot be used as a gluconeogenic precursor by mammals for the reasons explained below Since glucose is a vital fuel for brain and red blood cells, this presents a serious difficulty during prolonged starvation once the glycogen reserves have been depleted (although the brain can adapt to use ketone bodies as a respiratory fuel) It is unfortunate that, because the fatty acids derived from triacylglycerol in adipose tissue cannot be used for gluconeogenesis, muscle proteins must be degraded to maintain glucose homeostasis in the starving state, thereby causing wasting of the skeletal muscles H O H OH H2O OH CH2OH HO fructose 6-phosphate H Pi fructose 1,6-bisphosphatase Glycerol derived from triacylglycerol can be used for glucose synthesis H2O 2- OPO3CH2 H O H OH CH2OPO32- HO OH When the triacylglycerol stored in adipose tissue is hydrolysed by adipose triacylglycerol lipase and hormone‐sensitive lipase, fatty acids and glycerol are released Unlike fatty acids, glycerol can be used for glucose synthesis by liver (see Chapter 18) Glycerol is transported in the blood to the liver, where it is phosphorylated by g lycerol kinase to glycerol 3‐phosphate, which is reduced to dihydroxyacetone p hosphate, two molecules of which are converted to glucose by gluconeogenesis, as shown in Chart 20.1 fructose 1,6-bisphosphate H aldolase CH2OPO32C HC O CH2OH dihydroxyacetone phosphate O HCOH triose phosphate isomerase CH2OPO32glyceraldehyde 3-phosphate NAD+ Pi glyceraldehyde 3-phosphate dehydrogenase NADH+H+ + NADH+H O C OPO32- NADH+H+ HCOH glycerol 3-phosphate dehydrogenase CH2OPO321,3-bisphosphoglycerate NAD+ ADP NAD+ Possible gluconeogenic pathways using fatty acid precursors in mammals phosphoglycerate kinase ATP COO- glycerol 3-phosphate HCOH Draye and Vamecq have challenged the standard textbook dogma that mammals are unable to convert fatty acids to glucose They point out that fatty acids with an odd number of carbon atoms, and branched‐chain fatty acids, can be CH2OPO323-phosphoglycerate phosphoglycerate Mg2+ mutase COOHCOPO32- Cytosol GTP COOO enolase Mg2+ NAD+ CH2 phosphoenolpyruvate pyruvate kinase ADP malate dehydrogenase COO- CHOH NAD+ COO- NADH+H+ C HCOH H2C COOmalate lactate dehydrogenase CH3 lactate O CH3 CoASH ATP4 - F1 H+ HPO422H+ IV / O2 H2O 4H+ C O H2C COO- malate dehydrogenase oxaloacetate succinate dehydrogenase CH2COO- succinate CoASH GTP even numbered fatty acids (ω-oxidation) 40 tripalmitin (triacylglycerol) CHOH glycerol Pi CoASH citrate lyase PPi+AMP pyrophosphatase O C SCoA succinyl CoA Pi GDP NADH H+ CO2 CoASH fatty acids long chain acyl CoA synthetase palmitoylcarnitine glycerol phosphate shuttle tricarboxylate carrier outer CPT carnitine inner CPT O CH3(CH2)12 CH2 CH2 C + NADH+H (8) acetyl CoA SCoA C12 CH2COOHOC COO- CoASH α-ketoglutarate dehydrogenase CH2 ATP palmitoyl CoA H O FADH2 NADH+H+ βOxidation H2O enoyl CoA hydratase FADH2 [cis-aconitate] + NADH+H H O + NAD CoASH O C COOα-ketoglutarate CH2COOHC COOHOCH COOisocitrate isocitrate dehydrogenase 2+ Mg C6 OH CH3(CH2)12 FADH NADH+H+ C4 FADH2 C O SCoA H L-3-hydroxyacyl CoA L-3-hydroxyacyl CoA dehydrogenase NAD+ NADH+H+ NADH+H+ CH3COCH2COSCoA acetoacetyl CoA CH3(CH2)12 NAD+ CoASH thiolase NADH+H+ Mitochondrion H O CH2 C O O C CH2 C SCoA 3-ketoacyl CoA CoASH O CO2 FAD FADH2 H O NADH+H+ CH2COOCH2 acyl CoA dehydrogenase C C SCoA H trans-Δ -enoyl CoA C8 SCoA palmitoyl CoA CH3(CH2)12 C FADH aconitase H2C COO- citrate FADH2 C10 branched chain fatty acids (phytanic acid see Chapters 40 & 41) CH2COO- adipose triacylglycerol lipase & hormone sensitive lipase H2O CH2OH CoASH Krebs cycle methylmalonyl CoA succinyl CoA synthetase CH2COO- O CH2OC(CH2)14CH3 C14 propionyl CoA Q FAD C CHOC(CH2)14CH3 ADP ATP aconitase odd numbered fatty acids -OOCCH FADH H2C COOoxaloacetate fumarase fumarate II ADP+Pi A ATP CoASH O CH2OH NADH+H+ citrate synthase H O glycerol kinase (not in white adipose tissue) SCoA acetyl CoA O malate/ aspartate shuttle acetyl CoA COO- HCCOO- C III NADH+H+ malate 4H+ NAD+ CHOH H2C COO- ADP3- 2H+ H2O 2H+ H3C COO- HPO42- 6H+ H2C COOmalate malate dehydrogenase C O 3H+ H+ CHOH CH2OC(CH2)14CH3 glycerol 3-phosphate acetyl CoA carboxylase o (biotin) HCO -+ATP A COO- pyruvate dehydrogenase CO2 ADP+Pi HCO3- FO malic enzyme H+ NAD+ NADH COO- + NAD thiamin PP lipoate riboflavin pyruvate carboxylase (biotin) 3- ADP 4H+ NADPH DP H+ NADP+ pyruvate carrier ATP ATP4- CO2 pyruvate dicarboxylate carrier H++ADP+Pi Mg2+ K+ ATP COO- O O -O C CH C malonyl CoA COPO32- O CH2OPO32- malonyl transacylase ACP esterification CHOH CoASH COO- CO2 GDP phosphoenolp phosphoenolpyruvate l yr y uvate v carboxykinase o H2C COOoxaloacetate NADH+H+ CH2OH malonyl ACP H2O C palmitate CH2OH 2-phosphoglycerate CH3(CH2)12 C SCoA myristoyl CoA Metabolism at a Glance, Fourth Edition J G Salway © 2017 John Wiley & Sons Ltd Published 2017 by John Wiley & Sons Ltd thiolase O H3C C SCoA acetyl CoA lipid body glyoxysome glycerol triacylglycerol Cytosol CoASH fatty acids (e.g palmitate) lipase O acyl CoA synthetase ATP CH3(CH2)12 CH2 AMP+PP C14 NAD+ CHOH NADH+H+ C malate dehydrogenase H2C COO- H2O C12 CoASH H2C C10 citrate aconitase H2O O CHO COO- SCoA C Glyoxylate cycle acetyl CoA isocitrate lyase glyoxylate CH2COOHC COOHOCH COO- isocitrate C C 2H+ dehydroascorbate CH2OH + C + O CH2 C SCoA NAD+ NADH+H+ L-3-hydroxyacyl CoA dehydrogenase FADH NADH+H C4 + O FADH NADH+H+ CH3(CH2)12 CH3COCH2COSCoA acetoacetyl CoA CH O H FADH C6 HCOH SCoA H2O OH CH3(CH2)12 NADH+H aconitase H2O H3C C8 [cis-aconitate] CoASH malate synthase molecules of ascorbate H2O2 2H2O H trans-Δ -enoyl CoA + FADH2 NADH+H COO- C FADH NADH+H CH2COOHOC COO- citrate synthase FADH2 enoyl CoA hydratase (bifunctional enzyme) + NADH+H SCoA O H2C COO- oxaloacetate malate FADH acetyl CoA COO- catalase H2O2 O2 H O CH3(CH2)12 O COO- 1/ O2 FAD acyl CoA oxidase (8) acetyl CoA C H2O SCoA i β-oxidation H3C CH2 C palmitoyl CoA NADH+H+ NAD+ CH2OH HCOH CH CoASH O thiolase O C OH C OH C O ascorbate O H3C C SCoA acetyl CoA OH monodehydroascorbate reductase O CH3(CH2)12 C SCoA myristoyl CoA O C C O monodehydroascorbate radical C CH2 C SCoA 3-ketoacyl CoA CoASH thiolase · C 2H+ 2H+ CH2OH HCOH CH O succinate C O C O C O dehydroascorbate metabolized via propionyl CoA to succinyl CoA (see Chapters 40 and 41) Also, α‐oxidation of phytanic acid yields succinate (see Chapter 40) Both of these products are gluconeogenic precursors However, gluconeogenesis from these fatty acids is unlikely to be quantitatively significant in physiological terms O H cellulose H OH H O P O P O CH2 H OH HO cellulose synthase C CH2OH O H O- H HO H Cytosol CH2OH O H H OH CH2OPO32O H OH H H OH OPO3CH2 H O H 2- OPO3CH2 H H O H H H OH OH H Chart 20.2: the Kornberg Krebs glyoxylate cycle enables fat to be converted to sugars Glyoxysomes in plants H During germination, oil‐rich seeds can metabolize their stored fat to sugar, notably sucrose, for distribution throughout the developing seedling, and to uridine diphosphate (UDP) glucose, which is the precursor of cellulose This process occurs in specialized peroxisomes (or microbodies) known as g lyoxysomes Glyoxysomes are temporary organelles present for approximately week during germination They contain all the enzymes for β‐oxidation but only three of the Krebs TCA cycle enzymes, namely malate dehydrogenase, citrate synthase and aconitase In addition they contain isocitrate lyase and malate synthase, which enable the glyoxylate cycle to proceed The glyoxylate cycle also occurs in yeast and bacteria More recently it has been controversially reported that the glyoxylate cycle is active in animals OH CH2OH fructose 6-phosphate OH HO OH H Pi OH HO OH pyrophosphatase UTP OPO32- OH 2- CH N UDP-glucose pyrophosphorylase H H HO O C O O O uridine diphosphate glucose PPi CH HN O- CH2OPO32- H CH2OPO32- HC C HCOH O O CH2OPO32- CH2OH O C OPO32HCOH CH2OPO32- COOHCOH Gluconeogenesis CH2OPO32- COO- Glyoxylate cycle HCOPO32CH2OH COO- COO- C O COPO32- COO- CH2 H2C COO- COO- COO- CHOH HCOH C O H2C COOmalate CH3 CH3 pyruvate dicarboxylate carrier pyruvate carrier CoASH ATP ATP4 - COO- H 24 HPO 24 6H+ + 2H IV 2H+ H2O + / O2 2H 3- ADP H2C COO- III + 4H + NADH+H malate dehydrogenase malate C C SCoA acetyl CoA COOO H2C COOoxaloacetate H2O citrate synthase CH2COOCOO- HOC CoASH H2C COO- citrate aconitase H2O [cis-aconitate] aconitase fumarase H2O H2O HCCOO- C + NAD+ CHOH H HPO 4H H3C + + NADH+H+ O 3H F1 FO + pyruvate dehydrogenase CO2 ADP+Pi HCO3- 4H+ NAD+ thiamine PP lipoate riboflavin pyruvate carboxylase (biotin) 3- ADP ATP4- The glyoxylate cycle was originally called the ‘glyoxylate bypass of the citric acid cycle’ It resembles Krebs TCA cycle, with some notable differences In particular, the CO2‐losing stages of the latter (the isocitrate and α‐ketoglutarate dehydrogenases) are absent Instead, isocitrate lyase forms glyoxylate and succinate Succinate leaves the glyoxysome, enters the mitochondrion and is oxidized to malate The latter leaves the mitochondrion for gluconeogenesis in the cytosol Meanwhile, back in the glyoxysome, the glyoxylate combines with acetyl CoA in the presence of malate synthase to produce malate, which is oxidized to oxaloacetate, thereby completing the cycle (NB: it is oxaloacetate that is recycled in Krebs cycle (see Chapter 19)) Krebs cycle -OOCCH fumarate HOCH COOisocitrate Q II FADH2 succinate dehydrogenase isocitrate dehydrogenase Mg2+ FAD CH2COOCH COO- CH2COO- succinyl CoA synthetase CH2 succinate CoASH GTP O C SCoA CO succinyl CoA + HPO 2- H Pi Mitochondrion α-ketoglutarate dehydrogenase NADH H+ NAD+ CoASH CH2COOCH2 O C COO- α-ketoglutarate GDP translocase GTP4ADP GDP3- HPO 2- H+ nucleoside diphosphate kinase CH2COOHC COO- ATP CO2 NAD+ NADH+H+ β‐Oxidation in plants Until the late 1990s, a dogma of plant biochemistry was that ‘plant mitochondria lack the enzymes needed for the β‐oxidation of fatty acids’ and instead the pathway occurred exclusively in the peroxisomes (glyoxysomes) of higher plants However, it is now generally accepted that plants are indeed capable of β‐ oxidation in both mitochondria and peroxisomes (glyoxysomes of germinating seeds) In glyoxysomes, the first oxidation reaction catalysed by acyl CoA oxidase uses molecular oxygen and produces hydrogen peroxide (Chart 20.2) The NADH formed by hydroxyacyl CoA dehydrogenase (and probably malate dehydrogenase of the glyoxylate cycle) is reoxidized by monodehydroascorbate reductase In both cases energy is not conserved as ATP but will be dissipated as heat, which might be an advantage during the germination process Chart 20.2 The Kornberg Krebs glyoxylate cycle in the glyoxysome of plants Part 2 Carbohydrate metabolism 41 Supermouse: overexpression of cytosolic PEPCK in skeletal muscle causes super‐athletic performance 21 a ‘supermouse’ that was seven times more physically active than the control animal What is the explanation? (i) Supermouse is able to store massive amounts of fat in skeletal muscle for use as a fuel; and (ii) supermouse’s Krebs cycle is boosted to enhance the use of this fuel for muscle contraction Rarely does experimental enzymology raise a hint of public interest but this experimental model received worldwide press and TV coverage in 2007 Hakim et al., in Hanson’s laboratory, overexpressed cytosolic phosphoenolpyruvate carboxykinase (PEPCK‐C) in the skeletal muscle of mice to make CH2OPO32- CH2OPO32- HC CHOH C HCOH CH2OH glycerol 3-phosphate glycerol 3-phosphate dehydrogenase O O CH2OPO32- CH2OH dihydroxyacetone phosphate chy lomicron triacylglycerol in VLDL and chylomicrons VLDL glyceraldehyde 3-phosphate triose phosphate isomerase NAD+ NADH+H fatty acids Glyceroneogenesis phenylalanine NAD + Pi glyceraldehyde 3-phosphate dehydrogenase NADH+H + tyrosine glycerol 3-phosphate Esterification glutamate NAD+ glutamate dehydrogenase 1,3-bisphosphoglycerate ADP NADH+H+ phosphoglycerate kinase α-ketoglutarate ATP glycine serine 3-phosphoglycerate Cytosol phosphoglycerate mutase 2-phosphoglycerate DNA enolase aspartate H2O mRNA COO- COOC H2C COPO32- cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) O COO- CH2 phosphoenolpyruvate oxaloacetate GTP NADH+H + GDP CO2 ADP malate dehydrogenase NAD + lactate dehydrogenase serine cysteine alanine dicarboxylate carrier pyruvate translocase pyruvate carrier NAD + CoASH pyruvate dehydrogenase NADH+H + ATP pyruvate carboxylase ADP+Pi – HCO3 CO2 acetyl CoA NAD+ malate dehydrogenase malate oxaloacetate citrate synthase H2O CoASH NADH+H+ fumarase H2O citrate Krebs cycle fumarate GTP FADH2 pyruvate + NAD+ NADH+H malate 42 creatine phosphate ATP lactate Chart 21.1 Resting skeletal muscle during feeding In resting skeletal muscle during feeding, overexpression of cytosolic PEPCK promotes the formation of abundant glycerol 3‐phosphate, which esterifies dietary fatty acids ATP pyruvate kinase M succinate dehydrogenase GDP succinyl CoA synthetase FAD Mitochondrion aconitase H2O [cis-aconitate] H2O aconitase isocitrate isocitrate dehydrogenase CO2 NAD+ NADH+H+ succinyl CoA succinate CoASH lysine tryptophan tyrosine leucine isoleucine phenylalanine α-ketoglutarate dehydrogenase CO2 α-ketoglutarate NAD+ CoASH NADH+H+ Pi threonine methionine valine leucine histidine proline tyrosine phenylalanine Inner membrane Intermembrane space Outer membrane Metabolism at a Glance, Fourth Edition J G Salway © 2017 John Wiley & Sons Ltd Published 2017 by John Wiley & Sons Ltd glycerol triacylglycerol triacylglycerol deposits within skeletal muscle Metabolism of supermouse when resting and feeding: ‘glyceroneogenesis increases fat reserves in muscle’ exhausted their reserves of muscle glycogen and can no longer use fatty acids as a fuel This is because they have depleted anaplerotic metabolites, notably oxaloacetate, which ‘top up’ the metabolites in Krebs cycle It is thought overexpression of PEPCK‐C increases the flux through Krebs cycle as follows: β‐oxidation of fatty acids produces acetyl CoA which combines with oxaloacetate to form citrate for oxidation in Krebs cycle This is coupled to the generation of ATP by oxidative phosphorylation for muscle contraction (see Chapter 9) Remember, oxaloacetate is normally present at a low concentration just sufficient to maintain an adequate flux through Krebs cycle and it is oxaloacetate that is recycled (see Chapter 19) When PEPCK‐C is overexpressed, flux through Krebs cycle is stimulated because: (i) the concentration of oxaloacetate is increased; and (ii) PEPCK‐C uses GTP and produces GDP needed for the succinyl CoA synthetase reaction Also, supermouse has more mitochondria than control mice In the muscle of supermouse, it is glyceroneogenesis (see Chapter 32), not glycolysis, that provides an abundant supply of glycerol 3‐phosphate for triacylglycerol (TAG) biosynthesis (see Chapter 29) Overexpression of PEPCK‐C increases production of glycerol 3‐phosphate, which esterifies (‘captures’) dietary fatty acids delivered to muscle by VLDL and chylomicrons producing TAG Consequently, the concentration of TAG in skeletal muscle is 10 times that of control animals (Chart 21.1) Regulation of pyruvate kinase NB: (i) In resting muscle during feeding, pyruvate kinase is inhibited by high concentrations of ATP and creatine phosphate: this favours glyceroneogenesis (Chart 21.1) However, (ii) in exercising muscle, ATP and creatine phosphate concentrations fall, consequently the inhibition of pyruvate kinase is relieved promoting entry of metabolites into Krebs cycle: this favours energy metabolism (Chart 21.2) Chart 21.2 Skeletal muscle during exercise During exercise, skeletal muscle in which cytosolic PEPCK is overexpressed produces an abundant supply of oxaloacetate for the oxidation of acetyl CoA in Krebs cycle to generate ATP for muscle contraction (see Chapter 9) Reference Hakim P., Yang J., Casadeus G., et al (2007) Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse J Biol Chem 282, 32844–32855 Also see ‘PEPCK‐Cmus mouse’ on YouTube Metabolism of supermouse when exercising Remember the aphorism: ‘fats burn in the flame of carbohydrates’ In other words, a supply of glucose‐derived metabolites is needed to oxidize fats; a fact familiar to long‐distant runners who ‘hit the wall’ when they have triacylglycerol triacylglycerol deposits within skeletal muscle DNA aspartate mRNA COOC COPO32- phosphoenolpyruvate carboxykinase (PEPCK) O COO- H2C CH2 oxaloacetate NADH+H + phosphoenolpyruvate malate dehydrogenase NAD + Lipolysis COO- GTP ADP GDP CO2 ATP pyruvate kinase glycerol to liver for guconeogenesis pyruvate malate pyruvate fatty acids eg palmitate CoASH CoASH pyrophosphatase Pi PPi+AMP palmitoyl CoA carnitine acyltransferase I ATP long chain acyl CoA synthetase outer CPT palmitoylcarnitine dicarboxylate carrier translocase ATP pyruvate carboxylase pyruvate dehydrogenase NADH+H + CO2 FO H+ Pi NADH+H+ (8) acetyl CoA 4H+ HCO3 NAD+ malate dehydrogenase malate ADP Complex IV C Complex III Q acetyl CoA oxaloacetate – 3H+ H+ Pi 6H+ 2H+ F1 citrate synthase H2O NADH+H+ 2H+ H2O 2H+ H O1 fumarase H2O –O 2 FADH2 GTP succinate dehydrogenase Complex II GDP succinyl CoA synthetase FAD succinate CoASH Complex I 4H+ Q NADH+H+ 2H+ 2H+ H2O 4H+ Pi H+ 3H C6 isocitrate C4 10H+ Pi ATP FADH2 NADH+H+ NAD+ acetoacetyl CoA CoASH thiolase 3-ketoacyl CoA NADH+H+ total of NADH+H+ CoASH CO2 thiolase myristoyl CoA (C14) NAD+ CoASH acetyl CoA β-Oxidation Mitochondrion ATP Inner membrane Intermembrane space Outer membrane Complex IV 2H+ NAD+ L-3-hydroxyacyl CoA dehydrogenase α-ketoglutarate FO C L-3-hydroxyacyl CoA FADH2 + F1 H2O FADH2 total of FADH2 enoyl CoA hydratase FADH2 NADH+H+ isocitrate dehydrogenase α-ketoglutarate dehydrogenase succinyl CoA –O ADP 4H+ [cis-aconitate] H2O aconitase CO2 Pi Complex III trans-Δ2-enoyl CoA FADH2 NADH+H+ NADH+H+ NAD+ NADH+H+ C10 NADH+H+ H2O Respiratory chain 4H+ FAD acyl CoA dehydrogenase FADH2 C8 aconitase Krebs cycle fumarate 4H+ C12 NADH+H+ citrate CoASH palmitoyl CoA (C16) FADH2 ADP+Pi 4H+ CoASH C14 NAD + CoASH ATP carnitine inner CPT pyruvate carrier H+ 4H+ ATP muscle contraction AMP ADP Part 2 Carbohydrate metabolism 43 Sorbitol, galactitol, glucuronate and xylitol 22 Chart 22.1: sorbitol, the dietary (exogenous) friend but endogenous foe Dietary sorbitol as a food sweetener Sorbitol is a sugar alcohol used as a food sweetener in diabetic diets, and has a sweetness value approximately 50% that of sucrose Patients with diabetes can eat small quantities of sorbitol safely because it is transported relatively slowly across cell membranes, and is absorbed slowly from the intestines Endogenously produced sorbitol and cataracts: ‘the polyol osmotic theory for the formation of diabetic cataracts’ Although the poor ability of extracellular sorbitol to cross cell membranes favours its use as a sweetener for diabetic food, paradoxically this property can also cause problems This is because sorbitol produced endogenously within cells such as neurons and the optical lens, accumulates within the cell and is metabolized very slowly Under normal circumstances this is not a problem, since aldose reductase, the enzyme that converts glucose to sorbitol, has a Km for glucose of 70 mmol/l Hence, it is relatively inactive when the blood glucose concentration is within normal limits of around 3.5–6 mmol/l However, in uncontrolled diabetes with glucose levels of 25 mmol/l or higher, sorbitol formation occurs at a greater rate, and e levated tissue sorbitol levels have been implicated with certain complications of diabetes such as neuropathy, cataracts and vascular disease For example, in vitro studies have shown that if rabbit lenses are incubated in media c ontaining very high glucose concentrations (35 mmol/l), they accumulate sorbitol Consequently, the intralenticular osmotic pressure increases causing the lens to swell and become opaque This can be prevented by aldose reductase inhibitors, such as sorbinil Sorbitol catabolism Sorbitol is metabolized by sorbitol dehydrogenase (Chart 22.1), which is particularly active in liver, to form fructose in a reaction coupled to the formation of NADH This increases the cytosolic NADH/NAD+ ratio, which both Chart 22.2 Galactose and galactitol metabolism from pentose phosphate pathway lactose H CH2OH HCOH HOCH ATP HOCH HOCH aldose reductase HCOH UDP HCOH NADPH NADP+ H+ HOCH C O ADP galactose 1-phosphate galactokinase HCOH galactose 1-phosphate uridyltransferase branching enzyme glycogen synthase O α (1– –> 4) glucose oligosaccharide primer (n residues) H HO H OH O P O P O CH2 H glycogen H OH O O- H phosphorylase (pyridoxal 5' P) HO debranching enzyme (i) glycosyltransferase (ii) α (1– –> 6) glucosidase glycogen (n–1 residues) CH2OH O H OH H H OH pyrophosphatase PPi H CH2OH O H OH H H OH ADP DP H+ A ATP Mg2+ H glucokinase OH UTP OPO32glucose 1-phosphate CH2OPO32O H H HO glucose OH H OH H OH glucose 6-phosphate phosphoglucose isomerase Pi 2- OPO3CH2 glucose 6-phosphatase H2O Endoplasmic reticulum H O H OH OH HO H Inborn errors of galactose metabolism Classic galactosaemia is caused by a deficiency of galactose 1‐phosphate uridyltransferase (Gal‐1‐PUT) The alternative form is galactokinase deficiency, but both disorders have similar clinical features In both conditions dietary galactose cannot be metabolized Consequently, it accumulates in the blood and enters the cells of the lens, where it is reduced to galactitol by aldose reductase It is believed that this can cause cataracts by a mechanism similar to that described for sorbitol Chart 22.3: glucuronate and xylitol metabolism Glucuronate conjugates with bilirubin, steroids and drug metabolites Uridine diphosphate (UDP) glucuronate is formed by oxidation of UDP glucose in the presence of UDP glucose dehydrogenase Hydrophobic molecules such as bilirubin, steroid hormones and many drugs are conjugated with glucuronate by UDP glucuronyltransferase to form a water‐soluble glucuronide derivative before excretion by the kidney In Crigler–Najjar syndrome (see Chart 57.1), deficiency of UDP glucuronyltransferase causes increased levels of unconjugated bilirubin, which is bound to albumin, to accumulate in the blood If the levels exceed the binding capacity of albumin, the unconjugated bilirubin will be taken up by the brain, causing kernicterus CH CH O N H Pi H H OH OH H Metabolism of glucuronate and xylitol: the glucuronate/ xylulose pathway UDP glucuronate is metabolized via the ketose l‐xylulose to xylitol Xylitol is oxidized to d‐xylulose, which is phosphorylated to xylulose 5‐phosphate, which enters the pentose phosphate pathway before joining the glycolytic (or gluconeogenic) pathway UDP-glucose pyrophosphorylase phosphoglucomutase H HN O C O uridine diphosphate glucose Pi 44 C CH2OH O H O- Galactose is a component of cerebrosides and glycoproteins and, during lactation, is used to synthesize lactose The major dietary source of galactose is lactose in milk Hydrolysis of lactose by intestinal lactase yields glucose and galactose Surplus galactose is metabolized to glucose as shown in Chart 22.2 UDP glucuronate is metabolized to l‐gulonate In most animals (with the notable exception of humans, other primates, guinea‐pigs and fruit bats), l‐gulonate can be metabolized to ascorbate (vitamin C) UDP-glucose α (1– –> 4) glucose oligosaccharide (n +1 residues) UDP-glucose Chart 22.2: galactose and galactitol metabolism Uses of galactose Glucuronate is the precursor of vitamin C, but not in humans glucose 1-phosphate Cytosol Pi epimerase galactose galactitol HO glucose UDP-galactose CH2OH CH2OH H lactose synthase favours the reduction of dihydroxyacetone phosphate to glycerol 3‐phosphate and inhibits glycolysis by favouring the reduction of 1,3‐bisphosphoglycerate to glyceraldehyde 3‐phosphate Also, experiments with rat lenses incubated with glucose have demonstrated that, when the aldose reductase pathway is active, the sorbitol formed is metabolized by sorbitol dehydrogenase to form fructose This is metabolized to glycerol 3‐phosphate, since glycolysis is inhibited at the glyceraldehyde 3‐phosphate dehydrogenase reaction Finally, because aldose reductase generates NADP+, the pentose phosphate pathway is stimulated CH2OH fructose 6-phosphate Inborn error of metabolism: essential pentosuria This is a very rare benign condition, most frequently found in Jewish people, in which large quantities (up to 4 g per day) of l‐xylulose are excreted in the urine The condition is due to deficiency of l‐xylulose reductase Xylitol in chewing gum prevents dental decay Xylitol helps to prevent dental caries and is used as a sweetener Clinical trials indicate that 7–10 g per day of xylitol in chewing gum can provide good resistance to dental decay in children This cariostatic effect is thought to be due to both its ability to interfere with the metabolism of Streptococcus mutans (the organism in plaque responsible for caries) and also its ability to stabilize solutions of calcium phosphate, which favours remineralization of enamel Metabolism at a Glance, Fourth Edition J G Salway © 2017 John Wiley & Sons Ltd Published 2017 by John Wiley & Sons Ltd H Sorbitol metabolism HO CH2OPO32O OH H H OH NADP+ H H NADPH H+ OH CO2 NADPH + H + NADP H2O glucose 6-phosphate dehydrogenase 6-phosphogluconate dehydrogenase lactonase glucose 6-phosphate ribulose phosphate 3-epimeras Pentose Phosphate Pathway CH2OH HCOH NADPH H+ NADP+ HOCH HCOH CH2OH H H OH H OH HO O H H OH HCOH H OH glucose 6-phosphate HCOH NADH H+ HO H HO NAD+ 2- OPO3CH2 CH2OH O H H H OH fructose H H OH HC HO H H fructose 1-phosphate HO CH2OPO32- H fructose 6-phosphate CH2OPO32- Cytosol fructose 1,6-bisphosphate aldolase C CH2OH HC O NADH+H+ NAD+ CH2OPO3 glyceraldehyde 3-phosphate dehydrogenase glycolysis inhibited by NADH high NAD+ O C OPO32- CH2OH glycerol 3-phosphate glyceraldehyde 3-phosphate i NAD+ CHOH 2- Vascular damage in diabetes Sorbitol metabolism leads to activation of protein kinase C which might damage blood vessels by increasing basement membrane synthesis and vascular permeability P NADH H+ CH2OPO32- O HCOH CH2OPO32glyceraldehyde 3-phosphate glycerol 3-phosphate dehydrogenase triose kinase ADP O HCOH triose phosphate isomerase CH2OH dihydroxyacetone phosphate glyceraldehyde HC HCOH HCOH OH CH2OPO32- HCOH ATP H OH fructose 1-phosphate aldolase O O transketolase transaldolase HOCH glyceraldehyde 3-phosphate OPO3CH2 OH C O CH2OPO32- ADP 2- CH2OPO32- O 2+ Mg (thiamine PP) CH2OH O HCOH Mg H O HOCH2 HC phosphofructokinase-1 2+ fructose 1,6-bisphosphatase fructokinase fructose 6-phosphate ATP i ATP CH2OH H P ADP fructose 6-phosphate OH HO OH 2+ Mg (thiamine PP) CH2OPO32- phosphoglucose isomerase OH H transketolase C O HOCH OH H sorbitol dehydrogenase CH2OH CH2OPO32O H H ADP H+ glucose sorbinil sorbitol OH glucokinase hexokinase Mg2+ ATP H H HO aldose reductase HCOH CH2OH O H ribose 5-phosphate isomerase P i CH2OPO321,3-bisphosphoglycerate ADP acyl CoA phosphoglycerate kinase ATP DAG (diacyglycerol) phosphatidate HCOH lysophosphatidate PKC PKC Protein kinase C (inactive) Protein kinase C (active) Glycolysis inhibited acyl CoA Chart 22.1 Sorbitol metabolism COOO H drug metabolite, bilirubin or steroid O H HO OH H H OH CH2OH HCOH H CH β-glucuronide conjugate Cytosol COH O COH C O ascorbate (vitamin C) UDP-glucuronyltransferase acceptor molecule e.g drug metabolite, bilirubin or steroid Crigler–Najjar syndrome L-gulonolactone oxidase (not in primates, fruit bats or guinea-pigs) O CH2OH C OO H OH H2O H H HO H O UMP Pi NADPH glucuronate phosphatase glucuronic acid 1-phosphate UDP HOCH C O reductase NADH H+ NAD+ L-3-hydroxyacid dehydrogenase HCOH COOL-gulonate OH H CH2OH HCOH NADP+ UDP glucuronate Essential pentosuria CH2OH HCOH CH2OH HCOH HOCH HCOH L-xylulose reductase HOCH C O HCOH HOCH HCOH C O 3-ketogulonate decarboxylase CH2OH CO2 COO3-ketogulonate L-xylulose NADPH NADP+ H+ CH2OH xylitol NAD+ xylitol dehydrogenase Glucuronate/xylulose pathway NADH+H+ NADH+H+ CH2OH UDP glucose dehydrogenase C O HOCH NAD+ HCOH CH2OH D-xylulose ATP glycogen synthase glycogen α (1–> 4) glucose oligosaccharide primer (n residues) CH2OH O H H HO OH H H OH C H O- HO PPi CH2OH O H OH H H O pyrophosphatase H Pi H OH H OH H H HO OH H H OH OH glucose 6-phosphate dehydrogenase H HO CH2OPO32O H OH H H OH ADP COOH2O O 6-phosphogluconoδ-lactone + HCOH NADP NADPH CO2 H+ CH2OH HOCH lactonase HCOH C O 6-phosphogluconate dehydrogenase HCOH HCOH HCOH 2- CH2OPO32- CH2OPO3 6-phosphogluconate ribulose 5-phosphate Pentose Phosphate Pathway glucose 1-phosphate H OH H OH OH glucose 6-phosphate CH2OH C O HOCH phosphoglucose isomerase OH NADPH H+ glucose 6-phosphate OPO32- H CH2OPO3 O H H CH N NADP+ UDP-glucose pyrophosphorylase 2- HO O CH2OPO32O H H UTP phosphoglucomutase H O C O P O P O CH2 O CH HN O- uridine diphosphate glucose H xylulose kinase O CH2OPO32fructose 6-phosphate ribose 5-phosphate isomerase transketolase Mg2+ (thiamine PP) CH2OH CH2OH C O HCOH HCOH ribulose phosphate 3-epimerase C O HOCH CHO HCOH HCOH HCOH HCOH CH2OPO32erythrose 4-phosphate HOCH HCOH HCOH CH2OPO32- 2- CH2OPO3 sedoheptulose 7-phosphate CHO HCOH HCOH HCOH CH2OPO32- ribose xylulose 5-phosphate 5-phosphate Chart 22.3 Glucuronate and xylitol metabolism Part 2 Carbohydrate metabolism 45 Fructose metabolism 23 Fructose does not need insulin to enter muscle that glycogen and/or glucose will be formed Alternatively, the substrates could be converted to acetyl CoA and used for fatty acid synthesis The average daily intake of fructose in the UK is around 35–50 g, mainly as the disaccharide sucrose This is hydrolysed by sucrase in the intestinal cells, forming glucose and fructose Unlike glucose, however, fructose is able to enter muscle cells and adipocytes in the absence of insulin by using the (confusingly named) glucose transporter GLUT5 Consequently, it has been suggested that intravenous fructose should be given as an energy source in patients suffering major trauma However, this practice is not favoured currently because of the risk of lactic acidosis, as described below Metabolism of fructose by muscle It is likely that the normal dietary quantities of fructose that are presented to the liver in the portal blood will be largely converted to glucose or hepatic glycogen, as described above Consequently, relatively little fructose will remain for metabolism by muscle However, if fructose is administered intravenously under experimental conditions, it is metabolized to fructose 6‐phosphate by hexokinase, since fructokinase is absent from muscle (Chart 23.2) The subsequent fate of this fructose 6‐phosphate will depend on the prevailing nutritional status, which will determine whether it is converted to glycogen or used as a respiratory fuel Metabolism of fructose by liver Fructose enters the cell via the fructose transporter GLUT5 Then, the liver enzyme fructokinase phosphorylates fructose to fructose 1‐phosphate (Chart 23.1) This is cleaved by fructose 1‐phosphate aldolase (aldolase B) to form dihydroxyacetone phosphate and glyceraldehyde Glyceraldehyde is then phosphorylated by triose kinase to glyceraldehyde 3‐phosphate Thus the intermediary metabolites of fructose enter glycolysis as triose phosphates Their fate now depends on the prevailing metabolic status However, in the typical circumstances of refeeding after a period of fasting, it is most likely that gluconeogenesis will dominate in the early fed state, so glycogen synthase α (1–> 4) glucose oligosaccharide (n+1 residues) branching enzyme α (1–> 4) glucose oligosaccharide primer (n residues) H glycogen C CH2OH O H H OH H O P O P O CH2 H OH OO O- glycogenolysis is inhibited by fructose 1-phosphate in fructose 1-phosphate aldolase deficiency phosphorylase HO debranching enzyme (i) glycosyltransferase (ii) α (1–> 6)glucosidase glycogen (n–1 residues) PPi CH2OH O H H HN CH O C CH O N O uridine diphosphate glucose i Fructose is metabolized rapidly in humans, having a half‐life of 18 minutes In fact, it disappears from the circulation twice as rapidly as glucose Although intravenous fructose was once recommended for use in parenteral nutrition, it was not without risk This is because fructose bypasses the regulatory steps of glucose catabolism in the following ways: Fructose entry into muscle uses GLUT5, which is independent of insulin Intravenous feeding with large quantities of fructose depletes cellular inorganic phosphate (Pi) and lowers the concentration of ATP Thus phosphofructokinase is deinhibited in muscle, and uncontrolled glycolysis from fructose 6‐phosphate proceeds with the production of lactic acid In liver, fructose evades the rate‐limiting control mechanism by entering glycolysis as dihydroxyacetone phosphate or glyceraldehyde 3‐phosphate, i.e beyond the regulatory enzyme, phosphofructokinase‐1 Consequently, in anoxic states, e.g from the shock of severe trauma, rapid intravenous infusion of fructose may cause a massive unregulated flux of metabolites through glycolysis In extreme circumstances this has produced excessive quantities of lactic acid and precipitated fatal lactic acidosis O HO P Dangers of intravenous fructose pyrophosphatase H Pi H H OH OH H UDP-glucose pyrophosphorylase H UTP OPO32- OH H H OH glucose 1-phosphate phosphoglucomutase CH H2OH H O H HO OH H H OH H ATP OH Pi CH2OPO32O H H ADP DP H+ glucokinase Mg2+ H Mg2+ glucose 6-phosphatase OH HO H2O H glucose 2- O H HO H OH OPO3CH2 OH HO H CH2OH P H CH2OPO32- O H HO OH CH2 H OH fructose 1-phosphate H fructose 1-phosphate aldolase (aldolase B) CH2OPO32O CH2OH O H HO H HC CH2OPO32 - glyceraldehyde 3-phosphate P i glyceraldehyde 3-phosphate dehydrogenase HCOH CH2OPO321,3-bisphosphoglycerate CH2OH glyceraldehyde ATP ADP triose kinase ATP ADP OH H H OH H ATP HO O H H OH Mg2+ H OH H OH O P O P O CH2 OH O- O- HO OH CH2OH hexokinase 2-OPO O N O O pyrophosphatase i H 2P i H H OH OH Glycogenesis H H OH H OH glucose 6-phosphate phosphoglucose isomerase 3CH2 O H ADP OH CH2OH HO OH H ATP fructose 6-phosphate phosphofructokinase-1 Mg2+ 2-OPO CH Cytosol H phosphoglycerate kinase O H OH CH2OPO32C H 2- CH2OPO3 fructose 1,6-bisphosphate aldolase A O Chart 23.2 Metabolism of fructose in muscle HC O HCOH CH2OPO32- CH2OH dihydroxyacetone phosphate Glycolysis OH HO H UTP ADP Metabolism at a Glance, Fourth Edition J G Salway © 2017 John Wiley & Sons Ltd Published 2017 by John Wiley & Sons Ltd CH UDP-glucose pyrophosphorylase OH fructose CH2OPO323-phosphoglycerate CH O C glucose 1-phosphate O H ATP H HN OPO32- H HO HCOH Glycolysis H H phosphoglucomutase CH2OPO32- ADP DP + H hexokinase COO- O Chart 23.1 Metabolism of fructose to glycogen in liver 46 O H H H H OH H OH O C OPO32- HCOH glyceraldehyde 3-phosphate O HCOH triose phosphate isomerase H PP CH2OH O H glucose NADH+H+ CH2OPO32 - HO aldolase A O HCOH H HO debranching enzyme (i) glycosyltransferase (ii) α (1–> 6)glucosidase CH H2OH H fructose 1,6-bisphosphate + NAD HC glycogen (n–1 residues) CH2OPO32 - C CH2OH O H uridine diphosphate glucose phosphorylase (pyridoxal 5' P) OH dihydroxyacetone phosphate HC glycogen P i phosphofructokinase-1 2+ Mg OH C Cytosol ADP H HO fructose 6-phosphate H O 2-OPO O α (1–> 4) glucose oligosaccharide primer (n residues) ATP i fructose 1,6-bisphosphatase ADP HOCH2 branching enzyme CH2OH H glycogen synthase α (1–> 4) glucose oligosaccharide (n +1 residues) OH HO OH fructose fructokinase OH glucose 6-phosphate O H H ATP OH phosphoglucose isomerase H H H triose phosphate isomerase glyceraldehyde 3-phosphate Inborn errors of metabolism Fructokinase deficiency (essential fructosuria) to produce gluconeogenic amino acids and glycerol Because gluconeogenesis is inhibited at the fructose 1,6‐bisphosphatase reaction, the gluconeogenic metabolites accumulate and form large quantities of lactate Similarly, ingestion of fructose leads to the formation of lactic acid, precipitating lactic acidosis In this condition, glycogenolysis by liver to release glucose is normal However, once glycogen is depleted, hypoglycaemia follows due to the failure of gluconeogenesis to maintain glucose homeostasis These patients must therefore eat frequent meals to maintain normoglycaemia Fructose 1‐phosphate aldolase deficiency (hereditary fructose intolerance) Fructose phosphates regulate glucokinase activity Fructose 1,6‐bisphosphatase deficiency ‘Fructose 6‐phosphate paradox’: F 6‐P binds glucokinase to GKRP inactivating it within the nucleus This benign condition is due to a congenital absence of fructokinase and is most commonly found in Jewish families The deficiency means that ingested fructose is limited to metabolism by the hexokinase route only Consequently, fructose is metabolized much more slowly than usual, so that the blood concentration rises and fructose appears in the urine Subjects with essential fructosuria have an entirely normal life expectancy After feeding, the concentration of glucose in blood rises rapidly and must be controlled to prevent harmful consequences (see Chapter 10) In liver, glucokinase plays an important role in this process However, note that glucokinase and its opposing enzyme, glucose 6‐phosphatase, could operate as an ATP‐wasting, futile cycle with glucose → glucose 6‐phosphate → glucose To prevent this, an elaborate mechanism occurs that inactivates glucokinase by incarcerating it within the nucleus bound to glucokinase regulatory protein (GKRP) (Diagram 23.1) Fructose 6‐phosphate (F 6‐P) binds GKRP to, and inactivates, glucokinase On the otherhand, fructose 1‐phosphate and high concentrations of glucose activate glucokinase by liberating it from GKRP, allowing its translocation to the cytosol Once within the cytosol, glucokinase is bound to the non‐phosphorylated form of phosphofructokinase‐2/fructose 2,6‐bisphosphatase (PFK‐2/F 2,6‐bisPase) (see Chapter 16) which maintains glucokinase in an active state This serious condition usually presents when an infant is weaned from breast milk on to fructose‐containing food The response to fructose ingestion is a dramatic onset of vomiting and hypoglycaemia within 15–30 minutes The disorder is due to a deficiency of fructose 1‐phosphate aldolase (aldolase B), which results in a massive accumulation of fructose 1‐phosphate in the tissues (Chart 23.1) This process sequesters intracellular inorganic phosphate, and moreover inhibits both glycogen phosphorylase and fructose 1,6‐bisphosphate aldolase (aldolase A) The resulting inhibition of glucose production by both glycogenolysis and gluconeogenesis causes the severe hypoglycaemia that is such a serious feature of this condition Treatment involves avoiding dietary fructose Patients tend to develop a natural aversion to sweet foods and this usually leads to a complete absence of dental caries If not diagnosed and treated, the disease is fatal This is a disease caused by impaired hepatic gluconeogenesis due to deficiency of this enzyme (Chart 23.1) It is surprising that, given the strategic importance of fructose 1,6‐bisphosphatase in maintaining gluconeogenesis, some patients are relatively unaffected by this disorder However, in other cases, infants may be hospitalized during the first months of life when the metabolic stress of an infection or fever precipitates hypoglycaemia and lactic acidosis Although some children with this condition have hepatomegaly and are extremely ill, curiously in other cases this disorder may not be manifested until adult life The biochemical pathology results from the stress of trauma or infection provoking a catabolic state in which lipolysis and muscle breakdown combine Fed state Insulin causes dephosphorylation of PFK-2/F2,6-bisPase (Diagram 16.2) This binds to glucokinase favouring its translocation to the cytosol (glucokinase active in lipogenesis) inactive F 2,6bisPase Fed State active PFK-2 CH2OH O GLUT2 H OH H H OH glu active cok inas e H ADP H OH H OH glucose 6-phosphate H2O Endoplasmic reticulum H H GLUT5 O H HO HO OH 2- OPO3CH2 OH H H CH2OH H fructose ATP O H OH gluconeogenesis during fasting tive inackinase co glu pentose phosphate pathway glucose 6-phosphatase Pi cytosol active ctiv F2 2,66bisPase bi P nucleus OH Pi fructose P CH2OPO32O H H HO ATP OH HO CH2OH Diagram 23.1 Following feeding, fructose 1‐phosphate and high concentrations of glucose activate glucokinase in liver by liberating it from the nucleus where it is bound to glucokinase regulatory protein (GKRP) During fasting, fructose 6‐phosphate binds glucokinase to GKRP within the nucleus iinactive e PFK-2 liver glycogen store full (Chapter 26) OH glucose glucose Starvation (glucokinase inactive) Glucagon causes phosphorylation of PFK-2/F2,6-bisPase on serine 32 (Diagram 16.2) This induces transfer of glucokinase from PFK-2/F2,6-bisPase to GKRP promoting its translocation to the nucleus H H HO During fasting this makes sense when F 6‐P is an intermediate in gluconeogenesis, consequently glucokinase must be inactive However, paradoxically F 6‐P is an omnipresent intermediary metabolite After feeding when glucokinase is active, F 6‐P is also present as an intermediate in glycolysis and the pentose phosphate pathways, which are involved in fatty acid synthesis This tendency for F 6‐P to inactivate glucokinase is overcome after feeding by fructose 1‐phosphate and high concentrations of glucose that overwhelm the F 6‐P effect, causing active glucokinase to dissociated from GKRP and be translocated from the nucleus to the cytosol glu active cok inas e fructose 6-phosphate fructose1-phosphate P RP R GKR GK glucose GKR P H fructose 6-phosphate fructokinase ADP HOCH2 H CH2OPO32- O H OH HO H OH fructose 1-phosphate fatty acid synthesis (Chapter 28) Fed state High concentrations of glucose and fructose 1-phosphate, and low glucagon, favour dissociation of GKRP from glucokinase and its translocation to the cytosol where it binds to PFK-2/F2,6-bisPase (glucokinase active in lipogenesis) Part 2 Carbohydrate metabolism 47 Ethanol metabolism 24 Alcohol, or more precisely ethanol, is a popular mood‐altering compound that has been consumed over the centuries as wine, beer and, more recently, as spirits Whereas there is evidence to suggest that the intake of small quantities of ethanol with food can be beneficial, excessive consumption can cause cirrhosis of the liver, or metabolic disturbances including fatty liver and hypoglycaemia Ethanol is metabolized by three enzyme systems Chart 24.1 (opposite) Metabolism of ethanol Ethanol is rapidly oxidized in the liver by three enzyme systems, but the relative physiological importance of these is not clear (Diagram 24.1 and Chart 24.1) All three systems produce acetaldehyde, which is normally oxidized rapidly to acetate Alcohol dehydrogenase in the cytosol There may be up to 20 different isoenzymes of alcohol dehydrogenase The rate of this pathway is largely regulated by the availability of NAD+ This in turn depends on the ability of the malate/aspartate shuttle (see Chapter 4) to transport reducing equivalents into the mitochondrion and, moreover, on the ability of the respiratory chain to oxidize NADH to NAD+ Microsomal ethanol‐oxidizing system (MEOS) This system is located in the smooth endoplasmic reticulum and involves a cytochrome P450 enzyme These are a family of monooxygenases concerned with the detoxification of ingested drugs and xenobiotics Diagram 24.1 The three enzyme systems responsible for ethanol metabolism Peroxisomal oxidation of ethanol Catalase uses hydrogen peroxide to oxidize alcohols such as methanol and ethanol to their corresponding aldehydes peroxisome CH3CH2OH ethanol H2O2 catalase aminotriazole H2O CH3CHO acetaldehyde CH3CH2OH ethanol NADPH+H+ O2 H2O endoplasmic reticulum Metabolism of acetaldehyde The acetaldehyde formed by any of the three systems mentioned above must now enter the mitochondrion for further oxidation by aldehyde dehydrogenase to form acetate Finally, this acetate could, theoretically, be activated to acetyl CoA for oxidation by Krebs cycle However, in liver, Krebs cycle is unable to oxidize this acetyl CoA, as we will see below, because of the prevailing high ratio of NADH/NAD+ in the mitochondrial matrix Consequently the acetate will probably leave the liver for oxidation by the extrahepatic tissues Evidence suggests that accumulation of acetaldehyde may be responsible for some of the unpleasant effects caused by drinking ethanol, for example the flushing and nausea that is often seen in those people who are genetically deficient in aldehyde dehydrogenase (45% of Japanese and Chinese) This phenomenon is used to discourage drinking in alcoholics, who may be given disulfiram (Antabuse), which inhibits aldehyde dehydrogenase causing the accumulation of acetaldehyde if ethanol is consumed Finally, the sulphonylurea drug chlorpropamide inhibits aldehyde dehydrogenase and is known to cause ‘chlorpropamide alcohol flushing’ in diabetic patients treated with this drug Biochemical effects of ethanol Increased NADH/NAD+ ratio Following ingestion of ethanol, the cytosolic alcohol dehydrogenase reaction and the mitochondrial aldehyde dehydrogenase reaction both produce NADH, with relative depletion of NAD+ so that the ratio of NADH/NAD+ is significantly increased This has the following effects: Gluconeogenesis is inhibited As shown in the chart opposite, the high NADH/NAD+ ratio in the cytosol displaces the equilibrium of the dehydrogenase reactions in favour of the reduced reactant In particular, pyruvate is reduced to lactate, and oxaloacetate is reduced to malate, thereby preventing the flow of metabolites in the direction of gluconeogenesis This can cause hypoglycaemia (see below) Krebs cycle is inhibited in liver The high NADH/NAD+ ratio in the mitochondrial matrix prevents the oxidation of isocitrate to α‐ketoglutarate, of α‐ketoglutarate to succinyl CoA, and of malate to oxaloacetate Consequently, although acetate can be activated to acetyl CoA for metabolism in the liver, it is more likely that acetate will be exported for metabolism by the extrahepatic tissues Hyperlactataemia and gout cytosol microsomal ethanoloxidizing system (MEOS) CH3CH2OH ethanol (cytochrome P-450-II-E1) NADP+ NAD+ CH3CHO acetaldehyde alcohol dehydrogenase pyrazole NADH+H+ Ethanol interactions with drugs CH3CHO acetaldehyde acetaldehyde mitochondrion + NAD NADH+H aldehyde dehydrogenase Antabuse (disulfiram) + CH3COO- acetate The accumulation of lactate results in hyperlactataemia This can cause hyperuricaemia because lactate and urate share, and so compete for, the same mechanism for renal tubular secretion Gout occurs when uric acid, which is sparingly soluble in plasma, crystallizes in the joints, particularly the toes Long‐term treatment with many drugs, for example the barbiturates, causes proliferation of the smooth endoplasmic reticulum and increases the activity of the cytochrome P450 isoenzymes involved in their metabolism and clearance from the body Similarly, chronic ingestion of excessive quantities of ethanol causes increased proliferation of the endoplasmic reticulum and induction of these enzymes This means that a sober alcoholic patient will metabolize and inactivate these drugs very rapidly and may need higher than normal doses for treatment However, in the drunken alcoholic, ethanol preferentially competes with these drugs for metabolism by the cytochrome P450 isoenzymes As a result, the inactivation and clearance of the barbiturates is suppressed, with the risk of lethal consequences Ethanol‐induced fasting hypoglycaemia This condition develops in chronically malnourished individuals several hours after a heavy drinking binge This is caused by the inhibition of gluconeogenesis, as described above metabolized mainly by extra hepatic tissues 48 Metabolism at a Glance, Fourth Edition J G Salway © 2017 John Wiley & Sons Ltd Published 2017 by John Wiley & Sons Ltd glycogen synthase α (1—> 4) glucose oligosaccharide (n+1 residues) UDP branching enzyme O α (1—> 4) glucose oligosaccharide primer (n residues) H HO C CH2OH O H H OH O P O P O H O- OCH2 O O OH H uridine diphosphate glucose glycogen i H phosphorylase (pyridoxal 5' P) OH HO debranching enzyme (i) glycosyltransferase (ii) α (1—> 6) glucosidase glycogen (n–1 residues) i CH O C CH O H N CH2OPO32O H H HO H H H OH OH H HO H OH OH H H glucokinase ATP Mg2+ H CH2OH H OH H OH glucose 6-phosphate 2- OPO3CH2 glucose 6-phosphatase Pi O H H H2O OH Endoplasmic reticulum Pi Gluconeogenesis (inhibited) OPO3CH2 H OH HC HCOH HCOH HCOH HC H3C O O H H3C C glyceraldehyde 3-phosphate dehydrogenase H3C C HS-ACP H2 O ethanol microsomal ethanoloxidizing system ethanol NADH+H+ H2O NADP+ CH3CHO acetaldehyde CH3CHO 2-phosphoglycerate C O NADH+H+ malate dehydrogenase NAD+ pyruvate kinase Mg2+ K+ ADP ATP NAD+ COO- COO- + NADH+H HCOH lactate dehydrogenase CH3 NADPH+H+ NAD+ NADP+ COO- CO2 C malic enzyme i HCO3-+ATP COO- CHOH CH3 C16 CO2 CoASH CoASH CoASH CH3(CH2)14C O- CoASH palmitate malonyl-acetyl CoA-ACP transacylase (MAT) CH2OH esterification CHOH O 2- malonyl CoA CH2OPO3 CH2OC(CH2)14CH3 glycerol 3-phosphate O SCoA ADP glycerol kinase (not in white adipose tissue) CHOC(CH2)14CH3 O ATP CH2OC(CH2)14CH3 H++ADP+P pyruvate C14 CO2 NADH+H+ C O lactate CoASH malonyl-acetyl CoA-ACP transacylase (MAT) O O -O C CH C malonyl CoA CH2 phosphoenolpyruvate gluconeogenesis inhibited SACP CoASH —SH of acyl carrier protein (ACP) COPO32- phosphoenolpyruvate carboxykinase H2C COOoxaloacetate C12 CO2 HS-ACP O CH2 C CoASH COO- CO2 GDP CO2 O translocation acyl-KS malonyl ACP enolase Mg2+ H2O GTP COO- O -O C CH2OH acetaldehyde acetaldehyde C10 C8 CO2 acyl carrier protein (ACP) condensation HCOPO32- CH3CHO SACP HS–KS β-ketoacyl-ACP synthase (KS) (condensing enzyme) COO- H2O thioesterase (TE) O CH2 C acyl ACP CO condensation phosphoglycerate Mg2+ mutase palmitoyl ACP C6 CO2 3-phosphoglycerate alcohol dehydrogenase catalase hexanoyl ACP C4 CH2OPO32- SACP enoyl ACP reductase (ER) + H3C CH2 HCOH NAD+ H2O2 NADPH+H+ NADP acetoacetyl ACP C C H enoyl ACP acetyl—KS COO- CH3CH2OH O H phosphoglycerate kinase ATP β-hydroxyacyl ACP dehydratase (DH) H2O cysteine-SH of KS (condensing enzyme) CH2OPO3 1,3-bisphosphoglycerate ADP O CH2 C SACP OH D-3-hydroxybutyryl ACP SACP acetyl ACP Pi Fatty acid synthesis β-ketoacyl ACP reductase (KR) H3C C O 2- ethanol CH2OPO32- acetoacetyl ACP C4 NADP+ HCOH NADPH+H+ O2 O O NADPH+H+ HS-ACP CoASH CH2OPO32glyceraldehyde 3-phosphate O C OPO32- CH3CH2OH Mg2+ (thiamine PP) glyceraldehyde 3-phosphate H3C C CH2 C SACP SCoA C malonyl-acetyl CoA-ACP transacylase (MAT) HCOH NADH+H+ CH3CH2OH ribose 5-phosphate HCOH HCOH acetyl CoA NAD+ Cytosol CH2OPO32- xylulose 5-phosphate transketolase HC HCOH O fructose 1,6-bisphosphate dihydroxyacetone phosphate HCOH fructose 6-phosphate CH2OPO3 CH2OH HCOH CH2OPO32- transaldolase CH2OPO32- triose phosphate isomerase HOCH CH2OPO32- C O CH2OPO3 HCOH HCOH HOCH glyceraldehyde 3-phosphate CHO C O sedoheptulose 7-phosphate CH2OH 2- 2- O ribose 5-phosphate isomerase HCOH HCOH O HCOH aldolase C ribulose phosphate 3-epimerase HOCH CH2OPO32- CH2OPO32- H ribulose 5-phosphate C O OH HO CH2OPO32- CH2OPO3 6-phosphogluconate erythrose 4-phosphate phosphofructokinase-1 O H HCOH HCOH 2- CH2OH ADP 2- HCOH CHO fructose 6-phosphate Mg2+ H2O C O CH2OH CH2OPO32- fructose 6-phosphate CH2OH CO 6-phosphogluconate dehydrogenase HCOH HCOH ATP fructose 1,6-bisphosphatase OH HCOH CH2OH H H lactonase Mg2+ (thiamine PP) OH HO H NADPH + H + NADP HOCH transketolase HOCH phosphoglucose isomerase Pi OH O HCOH Pentose phosphate pathway C O OH HO H O 6-phosphogluconoδ-lactone glucose 1-phosphate OH glucose OH OPO3 H OH OH UTP CH2OPO3 O H HO H COO- CH2OPO32O H H glucose 6-phosphate dehydrogenase 2- 2- ADP H+ H NADPH + H glucose 6-phosphate phosphoglucomutase CH2OH O H OH + NADP UDP-glucose pyrophosphorylase H H H pyrophosphatase PP CH2OH O H P H HN malate H2C COOH C COOdehydrogenase malate oxaloacetate ADP+Pi CoASH ATP H2O malate (triacylglycerol) CHOH H2O CH2OH acetyl CoA O tripalmitin CH2OH acetyl CoA carboxylase (biotin) glycerol citrate lyase Pi ATP PPi+AMP pyrophosphatase palmitoyl CoA CoASH ATGL & hormonesensitive lipase (adipose tissue) (3) palmitate long chain acyl CoA synthetase dicarboxylate carrier pyruvate carrier acetaldehyde CoASH ATP NAD+ Antabuse (disulfiram) thiamine PP lipoate riboflavin (as FAD) pyruvate carboxylase (biotin) aldehyde dehydrogenase chlopropamide CO2 ADP+Pi NADH+H+ HCO3- H3C NAD+ COO- COO- CHOH metabolized mainly by extra-hepatic tissues C COO- H2C malate malate dehydrogenase oxaloacetate NADH+H+ NADH SCoA CoASH fumarate succinate dehydrogenase FAD CH2COOCH COO- succinyl CoA synthetase CoASH GTP CH2 O C SCoA succinyl CoA H NADH+H+ H2O NADH+H+ dehydrogenase + HPO42- H NADH C6 CH2COOHC COO- C4 CH2 O C COOα-ketoglutarate CO2 NAD+ NADH H+ 4H+ I translocase Respiratory chain / O2 2H+ 2H+ 4H+ III Q GDP3- HPO 2- H+ nucleoside diphosphate kinase 4H+ ATP 4H+ CH2 C H L-3-hydroxyacyl CoA L-3-hydroxyacyl CoA dehydrogenase CoASH thiolase SCoA NAD+ NADH+H+ H2O CoASH O F1 + HPO42- H O CH3(CH2)12 C CH2 C SCoA 3-ketoacyl CoA CH3(CH2)12 C SCoA myristoyl CoA thiolase O ATP4- matrix H3C C SCoA acetyl CoA FO inner membrane IV 2H+ O ADP3- C GTP4- CH3COCH2COSCoA acetoacetyl CoA 3H+ NAD+ C NADH+H+ CoASH NADH+H+ FADH2 H2O O OH CH3(CH2)12 FADH2 NADH+H+ HOCH COOisocitrate C C SCoA trans-Δ2-enoyl CoA enoyl CoA hydratase FADH2 [cis-aconitate] FAD FADH2 H O aconitase isocitrate dehydrogenase CH2COOMg2+ NADH + H+ α-ketoglutarate NAD acyl CoA dehydrogenase CH3(CH2)12 C FADH2 C8 SCoA palmitoyl CoA NADH+H+ COO- H2O CO2 Pi GDP ADP FADH2 C10 citrate CH2COO- succinate Mitochondrion C12 (8) acetyl CoA CH2COOCOO- Krebs cycle (inhibited) -OOCCH FADH2 βOxidation FADH2 aconitase HCCOO- O CH3(CH2)12 CH2 CH2 C NADH+H+ H2C H2O carnitine inner CPT C14 acetyl CoA HOC citrate synthase outer CPT CoASH fumarase H2O tricarboxylate carrier pyruvate dehydrogenase O H2C COO- NADH+H+ C palmitoylcarnitine glycerol phosphate shuttle NAD+ O CH3COO- acetate malate/ aspartate shuttle + HPO42- H 10H+ 4H+ ATP4- ADP3- intermembrane space Part 2 Carbohydrate metabolism 49 Pyruvate/malate cycle and the production of NADPH 25 Relative contributions of the pentose phosphate pathway and the pyruvate/malate cycle to the provision of NADPH for fatty acid synthesis The pyruvate/malate cycle has two main functions associated with l ipogenesis: (i) it transports acetyl CoA units from the mitochondrion into the cytosol; and (ii) it generates NADPH in the reaction catalysed by the malic enzyme For each acetyl unit added to the acyl carrier protein chain (ACP chain) during fatty acid synthesis, two molecules of NADPH are needed (Chapter 27) Experimental evidence suggests that if glucose is used for fatty acid synthesis, the pentose phosphate pathway supplies 60% of the NADPH needed with 40% produced by the pyruvate/malate cycle Fatty acid synthesis is also possible from other precursors, for example amino acids (see Chapter 33) or lactate (Chart 25.2) For instance, if lactate is used for fatty acid synthesis, only 25% of the NADPH needed is provided by the pyruvate/malate cycle Chart 25.1: pyruvate/malate cycle Fatty acid synthesis occurs in the cytosol However, the carbon source, namely acetyl CoA, is produced by pyruvate dehydrogenase in the mitochondrion Transport of acetyl CoA from the mitochondrion into the cytosol involves the pyruvate/malate cycle The principal stages are: One molecule of pyruvate is carboxylated by pyruvate carboxylase to form oxaloacetate A second pyruvate molecule forms acetyl CoA by the pyruvate dehydrogenase reaction The acetyl CoA and oxaloacetate so formed condense to form citrate, which is transported to the cytosol for cleavage by citrate lyase to o xaloacetate and acetyl CoA for lipogenesis Oxaloacetate is reduced by cytosolic malate dehydrogenase and malate is formed Malate is oxidatively decarboxylated by the malic enzyme (malate dehydrogenase, decarboxylating) with the formation of NADPH, CO2 and pyruvate, thus completing the cycle Chart 25.2 Lactate as a substrate for fatty acid synthesis O O H3C C acetyl CoA malonyl-acetyl CoA-ACP transacylase (MAT) H H3C glyceraldehyde 3-phosphate dehydrogenase NADH+H+ C ADP Glycolysis NADPH H+ NADP+ H3C acetoacetyl ACP H O C H2C COOoxaloacetate + NADH+H phosphoenolpyruvate malate dehydrogenase NAD+ COO- COO- CHOH ADP NAD+ NADH H+ ATP COO- H2C COOmalate CH3 lactate dehydrogenase CH3 pyruvate lactate dicarboxylate carrier CoASH thiamine PP lipoate riboflavin (as FAD) pyruvate carboxylase (biotin) ADP34- ATP4 - ADP+P CO i HCO - + + H H HPO4 - HPO 24 6H+ + 2H IV C III Q 50 ADP 3- 4H+ H O + NAD + NADH+H CHOH H2C COOmalate 2H+ H O /2 O 2H+ 4H+ H3C 3H COO- H2C COO- malate malate dehydrogenase malate dehydrogenase H2C COO oxaloacetate COOC C Pyruvate/ malate cycle acetyl CoA H2C COO- H O citrate synthase CoASH -OOCCH fumarate SACP malonyl-acetyl CoA-ACP transacylase (MAT) CoASH CH3(CH2)14C O- CoASH esterification CHOH O CH2OPO32- malonyl CoA CH2OC(CH2)14CH3 glycerol 3-phosphate O ADP glycerol kinase (not in white adipose tissue) CHOC(CH2)14CH3 O ATP glycerol Pi citrate lyase palmitoyl CoA CoASH glycerol phosphate shuttle outer CPT carnitine inner CPT O CH3(CH2)12 CH2 CH2 C + NADH+H FADH F βOxidation F FAD acyl CoA dehydrogenase FADH F H O CH3(CH2)12 C FADH2 F C8 NADH+H+ HOCH COOisocitrate Metabolism at a Glance, Fourth Edition J G Salway © 2017 John Wiley & Sons Ltd Published 2017 by John Wiley & Sons Ltd C6 SCoA + NADH+H FADH2 F NADH+H+ C H2O O OH CH3(CH2)12 FADH2 F C4 C enoyl CoA r hydratase FADH F [cis-aconitate] C H trans-Δ -enoyl CoA aconitase CH2COOHC COO- SCoA palmitoyl CoA FADH2 F CH2 C SCoA H L-3-hydroxyacyl CoA L-3-hydro L-3-hydroxyacyl roxyacyl CoA dehydrogenase NAD+ NADH+H+ AGTL & hormone sensitive lipase (adipose tissue) (3) palmitate long chain acyl CoA synthetase palmitoylcarnitine NADH+H+ H2O ATP PP +AMP pyroi phosphatase + NADH+H H2O H2O CH2OH C10 COO- citrate (triacylglycerol) CHOH CoASH CH2COOHOC COOH 2C ADP+P i ATP CoASH H2O tripalmitin CH2OH acetyl CoA carboxylase (biotin) aconitase Krebs cy ccycle cle CoASH CH2OH SCoA C12 fumarase r HCCOO- palmitate C14 (8) acetyl CoA SCoA O oxaloacetate CH2 C tricarboxylate carrier O + 4H+ NADH+H+ CO O acetyl CoA O malate/ aspartate shuttle pyruvate dehydrogenase CoASH CoASH malonyl-acetyl CoA-ACP transacylase (MAT) HCO3-+ATP COOC CHOH malic enzyme NAD+ C16 CO HS-ACP CoASH H++ADP+P i NADH H+ NADP+ COO- pyruvate carrier ATP ATP NAD+ C O HCOH C14 CO acyl carrier protein (ACP) CH2OC(CH2)14CH3 NADPH H+ CO2 C12 CO O O O -O C CH C malonyl CoA CH2 pyruvate kinase Mg2+ K+ CO translocation —SH of acyl carrier protein (ACP) COPO32- phosphoenolpyruvate carboxykinase O C10 C8 CoASH COO- SACP HS–KS malonyl ACP enolase 2+ Mg CO2 GDP CH2 C acyl ACP acyl-KS O -O C CH2OH 2-phosphoglycerate GTP H2O thioesterase (TE) condensation HCOPO32- COO- palmitoyl ACP O β-ketoacyl-ACP synthase (KS) (condensing enzyme) COO- SACP enoyl ACP reductase (ER) CO2 condensation Mg C C6 CO2 2+ phosphoglycerate mutase CH hexanoyl ACP C4 CH2OPO323-phosphoglycerate C H enoyl ACP acetyl—KS HCOH Cytosol H3C C HS-ACP COO- O H phosphoglycerate kinase ATP β-hydroxyacyl ACP dehydratase (DH) H2O O C OPO32CH2OPO321,3-bisphosphoglycerate CH2 C SACP OH D-3-hydroxybutyryl ACP SACP cysteine-SH of KS (condensing enzyme) HCOH O H3C C acetyl ACP Pi β-ketoacyl ACP reductase (KR) NADP+ O NAD+ Fatty acid synthesis acetoacetyl ACP C4 + NADPH+H HS-ACP CoASH glyceraldehyde 3-phosphate O H3C C CH2 C SACP SCoA glycogen synthase >4) 4) glucose α (1—> oligosaccharide (n +1 residues) UDP branching enzyme O >4) 4) glucose α (1—> oligosaccharide primer (n residues) H OH HO H H O- O- O P O P O CH2 H uridine diphosphate glucose P i H phosphorylase r (pyridoxal 5' P) glycogen (n–1 residues) HO debranching enzyme (i) glycosyltransferase (ii) α (1—> 6)glucosidase pyrophosphatase e PP i CH2OH O H HN CH O C CH O H 2P i N HO H H OH CH2OPO32O H H H O O OH H glycogen C CH2OH O H OH H H OH OH OH H HO H OH OH H glucokinase hexokinase Mg2+ ATP glucose 1-phosphate H HO CH2OH OH glucose 6-phosphate H H OH O OPO3CH2 H H CH2OPO3 CH2OPO32- 2- HC CH2OPO3 triose phosphate isomerase O O CH2OPO32- H H3C glyceraldehyde 3-phosphate dehydrogenase + C H3C C HS-ACP CH2OPO321,3-bisphosphoglycerate acetyl—KS acetoacetyl ACP CH2OPO323-phosphoglycerate C O H2C COOoxaloacetate + NADH+H pyruvate kinase 2+ Mg K+ ADP ATP COO- COO- CHOH NAD+ + NADH+H COO- HCOH H2C COOmalate CH3 lactate dicarboxylate carrier CoASH (biotin) ADP+Pi ATP4 - H3 C + 4H+ F1 FO H+ 3H COO- H+ HPO42- HPO42- 6H+ + 2H IV 2H+ + NAD + NADH+H H2C COO- H2O / O2 COO- CHOH ADP3- malate dehydrogenase malate 2H+ C III 4H+ SCoA acetyl CoA O H2C COO- oxaloacetate H2O citrate synthase CoASH malate dehydrogenase CH2COOCH COO- CH2COOCH2 succinate CoASH GTP Mitochondrion O C SCoA succinyl CoA + HPO 2- H Pi -ketoglutarate k r rate α-ketogluta dehydrogenase CO2 NADH + H + NAD CoASH CoASH CH3(CH2)14C O- CoASH esterification CHOH O 2- CH2OPO3 CH2OC(CH2)14CH3 glycerol 3-phosphate O SCoA ADP glycerol kinase (not in white adipose tissue) CHOC(CH2)14CH3 O ATP CH2OH glycerol Pi palmitoylcarnitine glycerol phosphate shuttle outer CPT inner CPT C CH3(CH2)12 βOxidation FADH2 F NADH+H+ FADH F [cis-aconitate] acyl CoA dehydrogenase CH2COOHC COO- + NADH+H CO2 + / O2 NAD 4H + C H2O O OH CH3(CH2)12 CH2 C SCoA H L-3-hydroxyacyl CoA L-3-hydro L-3-hydroxyacyl roxyacyl CoA dehydrogenase FADH2 F CH3COCH2COSCoA acetoacetyl CoA Respiratory r chain + 4H SCoA NAD+ NADH+H+ + NADH+H CoASH thiolase 2H+ + 2H H2O O C CH2 C SCoA 3-ketoacyl CoA CoASH O thiolase O ADP3F1 + HPO 2- H O CH3(CH2)12 CH3(CH2)12 C SCoA myristoyl CoA + 3H GDP C enoyl CoA hydratase r + NADH+H O C COOα-ketoglutarate NADH+H+ C H trans-Δ -enoyl CoA FADH2 F C4 F FAD FADH F H O + NADH+H C6 SCoA palmitoyl CoA FADH F HOCH COOisocitrate CH2 CH2 CH2 C CH3(CH2)12 C FADH F C8 + NAD (3) palmitate O CoASH C14 aconitase H2O CoASH ATGL & hormone sensitive lipase (adipose tissue) carnitine NADH+H+ H2O ATP PPi+AMP pyrophosphatase palmitoyl CoA C10 CH2COO- 3H O + NADH+H COO- citrate (triacylglycerol) CHOH long chain acyl CoA synthetase CH2COOHOC COOH2C tripalmitin CH2OH C12 isocitrate isocitr trate dehydrogenase Mg2+ succin i yl CoA succinyl synthetase CoASH CH2OH malonyl CoA citrate lyase (8) acetyl CoA succinate dehydrogenase F FAD H2C COOoxaloacetate Pyruvate/ malate cycle Krebs cy ccycle cle -OOCCH fumarate FADH F ADP+Pi ATP CoASH H O tricarboxylate carrier Q II malonyl-acetyl CoA-ACP transacylase (MAT) aconitase HCCOO- + C COO- r fumarase H2O C 4H O CO2 palmitate acetyl CoA O malate/ aspartate shuttle NADH+H+ CoASH acetyl CoA carboxylase (biotin) HCO3-+ATP COOC malate pyruvate dehydrogenase CO HCO3- H++ADP+Pi NAD+ NADH H+ COO- malic enzyme H2C NAD+ thiamine PP lipoate riboflavin (as FAD) pyruvate carboxylase 3- ATP4- NADP + pyruvate carrier ATP ADP NADPH H+ CHOH CH3 C16 CO2 CH2OC(CH2)14CH3 CO2 pyruvate CoASH malonyl-acetyl CoA-ACP transacylase (MAT) O O -O C CH C malonyl CoA C O lactate dehydrogenase SACP CoASH —SH of acyl carrier protein (ACP) CH2 phosphoenolpyruvate malate dehydrogenase + NAD CH2 C CoASH COPO32- phosphoenolp phosphoenolpyruvate l yr y uvate v o carboxykinase C14 CO2 HS-ACP O malonyl ACP COO- CO2 GDP C12 CO2 O translocation acyl-KS O -O C enolase 2+ Mg H O GTP C10 C8 CO2 acyl carrier protein (ACP) condensation condensation CH2OH 2-phosphoglycerate COO- SACP HS–KS CO2 HCOPO32- Cytosol CH2 C acyl ACP β-ketoacyl-ACP synthase (KS) (condensing enzyme) COO- H2O thioesterase (TE) C6 CO2 phosphoglycerate mutase Mg2+ palmitoyl ACP O hexanoyl ACP C4 HCOH SACP enoyl ACP reductase (ER) NADP+ H3C CH2 COO- C C H enoyl ACP NADPH+H+ phosphoglycerate kinase ATP O H HCOH Glycolysis β-hydroxyacyl ACP dehydratase (DH) H2O O C OPO32- ADP CH2 C SACP OH D-3-hydroxybutyryl ACP SACP cysteine-SHCoASH of KS (condensing enzyme) NADH+H O H3C C acetyl ACP NAD+ Pi β-ketoacyl ACP reductase (KR) NADP+ O glyceraldehyde 3-phosphate dihydroxyacetone phosphate Fatty acid synthesis acetoacetyl ACP C4 CoASH HCOH CH2OH CH2OPO32 glyceraldehyde 3-phosphate O NADPH+H+ HS-ACP O HCOH H3C C CH2 C SACP acetyl CoA malonyl-acetyl CoA-ACP transacylase (MAT) Mg2+ (thiamine PP) transketolase HC CH2OPO32- SCoA CH2OPO32 ribose 5-phosphate xylulose 5-phosphate transaldolase HCOH O C HCOH CH2OPO32- HCOH O H3C HCOH CH2OPO32- sedoheptulose 7-phosphate fructose 6-phosphate fructose 1,6-bisphosphate HOCH HCOH C O glyceraldehyde 3-phosphate aldolase C HCOH OH HO OH HCOH HOCH 2- ADP 2- HCOH O CHO HCOH HCOH HCOH CH2OH HCOH Mg2+ H2O H HC ribose 5-phosphate isomerase C O C O CH2OPO32- fructose 6-phosphate ribulose phosphate 3-epimerase HOCH erythrose 4-phosphate ATP phosphofructokinase-1 Pi fructose 1,6-bisphosphatase ribulose 5-phosphate CH2OH fructose 6-phosphate CH2OH H CH2OPO32- 6-phosphogluconate CHO OH HO HCOH CH2OPO32- CH2OH phosphoglucose isomerase O HCOH HCOH Mg2+ (thiamine PP) CH2OPO32- H OPO3CH2 OH C O 6-phosphogluconate dehydrogenase HCOH HCOH OH 2- H lactonase HCOH H glucose H CH2OH CO2 HOCH transketolase HOCH OH OH H OH O NADPH + H NADP+ HCOH 6-phosphogluconoδ-lactone C O CH2OPO32O H H ADP H+ HO H O Pentose phosphate pathway UTP phosphoglucomutase CH2OH O H OH glucose 6-phosphate OPO32- H H H glucose 6-phosphate dehydrogenase COO- CH2OPO32O H UDP-glucose pyrophosphorylase r H OH NADPH + H NADP+ 4- ATP H3C C SCoA acetyl CoA F Chart 25.1 The pyruvate/malate cycle Part 3 Fat metabolism 51 Metabolism of glucose to fat (triacylglycerol) 26 Importance of fat rejoin the main glycolytic route, pass into the mitochondrion and enter Krebs cycle However, in the fed state the mitochondrial pathways will be working to capacity and generating large amounts of ATP and NADH Under these circumstances, a control mechanism (see Chapter 19) diverts citrate from Krebs cycle into the cytosol for fatty acid synthesis (see Chapter 27) Although Chart 26.1 shows the formation of palmitate, stearate is also formed by this pathway Both can be esterified with glycerol 3‐phosphate to form triacylglycerols (see Chapters 29 and 32) NB: The vitamin biotin is an essential cofactor for the regulatory enzyme acetyl CoA carboxylase in the pathway for fatty acid synthesis The statement ‘if you eat too much food, you will become fat’ is unlikely to surprise any reader of this book We know from experience that a surplus of fat in our diet will increase the fat in our body Furthermore, it is general knowledge that an excess of carbohydrate will be stored as fat However, a surprising number of people enjoy life under the delusion that they can eat large amounts of protein without the hazard of becoming obese Sadly, this misconception will be shattered by reality in Chapter 33 Let us turn to the physiological advantages of body fat Primitive man, like many other carnivorous mammals that hunted for food, was an intermittent feeder In the days before refrigeration he was unable to store joints from his woolly mammoth in the freezer, to be divided subsequently into a gastronomical routine of breakfast, lunch, dinner and supper Instead, when food was available the hunters and their families ate all they could, with any surplus to immediate energy requirements being stored in the body, to a certain extent as glycogen but mainly as fat This fat can provide an energy store for sustenance over periods of starvation lasting several days or even weeks Fat provides a very compact store for energy, largely because of its highly reduced and anhydrous nature In fact, 1 g of fat yields 9 kcal (37 kJ) This compares well with 1 g of carbohydrate, which yields 3.75 kcal (16 kJ), or 1 g of protein, yielding 4 kcal (17 kJ) Liver cells and fat cells (adipocytes) are both major producers of fat In addition, with the onset of lactation at the end of pregnancy, the mammary gland develops almost overnight the ability to synthesize prodigious amounts of fat for secretion in the milk Diagram 26.1: insulin and fat synthesis Adipocytes are the specialized cells of adipose tissue where triacylglycerols are synthesized and stored They contain the usual cellular organelles but, because the cell interior is almost completely occupied by a large, spherical fat droplet, the cytosol and organelles are displaced to the periphery Adipose tissue is widely distributed, being found beneath the skin and especially around the intestines, kidneys and other visceral organs Blood capillaries in adipose tissue bring supplies of glucose for fatty acid synthesis The diagram shows the relationship between adipocytes and a capillary, but is not to scale: in reality, the adipocytes would be much larger The glucose passes through the capillary wall into the extracellular fluid After feeding, insulin is released from the pancreas and causes a 30‐fold increased rate of transport of glucose into the adipocyte Insulin causes the translocation of a latent pool of GLUT4 glucose transporters from within the adipocyte cytosol to the plasma membrane These facilitate the transport of glucose into the cytosol, where it is metabolized to triacylglycerols, which are stored as a spherical droplet as described earlier Not all the body’s triacylglycerol is made by the adipose tissue Triacylglycerol is usually available in food and is absorbed from the gut as protein‐phospholipid‐coated packages known as chylomicrons, whose role is to transport the triacylglycerols from the intestines to the adipocytes for storage Alternatively, liver makes triacylglycerols from glucose for export in a similar package known as a VLDL (very low‐density lipoprotein) Likewise, these VLDLs transport triacylglycerol to adipose tissue for storage Chart 26.1: the flow of metabolites when glucose is converted to triacylglycerol The chart shows the metabolic pathways involved when a surplus of carbohydrate is taken in the diet We have seen how liver is able to conserve useful, but limited, supplies of energy as glycogen (see Chapter 10) Once these glycogen reserves are full, any additional carbohydrate will be converted to fat as follows: glucose enters the pentose phosphate pathway, the metabolites of which form a temporary diversion from the glycolytic pathway The metabolites eventually in in su su li n lin capillary in su lin in in su lin su lin insulin binds to insulin receptor insulin P adipocyte P β -S -S - α a re ins ctiv ce ul e pt in or β -S -S - α -S -S - plasma membrane fat droplet membranous vesicle containing glucose transporters (GLUT4) triacylglycerols cytosol glucose nucleus Diagram 26.1 Insulin stimulates the transport of glucose into adipocytes for triacylglycerol synthesis 52 glucose GLUT4 Metabolism at a Glance, Fourth Edition J G Salway © 2017 John Wiley & Sons Ltd Published 2017 by John Wiley & Sons Ltd glycogen synthase >4) 4) glucose α (1—> oligosaccharide oligosacc oligosac charide (n +1 residues) UDP branching enzyme O > 4) glucose α (1—>4) oligosaccharide primer (n residues) H P i glycogen (n–1 residues) OH HO debranching r enzyme glycosyltransferase (i) glycosyltr transfe f rase r (ii) α (1—> 6) glucosidase CH HN O- O- H pyrophosphatase e 2P i OH HO CH2OPO32O H H OH H H OH H HO H OH OH H H glucokinase ATP hexokinase 2+ Mg H OPO3 OH H glucose CH2OH OPO3CH2 H O H OPO3CH2 H O H OH H HC O NADPH+H+ HS-ACP H H3C C Glycolysis HS-ACP H3C CH2 hexanoyl ACP C4 O -O C CHOH COO- H2C COOmalate lactate dehydrogenase CH3 lactate CoASH ATP ADP3ATP4 - F1 FO H+ H+ HPO42- 2HPO4 6H+ 2H+ IV 4H+ malate dehydrogenase H2C COO- / O2 H2O COOC CHOH H2C COOmalate C H2C COO- H2O citrate synthase O ADP+Pi H2C COOoxaloacetate ATP CoASH H2O CoASH GTP + HPO42- H Mitochondrion Pi translocase GTP4- GDP3- HPO 2- H+ nucleoside diphosphate kinase ATP ATP PPi+AMP pyrophosphatase palmitoyl CoA H2O palmitoylcarnitine outer CPT CH2COO- O CH3(CH2)12 C12 βOxidation FADH F CH2 CH2 C acyl CoA dehydrogenase NADH+H+ CH2COOHC COO- CH2 inner membrane intermembrane space outer membrane NAD+ CH3COCH2COSCoA acetoacetyl CoA CoASH thiolase I 2H+ 2H+ III Q 4H+ SCoA H L-3-hydroxyacyl CoA L-3-hydro L-3-hydroxyacyl roxyacyl CoA dehydrogenase NAD+ H2O CH3(CH2)12 NADH+H+ O C CH2 C SCoA 3-ketoacyl CoA CoASH O thiolase O F1 + HPO42- H O H3C C SCoA acetyl CoA ATP4- FO IV C 4H+ CH2 C CH3(CH2)12 C SCoA myristoyl CoA ADP3- / O2 4H+ F FADH C H2O NADH+H+ NADH+H+ SCoA O OH CH3(CH2)12 FADH F C4 Respiratory r chain NADH+H+ C enoyl CoA hydratase r NADH+H+ 3H+ 4H+ C H trans-Δ -enoyl CoA FADH F HOCH COOisocitrate F FAD F FADH H O CH3(CH2)12 C FADH F C6 SCoA palmitoyl CoA NADH+H+ CO2 (3) palmitate carnitine inner CPT [cis-aconitate] NAD+ CoASH ATGL & hormone sensitive lipase (adipose tissue) long chain acyl CoA synthetase C8 matrix GDP (triacylglycerol) H2O CH2OH glycerol phosphate shuttle O C SCoA O C COO+ CO2 NADH NAD CoASH α-ketoglutarate succinyl CoA H+ Pi tripalmitin CHOH aconitase Mg2+ CH2 O A ATP NADH+H+ H2O succinate dehydrogenase succinate CHOC(CH2)14CH3 CH2OH C10 COO- citrate α-ketoglutarate dehydrogenase O ADP glycerol kinase (not in white adipose tissue) citrate lyase CH2COOHOC COO- FAD ADP C (8) acetyl CoA Q CH2COO- CH2OC(CH2)14CH3 glycerol 3-phosphate NADH+H+ isocitrate dehydrogenase inhibited CH2COO- O CH2OPO3 malonyl CoA FADH F Krebs cycle CH2COO- esterification 2- CoASH H2C CH3(CH2)14C O- CoASH CHOH aconitase fumarate II CH2OH C14 SCoA CoASH CoASH glycerol NADH+H+ acetyl CoA malonyl-acetyl CoA-ACP transacylase (MAT) acetyl CoA carboxylase (biotin) tricarboxylate carrier fumarase -OOCCH FADH2 malate dehydrogenase malate/ aspartate shuttle O oxaloacetate HCCOO- C III NADH+H+ malate 4H+ NAD+ CHOH ADP3- 2H+ H2O 2H+ H3C COO- CoASH O O 3H+ CoASH acetyl CoA pyruvate dehydrogenase CO2 ADP+Pi CO2 palmitate CH2 C SCoA malonyl CoA HCO3-+ATP COO- NAD+ thiamine PP lipoate riboflavin (as FAD) HCO3- 4H+ malic enzyme H+ NAD+ NADH COO- pyruvate carrier pyruvate carboxylase (biotin) CoASH malonyl-acetyl CoA-ACP transacylase (MAT) i CH3 CO2 CH2OC(CH2)14CH3 NADPH NADP+ H+ pyruvate dicarboxylate carrier ATP4- O -O C C O HCOH SACP CoASH H++ADP+P CO2 CO2 acyl carrier protein (ACP) C16 HS-ACP O CH2 C —SH of acyl carrier protein (ACP) pyruvate kinase Mg2+K+ ATP CO2 C14 O translocation CoASH CH2 phosphoenolpyruvate NADH+H+ CO2 C12 acyl-KS malonyl ACP enolase Mg2+ COPO32- NAD+ C10 condensation CH2OH 2-phosphoglycerate ADP SACP HS–KS CO2 HCOPO32- malate dehydrogenase H2O thioesterase (TE) O CH2 C acyl ACP β-ketoacyl-ACP synthase (KS) (condensing enzyme) COO- palmitoyl ACP enoyl ACP reductase (ER) C8 condensation condensation COO- SACP C6 CO2 phosphoglycerate Mg2+ mutase phosphoenolp phosphoenolpyruvate l yr y uvate v carboxykinase o NADPH+H+ NADP+ acetoacetyl ACP C C H enoyl ACP acetyl—KS HCOH H2O O H H3C C CH2OPO323-phosphoglycerate CO2 β-hydroxyacyl ACP dehydratase (DH) H2O cysteine-SH of KS CoASH (condensing enzyme) COO- Cytosol CH2 C SACP OH D-3-hydroxybutyryl ACP SACP phosphoglycerate kinase ATP O H3C C acetyl ACP glyceraldehyde 3-phosphate dehydrogenase Fatty acid synthesis β-ketoacyl ACP reductase (KR) NADP+ O Pi O acetoacetyl ACP C4 CoASH CH2OPO32glyceraldehyde 3-phosphate COO- CH2OPO32glyceraldehyde 3-phosphate H3C C CH2 C SACP acetyl CoA HCOH ADP COO- O HCOH HCOH SCoA malonyl-acetyl CoA-ACP transacylase (MAT) CH2OPO321,3-bisphosphoglycerate NAD+ transketolase HC O C HCOH NADH+H+ 2+ Mg (thiamine PP) transaldolase HCOH O C OPO32- O H2C COOoxaloacetate ribose 5-phosphate CH2OPO32sedoheptulose 7-phosphate C O O NADH+H+ C CH2OPO32- CH2OPO3 xylulose 5-phosphate HCOH CH2OPO32- H3C NAD+ GDP HCOH 2- fructose 6-phosphate triose phosphate isomerase GTP HCOH glyceraldehyde 3-phosphate fructose 1,6-bisphosphate dihydroxyacetone phosphate COO- HCOH HOCH CH2OPO32- CH2OPO32- HC O HCOH CH2OH HCOH HCOH HCOH HCOH O CHO HCOH HOCH C O erythrose 4-phosphate CH2OPO32CH2OH ribose 5-phosphate isomerase C O HOCH CH2OPO32- aldolase C ribulose phosphate 3-epimerase CH2OH OH HO CH2OPO32ribulose 5-phosphate 6-phosphogluconate CHO fructose 6-phosphate phosphofructokinase-1 inhibited Mg2+ ADP 2- HCOH CH2OH CH2OPO32- fructose 6-phosphate ATP H2O C O HCOH CH2OPO32- HCOH CH2OH H fructose 1,6-bisphosphatase HCOH HCOH glucose 6-phosphate HO OH OH CH2OH CO 6-phosphogluconate dehydrogenase HCOH 2+ Mg (thiamine PP) OH Pi H lactonase transketolase HOCH phosphoglucose isomerase 2- H 6-phosphogluconoδ-lactone C O OH OH H OH HOCH O glucose 1-phosphate OH OH HO HO glucose 6-phosphate dehydrogenase NADPH + H + HCOH NADP H2O Pentose phosphate pathway UTP 2- CH2OPO32O H H ADP + H OH COO- CH2OPO32O H H glucose 6-phosphate OH phosphoglucomutase CH2OH O H NADPH + H + NADP UDP-glucose pyrophosphorylase r H H H H PP i CH2OH O H H phosphorylase r (pyridoxal 5' P) H O C CH O P O P O CH2 O N O O OH H H H H H uridine diphosphate ph glucose OH HO liver glycogen stores full C CH2OH O H 2H+ + HPO42- H 10H+ 4H+ ATP4- ADP3- Chart 26.1 Metabolism of glucose to triacylglycerol Part 3 Fat metabolism 53 ... aminotransferase isomerase fumarylacetoacetate fumarylacetoacetase pyruvate kinase NADPH+H + GDP CO2 NAD + NADH+H + ATP NAD + fumarate pyruvate lactate malate lactate dehydrogenase acetoacetate... mitochondrion via the glutamate/aspartate carrier in exchange for the import of glutamate and a proton Once in the cytosol, aspartate is transaminated by aspartate aminotransferase, and thus oxaloacetate... CH2O aconitase OOCCH fumarate FADH2 CoASH malonyl-acetyl CoA-ACP transacylase (MAT) malonyl-acetyl CoA-ACP transacylase (MAT) tricarboxylate carrier fumarase Q II malate dehydrogenase C SCoA CoASH