Ebook High-Yield biochemistry (3rd edition): Part 1

(BQ) Part 1 book High-Yield biochemistry presents the following contents: Acid–Base relationships, amino acids and proteins, enzymes, citric acid cycle and oxidative phosphorylation, carbohydrate metabolism, lipid metabolism.

LWW-WILCOX-08-0701-0FM.qxd 1/16/09 2:18 PM High-Yield Biochemistry THIRD EDITION TM Page i LWW-WILCOX-08-0701-0FM.qxd 1/16/09 2:18 PM Page ii LWW-WILCOX-08-0701-0FM.qxd 1/16/09 2:18 PM High-Yield Biochemistry THIRD EDITION R Bruce Wilcox, PhD Professor of Biochemistry Loma Linda University Loma Linda, California TM Page iii LWW-WILCOX-08-0701-0FM.qxd 1/16/09 2:18 PM Page iv Acquisitions Editor: Susan Rhyner Managing Editor: Kelley A Squazzo Marketing Manager: Jennifer Kuklinski Project Manager: Paula C Williams Designer: Terry Mallon Production Services: Cadmus Communications, a Cenveo Company Third Edition Copyright © 2010, 2004, 1999 by Lippincott Williams & Wilkins, a Wolters Kluwer business 351 West Camden Street Baltimore, MD 21201 530 Walnut Street Philadelphia, PA 19106 Printed in United States of America All rights reserved This book is protected by copyright No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part of their official duties as U.S government employees are not covered by the abovementioned copyright To request permission, please contact Lippincott Williams & Wilkins at 530 Walnut Street, Philadelphia, PA 19106, via email at permissions@lww.com, or via website at lww.com (products and services) Library of Congress Cataloging-in-Publication Data Wilcox, R Bruce High-yield biochemistry / R Bruce Wilcox — 3rd ed p ; cm Includes index ISBN 978-0-7817-9924-9 (alk paper) Biochemistry—Outlines, syllabi, etc I Title [DNLM: Biochemistry—Outlines QU 18.2 W667h 2010] QP514.2.W52 2010 572—dc22 2008032773 DISCLAIMER Care has been taken to confirm the accuracy of the information present and to describe generally accepted practices However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication Application of this information in a particular situation remains the professional responsibility of the practitioner; the clinical treatments described and recommended may not be considered absolute and universal recommendations The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with the current recommendations and practice at the time of publication However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions This is particularly important when the recommended agent is a new or infrequently employed drug Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320 International customers should call (301) 223-2300 Visit Lippincott Williams & Wilkins on the Internet: http://www.lww.com Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST LWW-WILCOX-08-0701-0FM.qxd 1/16/09 2:18 PM Page v This book is dedicated to my father, H Bruce Wilcox, for endowing me with a passionate love for teaching, and to the freshman medical and dental students at Loma Linda University who for over 40 years have paid tuition at confiscatory rates so that I have never had to go to work LWW-WILCOX-08-0701-0FM.qxd 1/16/09 2:18 PM Page vi Preface High-Yield Biochemistry is based on a series of notes prepared in response to repeated and impassioned requests by my students for a “complete and concise” review of biochemistry It is designed for rapid review during the last days and hours before the United States Medical Licensing Examination (USMLE), Step 1, and the National Board of Medical Examiners subject exams in biochemistry Although this book provides information for a speedy review, always remember that you cannot review what you never knew vi LWW-WILCOX-08-0701-0FM.qxd 1/16/09 2:18 PM Page vii Acknowledgments Dr John Sands provided invaluable help in reviewing and editing Chapter 11, “Biotechnology,” for the first edition While preparing for the second edition, Lisa Umphrey, a third-year medical student at Loma Linda University, generously gave me access to her notations in the first edition Katherine Noyes and Daniel Rogstad, graduate students in Biochemistry at Loma Linda University, gave generously of their time and expertise in assisting with revisions to Chapter 10, “Gene Expression” and Chapter 11, “Biochemical Technology” in the second edition Daniel Rogstad assisted me again during preparation of the third edition I am also indebted to Dr J Paul Stauffer at Pacific Union College for instruction in the felicitous use of English, to P.G Wodehouse for continuing and enriching that instruction, and to General U.S Grant for providing an example of clear and laconic communication vii LWW-WILCOX-08-0701-0FM.qxd 1/16/09 2:18 PM Page viii Contents Preface vi Acknowledgments vii Acid–Base Relationships I II III IV V VI Acidic dissociation Measures of acidity Buffers Acid–base balance Acid–base disorders Clinical relevance: diabetic ketoacidosis Amino Acids and Proteins I II III IV V VI Functions of proteins Proteins as polypeptides Protein structure Protein solubility and R-groups Protein denaturation Clinical relevance Enzymes 11 I II III IV V VI VII Energy relationships 11 Free-energy change 11 Enzymes as biological catalysts 12 Michaelis-Menten equation 13 Lineweaver-Burk equation 14 Enzyme regulation 15 Clinical relevance: methanol and ethylene glycol poisoning 18 Citric Acid Cycle and Oxidative Phosphorylation I II III IV viii 19 Cellular energy and adenosine triphosphate 19 Citric acid cycle 19 Products of the citric acid cycle (one revolution) 20 Synthetic function of the citric acid cycle 20 LWW-WILCOX-08-0701-005.qxd 30 10/21/08 4:55 PM Page 30 CHAPTER Glucose 6-phosphate (G6-P) NADP+ Glucose 6-phosphate dehydrogenase NADPH + H+ 6-Phosphogluconolactone H 2O Lactonase Oxidative portion (not reversible) 6-Phosphogluconate NADP+ NADPH + H+ 6-Phosphogluconate dehydrogenase CO2 Ribulose 5-phosphate Phosphopentose isomerase Purine and pyrimidine nucleotide synthesis Phosphopentose epimerase CHO CH2OH H C OH C O H C OH HO C H H C OH H C OH CH2OPO3 2– CH2OPO3 2– Ribose 5-phosphate Xylulose 5-phosphate Transketolase Glyceraldehyde 3-phosphate (G3-P) Sedo7-P Nonoxidative portion (reversible) Transaldolase Ery4-P Transketolase Fructose 6-phosphate (F6-P) Reactions shared with glycolysis G3-P F6-P G6-P ● Figure 5-6 The pentose phosphate pathway Sedo7-P ϭ sedoheptulose 7-phosphate; ery4-P ϭ erythrose 4-phosphate; italicized terms ϭ enzyme names LWW-WILCOX-08-0701-005.qxd 10/21/08 4:55 PM Page 31 CARBOHYDRATE METABOLISM 31 C RIBOSE 5-PHOSPHATE, needed for nucleotide synthesis, can be formed from glucose 6-phosphate by either arm VII Sucrose and Lactose Metabolism A Sucrose (cane sugar) and lactose (milk sugar), the common dietary disaccharides, are digested in the small intestine and appear in the circulation as monosaccharides Some monosaccharides have specialized metabolic pathways B The enzyme sucrase in the small intestine converts sucrose to glucose and fructose The enzyme hexokinase can convert fructose to fructose 6-phosphate via ATPlinked phosphorylation in muscle and kidney Fructose enters glycolysis by a different route in the liver (Figure 5-7) a Dihydroxyacetone phosphate (DHAP) enters glycolysis directly b After glyceraldehyde is reduced to glycerol, it is phosphorylated and then reoxidized to DHAP C The enzyme lactase in the brush border of the lining of the small intestine converts lactose to glucose and galactose The enzyme galactokinase catalyzes ATP-linked phosphyrylation of galactose to galactose 1-phosphate In a series of reactions, galactose 1-phosphate becomes glucose 1-phosphate (Figure 5-8) VIII Clinical Relevance A Glycogen storage diseases are inherited enzyme deficiencies (Table 5-1) B Hereditary enzyme deficiencies in sucrose metabolism Fructokinase deficiency leads to essential fructosuria, a benign disorder Some individuals have fructose 1-phosphate aldolase deficiency, leading to hereditary fructose intolerance, characterized by severe hypoglycemia after ingesting fructose (or sucrose) Fructokinase ATP ADP Fructose 1-phosphate aldolase CH2OPO32– C O Fructose HOCH HCOH Dihydroxyacetone phosphate (DHAP) + Glyceraldehyde HCOH CH2OH Fructose 1-phosphate ● Figure 5-7 The liver pathway for fructose entry into glycolysis Italicized terms ϭ enzyme names LWW-WILCOX-08-0701-005.qxd 32 10/21/08 4:55 PM Page 32 CHAPTER Galactokinase ATP UDP-glucose: galactose 1-phosphate uridyl transferase ADP Galactose Galactose 1-phosphate Glucose 1-phosphate UDP-glucose 4-epimerase UDP-glucose UDP-galactose ● Figure 5-8 The pathway for converting galactose to glucose 1-phosphate Italicized terms ϭ enzyme names C Inherited enzyme deficiencies in lactose metabolism Lactase deficiency sometimes develops in adult life and leads to milk intolerance with bloating, flatulence, cramping, and diarrhea Galactokinase deficiency causes a mild form of galactosemia, with early cataract formation Galactose 1-phosphate uridyl tranferase deficiency causes a severe form of galactosemia with growth failure, mental retardation, and even early death TABLE 5-1 CLINICAL EFFECTS OF GLYCOGEN STORAGE DISEASES Name and Type of Disease Enzyme Defect Tissue Glycogen in Affected Cells Clinical Manifestation Von Gierke’s (type I) Glucose 6-phosphatase Liver and kidney Increased amount; normal structure Hepatomegaly, failure to thrive, hypoglycemia, ketosis, hyperuricemia, hyperlipidemia Failure of cardiac and respiratory systems, death before years of age Similar to type I, but milder Liver cirrhosis, death before years of age Pompe’s (type II) ␣-1-4 glucosidase Lysosomes, Increased amount, all organs normal structure Cori’s (type III) Anderson’s (type IV) Debranching enzyme Branching enzyme Muscle and liver Liver and spleen McArdle’s (type V) Phosphorylase Muscle Hers’ (type VI) Type VII Phosphorylase Phosphofructokinase Liver Muscle Type VIII Phosphorylase kinase Liver Increased amount; short outer branches Normal amount; very long outer branches Moderate increase in amount; normal structure Increased amount Increased amount; normal structure Increased amount; normal structure Painful muscle cramps with exercise Similar to type I, but milder Similar to type V Mild hepatomegaly, mild hypoglycemia LWW-WILCOX-08-0701-006.qxd 1/16/09 2:24 PM Page 33 Chapter Lipid Metabolism I Lipid Function A FAT (triacylglycerol, TG) Major fuel store of the body Padding to protect delicate tissues (e.g., eye, kidney) against trauma Insulation against heat loss B PHOSPHOLIPIDS These substances are key components of biological membranes and of the lipoproteins that transport lipids in blood C SPHINGOLIPIDS are also components of membranes D CHOLESTEROL Key component of membranes Precursor of bile acids, bile salts, and several hormones (e.g., adrenal cortico- steroids, sex steroids, calcitriol) II Lipid Digestion (Figure 6-1) A DIGESTION Because lipids are water insoluble, they must be emulsified so that the enzymes from the aqueous phase can digest them In the mouth and stomach, TGs are first hydrolyzed by the enzymes lingual lipase and gastric lipase, producing a mixture of fats (triacylglycerols), diacylglycerols, short-chain and medium-chain fatty acids, phospholipids, and cholesterol esters In the duodenum, dietary lipids are emulsified by bile salts, synthesized from cholesterol in the liver In the small intestine, the emulsified fats are hydrolyzed by pancreatic lipase, phospholipids by phospholipase A, and cholesterol esters by a cholesterol esterase Mixed micelles form, containing fatty acids; diacylglycerols; monoacylglycerols; phospholipids; cholesterol; vitamins A, D, E, and K (ADEK); and bile acids The micelles are absorbed into the cells of the microvilli of the small intestine, where they are further metabolized; the products are transported into the circulation a Medium-chain TGs are hydrolyzed b Medium-chain fatty acids (MCFAs, to 10 carbons) pass into the portal vein blood c Long-chain fatty acids (LCFAs, Ͼ12 carbons) are reincorporated into TG d The TGs are incorporated into chylomicrons, which pass into the lymphatics and enter the circulation via the thoracic duct 33 LWW-WILCOX-08-0701-006.qxd 34 10/21/08 4:57 PM Page 34 CHAPTER Mouth Lingual lipase Stomach Liver Bile acids Pancreatic lipase Phospholipase A Cholesterol esterase Pancreas Small intestine ● Figure 6-1 Illustration of fat digestion III Lipoprotein Transport and Metabolism A Lipids are transported to the tissues in the blood plasma primarily as lipoproteins, spherical particles with a core that contains varying proportions of hydrophobic triacylglycerols and cholesterol esters and an outer layer of cholesterol, phospholipids, and specific apoproteins B EXOGENOUS LIPID (from the intestine), except for MCFAs, is released into the plasma as chylomicrons Chylomicrons, the largest and least dense of the plasma lipoproteins, contain a high proportion of TGs Chylomicron TG is hydrolyzed to free fatty acids (FFAs) and glycerol by lipoprotein lipase on the surface of capillary endothelium in muscle and adipose tissue (Figure 6-2) The cholesterol-rich chylomicron remnants travel to the liver, where they are taken up by receptor-mediated endocytosis (RME) They are degraded in the lysosomes LWW-WILCOX-08-0701-006.qxd 10/21/08 4:57 PM Page 35 LIPID METABOLISM TG and CH from the diet 35 C Gut B48 CH E Chylomicron A Lipoprotein lipase TG CH, bile acids FFA TG Remnant A E Liver CH, CHE HDL Adipose tissue A,C,PL,CH C Peripheral tissues Fuel ● Figure 6-2 Transport of exogenous lipids in the blood A, B48, C, E ϭ apoproteins A, B48, C, E; CH ϭ cholesterol; CHE ϭ cholesterol esters; FFA ϭ free fatty acid; HDL ϭ high-density lipoprotein; PL ϭ phospholipid; TG ϭ triacylglycerol C Some FFAs are released by adipose tissue into the circulation, and they are absorbed by muscle cells for oxidation Other FFAs may be stored in adipose tissue FFAs may be bound to serum albumin, in which case they are called nonesterified fatty acids, and transported to other tissues Adipose tissue triacylglycerol is hydrolyzed by hormone-sensitive lipase to FFA and glycerol This lipase is activated by glucagon and epinephrine via the adenyl cyclase-cAMP-protein kinase A cascade D ENDOGENOUS LIPID (from the liver) is released into the blood as very-low-density lipoprotein (VLDL) (Figure 6-3) VLDL triglyceride is hydrolyzed by the enzyme lipoprotein lipase to FFAs and glycerol, yielding low-density lipoproteins (LDLs) LDLs are removed from the circulation by RME in tissues that contain LDL receptors, in part by peripheral tissues that need the cholesterol, but mostly by the liver a LDL cholesterol represses expression of the gene for HMG coenzyme A (CoA) reductase, the rate-limiting step in cellular cholesterol synthesis b LDL cholesterol down-regulates LDL receptor synthesis, in turn causing a decrease in LDL uptake High-density lipoproteins (HDLs) are synthesized by the liver HDLs function to exchange apoproteins and lipids between plasma lipoprotein particles and participate in reverse cholesterol transport a ATP-binding cassette lipid transporters (ABCA1) deliver surplus cholesterol esters from peripheral tissue cells to HDL b Scavenger receptors (SRB1) take cholesterol and cholesterol esters from HDL into liver cells LWW-WILCOX-08-0701-006.qxd 36 10/21/08 4:57 PM Page 36 CHAPTER CHE HL CETP PLTP A CH, CHE HDL CH, bile acids Gut Liver SRB1 C LDL receptor Feces TG VLDL Adipose tissue E TG CETP CHE FFA C C,E B100 E B100 LPL LDL FFA Peripheral tissues CH LDL receptor CHE ABCA1 ● Figure 6-3 Transport of endogenous lipids in the blood A, B100, C, A ϭ apoproteins A, B100, C, E; ABCA1 ϭ ATP-binding cassette lipid transporter; CETP ϭ cholesterol ester transfer protein; CH ϭ cholesterol; CHE ϭ cholesterol esters; HDL ϭ high-density lipoprotein; LDL ϭ low-density lipoprotein; LPL ϭ lipoprotein lipase; PLTP ϭ phospholipid transfer protein; SRB1 ϭ scavenger receptor; TG ϭ triacylglycerol; VLDL ϭ very-low-density lipoprotein c d IV HDL also transfers cholesterol esters to LDL This transfer is facilitated by cholesterol ester transfer protein (CETP) LDL can deliver cholesterol to the liver by receptor-mediated endocytosis Liver releases cholesterol and bile acids into the intestines Oxidation of Fatty Acids A Fatty acids are oxidized in the mitochondrial matrix The overall process is: ␤-oxidation RCH2CH2COOH Fatty acids h Citric acid cycle CH2COSCoA h CO2 ϩ H2O Acetyl CoA B Fatty acids must first be activated as their acyl CoA thioesters (Figure 6-4) LCFAs (Ͼ12) are activated in the cytosol Long-chain acyl CoAs cannot cross the mitochondrial inner membrane They are shuttled into the matrix by the carnitine transport system (see Figure 6-4) MCFAs (Ͻ12) pass directly into the mitochondria and are activated in the matrix C Fatty acyl CoAs are oxidized to CO2 and H2O by the mitochondrial ␤-oxidation system and the citric acid cycle (Figure 6-5) ␤-oxidation proceeds in a repetitive cycle until the fatty acid moiety has been completely converted to acetyl CoA LWW-WILCOX-08-0701-006.qxd 10/21/08 4:57 PM Page 37 LIPID METABOLISM ATP RCH2CH2COOH + CoASH 37 AMP + PPi RCH2CH2COSCoA Mitochondrial outer membrane Carnitine CPT-I CoASH RCH2CH2CO-Carnitine Mitochondrial inner membrane Mitochondrial matrix RCH2CH2CO-Carnitine CoASH CPT-II Carnitine RCH2CH2COSCoA ● Figure 6-4 Fatty acid activation and the carnitine shuttle for transport of long-chain fatty acids into the mitochondrial matrix CPT-I ϭ carnitine palmitoyl transferase I, CPT-II ϭ carnitine palmitoyl transferase II Each cycle of ␤-oxidation generates about 13 ATP: about ATP via the electron transport system and about ATP via the combined action of the citric acid cycle and the electron transport system The terminal three carbons of odd-numbered fatty acids yield propionyl CoA as the final product of ␤-oxidation a Propionyl CoA can be carboxylated to succinyl CoA in a three-reaction sequence requiring biotin and vitamin B12, and enter the citric acid cycle b Propionyl CoA can be used for gluconeogenesis D KETOGENESIS Some of the acetyl CoA from ␤-oxidation is metabolized to acetoacetate and ␤-hydroxybutyrate in the liver Acetyl CoA reacts with acetoacetyl CoA, forming hydroxymethylglutaryl CoA (HMG CoA) HMG CoA then splits to yield acetoacetate and acetyl CoA Acetoacetate may be reduced by NADH to ␤-hydroxybutyrate, and some of the acetoacetate spontaneously decarboxylates to acetone Extrahepatic tissues, especially heart muscle, can activate acetoacetate at the expense of succinyl CoA and burn the acetoacetyl CoA for energy The glucose-starved brain can use acetoacetate for fuel, because this substance is freely soluble in blood and easily crosses the blood–brain barrier V Fatty Acid Synthesis A This process is carried out by fatty acid synthase, a multienzyme complex in the cytosol The primary substrates are acetyl CoA and malonyl CoA (Figure 6-6) LWW-WILCOX-08-0701-006.qxd 38 10/21/08 4:57 PM Page 38 CHAPTER RCH2CH2COSCoA FAD 1.5 ATP Acyl CoA dehydrogenase FADH2 2.5 ATP RCH CH Electron transport COSCoA H2O Enoyl CoA hydratase RCHCH2COSCoA OH 3-Hydroxyacyl CoA dehydrogenase R C NAD NADH CH2COSCoA O CoASH CH3COSCoA R C O COSCoA 2CO2 + 2H2O Citric acid cycle ATP Electron transport ● Figure 6-5 The pathway for fatty acid ␤-oxidation Italicized terms ϭ enzyme names B ACETYL COA is formed in the mitochondria, principally by the enzyme pyruvate dehydrogenase Acetyl CoA is transported from mitochondria to cytosol by the citrate-malate-pyruvate shuttle (Figure 6-7) The electrons from one NADH are transferred to NADPH, which is then available for the reductive steps of fatty acid synthesis NADPH is also supplied by the pentose phosphate pathway (Figure 5-6) C MALONYL COA is formed by the biotin-linked carboxylation of acetyl CoA (see Figure 6-6) D The acetyl and malonyl moieties are transferred from the sulfur of CoA to active sulfhydryl groups in the fatty acid synthase (see Figure 6-6), where the synthetic sequence takes place (Figure 6-8) Enzyme activities in the complex carry out condensation, reduction, dehydration, and reduction Seven cycles lead to production of palmityl–enzyme, which is hydrolyzed to yield the final products, palmitate and fatty acid synthase LWW-WILCOX-08-0701-006.qxd 10/21/08 4:57 PM Page 39 LIPID METABOLISM 39 Most tissues Carbohydrate Pyruvate NAD+ + CoASH Pyruvate dehydrogenase NADH + CO2 Muscle, liver Amino acids CH3COSCoA Acetyl CoA transacetylase Acetyl CoA CO2 + ATP CH3COS Fatty acid synthase complex Acetyl CoA carboxylase CH2COS ADP + Pi COOH COOH CH2 + 2CoASH Malonyl CoA transferase C SCoA O Malonyl CoA ● Figure 6-6 Origin of the substrates for fatty acid synthesis Italicized terms ϭ enzyme names Acetyl CoA CoASH Citrate ATP + CoASH ADP Citrate OAA Acetyl CoA OAA NADH NAD Pyruvate ADP ATP + CO2 Mitochondria Pyruvate CO2 + NADPH Malate NADP Cytosol ● Figure 6-7 The citrate shuttle for transport of acetyl CoA from the mitochondrion to the cytosol E PALMITATE serves as the precursor for longer and unsaturated fatty acids Chainlengthening and desaturating systems allow synthesis of a variety of polyunsaturated fatty acids Chain-lengthening systems are present in the mitochondria and the endoplasmic reticulum C16 h C18 h C20 A desaturating system is also present in the endoplasmic reticulum NADPH ϩ Hϩ ϩ O2 h NADPϩ ϩ H2O R––CH2––CH2––(CH2)7––COOH h R––CH ϭ CH––(CH2)7––COOH LWW-WILCOX-08-0701-006.qxd 40 10/21/08 4:57 PM Page 40 CHAPTER Acyl-malonyl condensing enzyme CH3COS Cy ACP Condensation of acyl and malonyl groups to form a 3-ketoacyl group Carboxyl group of malonyl moiety released as CO2 HS Fatty acid synthase complex CO2 Fatty acid synthase complex ACP O CO2 CH3 C CH2COS CH2COS COOH NADPH 3-Ketoacyl reductase CH3CH2CH2COS Cy ACP Fatty acid synthase complex 3-Hydroxyacyl dehydratase CH2COS NADP+ H2O COOH CH2COOH COOH NADPH Malonyl CoA transferase Enoyl reductase NADP+ HS CH3CH2CH2CO S Fatty acid Cy synthase complex ACP HS Reduction, hydration, reduction: ("reverse" of β-oxidation) ACP CH3CH2CH2CO Fatty acid synthase complex S After cycles H2O Palmitate (16:0) ● Figure 6-8 The reactions of fatty acid synthesis ACP ϭ acyl carrier protein; Cy ϭ cysteinyl residue; HS ϭ sulfhydryl group This desaturating system can insert double bonds no further than nine carbons from the carboxylic acid group VI The limitations of the desaturating system impose a dietary requirement for essential fatty acids (those with double bonds Ͼ10 carbons from the carboxyl end) Lineoleic acid and linolenic acid fulfill this need The essential fatty acids serve as the beginning substrates for both the lipoxygenase and cyclooxygenase branches of the eicosanoid cascade that synthesizes leukotrienes, eicosanoates, prostaglandins, and thromboxanes Glycerolipid Synthesis This process is carried out by the liver, adipose tissue, and the intestine (Figure 6-9) A The pathways begin with glycerol 3-phosphate, which is mainly produced by reducing dihydroxyacetone phosphate with NADH LWW-WILCOX-08-0701-006.qxd 10/21/08 4:57 PM Page 41 LIPID METABOLISM 41 CH2OH HO C H CH2OPO3 2– Glycerol 3-phosphate O 2R C SCoA 2CoASH O O R2 C O H2C O C H C R1 O O CH2OPO3 2– R2 C Phosphatidate H2C O C H O CH2 C O H2O R1 C R3 O Triacylglycerol Pi CoASH O O R2 C O H2C O C H C R3COSCoA R1 CDP-choline CH2OH O CMP 1,2-Diacylglycerol O R2 C CDP-ethanolamine H2C O C H O H2C CMP R2 C O H2C O C H H2C C OPO3– OPO3– R1 CH2CH2N+(CH3)3 Phosphatidyl choline (lecithin) O O C R1 CH2CH2NH2 Phosphatidyl ethanolamine (cephalin) ● Figure 6-9 Synthesis of the major phospholipids CDP ϭ cytidine diphosphate; CMP ϭ cytidine monophosphate B Successive transfers of acyl groups from acyl CoA to carbons and of glycerol 3-phosphate produce phosphatidate, which can then be converted to a variety of lipids Triacylglycerol, which results from the transfer of an acyl group from acyl CoA Phosphatidyl choline and phosphatidyl ethanolamine, which result from transfer of the base from its cytidine diphosphate (CDP) derivative Phosphatidylserine, which results from the exchange of serine for choline Phosphatidylinositol, which results from reaction of CDP-diacylglycerol with inositol LWW-WILCOX-08-0701-006.qxd 42 VII 10/21/08 4:57 PM Page 42 CHAPTER Sphingolipid Synthesis (Figure 6-10) A The synthesis of sphingolipids, which not contain glycerol, begins with palmityl CoA and serine These substances are used to make dihydrosphingosine and sphingosine B When sphingosine is acylated on the C2ϪNH2, ceramide is produced Additional groups may be added to the C1ϪOH of ceramides VIII Cholesterol Synthesis A Cholesterol is synthesized by the liver and intestinal mucosa from acetyl CoA in a multistep process (Figure 6-11) B The key intermediate in cholesterol synthesis is HMG CoA The regulated enzyme is HMG CoA reductase, the reductant is NADPH, and the product is mevalonic acid Increasing amounts of intracellular cholesterol repress the expression of the HMG CoA reductase gene C Mevalonic acid is the precursor of a number of natural products called terpenes, which include vitamin A, vitamin K, coenzyme Q, and natural rubber CH2OH RCOSCoA CoASH CH2OH O CR H C NH2 H C NH H C OH H C OH H C C H C C H H (CH2)12 (CH2)12 CH3 CH3 Sphingosine Ceramide UDP-Gal Phosphatidyl choline UDP Gal O CH2 O H C NH CR H C OH H C C Diacylglycerol (CH3)3N+(CH2)2 O CH2 O (CH2)12 H C NH CR CH3 H C OH H C C H Galactocerebroside Ganglioside (ceramideoligosaccharide containing NAN) H (CH2)12 CH3 Sphingomyelin ● Figure 6-10 Synthesis of sphingolipids NAN ϭ N-acetyl neuraminic acid; R ϭ long-chain fatty acid; UDP-Gal ϭ UDPgalactose LWW-WILCOX-08-0701-006.qxd 10/21/08 4:57 PM Page 43 LIPID METABOLISM CH3COSCoA 43 HMG CoA reductase HMG CoA synthase Acetyl CoA HO CH3 2NADPH 2NADP+ + CoASH HO CH3 CH3COCH2COSCoA Acetoacetyl CoA HOOC COSCoA HOOC HMG CoA CH2OH Mevalonic acid Feedback inhibition Multistep process HO Cholesterol ● Figure 6-11 Sketch of cholesterol synthesis Italicized terms ϭ enzyme names D Cholesterol is also converted to the steroid hormones in the adrenal cortex, ovaries, placenta, and testes E The majority of cholesterol is oxidized to bile acids in the liver F IX 7-DEHYDROCHOLESTEROL is the starting point for synthesis of vitamin D Clinical Relevance A LIPID MALABSORPTION leading to excessive fat in the feces (steatorrhea) occurs for a variety of reasons Bile duct obstruction About 50% of the dietary fat appears in the stools as soaps (metal salts of LCFAs) The absence of bile pigments leads to clay-colored stools, and deficiency of the ADEK vitamins may result Pancreatic duct obstruction The stool contains undigested fat Absorption of ADEK vitamins is not sufficiently impaired to lead to deficiency symptoms Diseases of the small intestine (e.g., celiac disease, abetalipoproteinemia, nontropical sprue, or inflammatory bowel disease) may impair lipid absorption B HYPERLIPIDEMIAS Defective LDL receptors lead to familial hypercholesterolemia a Severe atherosclerosis and early death from coronary artery disease may occur b Treatment with HMG CoA reductase inhibitors such as lovastatin or pravastatin can lower the blood cholesterol Hypertriglyceridemia can result from either overproduction of VLDL or defective lipolysis of VLDL triglycerides Cholesterol levels may be moderately increased LWW-WILCOX-08-0701-006.qxd 44 10/21/08 4:57 PM Page 44 CHAPTER In mixed hyperlipidemias, both serum cholesterol and serum triglycerides are elevated a There are both overproduction of VLDL and defective lipolysis of triglyceriderich lipoproteins (VLDL and chylomicrons) b There is danger of acute pancreatitis C CLINICAL EXPRESSION OF DISRUPTIONS IN FATTY ACID OXIDATION Inherited defects in the carnitine transport system have widely varying symptoms a Hypoglycemia and some degree of muscle damage and muscle pain are usually present b Muscle wasting with accumulation of fat in muscle may occur in severe forms c Feeding fat with medium-chain triacylglycerols (e.g., butterfat) is helpful in some cases, because MCFAs can bypass the carnitine transport system Inherited deficiencies in the acyl CoA dehydrogenases are found, the most common being medium-chain (C6 to C12) acyl CoA dehydrogenase deficiency a Hypoketotic hypoglycemia and dicarboxylic aciduria occur, with vomiting, lethargy, and coma b This is believed to account for the condition called Reye-like syndrome D SPHINGOLIPIDOSES Sphingolipids are normally degraded within the lysosomes of phagocytic cells A number of sphingolipid storage diseases may occur (Table 6-1) as a result of deficiency of one of the lysosomal enzymes TABLE 6-1 SPHINGOLIPID STORAGE DISORDERS Disorder Accumulated Substance Clinical Manifestations Tay-Sachs disease Ganglioside GM2 Gaucher’s disease Glucocerebroside Fabry’s disease Niemann-Pick disease Globoid cell leukodystrophy (Krabbe’s disease) Metachromatic leukodystrophy Generalized gangliosidosis Sandhoff’s disease Fucosidosis Ceramide trihexoside Sphingomyelin Galactocerebroside Mental retardation, blindness, cherry-red spot on macula, death by third year Liver and spleen enlargement, bone erosion, mental retardation (sometimes) Skin rash, kidney failure, lower extremity pain Liver and spleen enlargement, mental retardation Mental retardation, myelin absent Sulfatide Ganglioside GM1 Ganglioside GM2, globoside Pentahexosylfucoglycolipid Mental retardation, metachromasia; nerves stain yellowish brown with crystal violet dye Mental retardation, liver enlargement, skeletal abnormalities Same as Tay-Sachs disease, but more rapid course Cerebral degeneration, spasticity, thick skin ...LWW-WILCOX-08-07 01- 0FM.qxd 1/ 16/09 2 :18 PM High-Yield Biochemistry THIRD EDITION TM Page i LWW-WILCOX-08-07 01- 0FM.qxd 1/ 16/09 2 :18 PM Page ii LWW-WILCOX-08-07 01- 0FM.qxd 1/ 16/09 2 :18 PM High-Yield Biochemistry. .. D.) 11 LWW-WILCOX-08-07 01- 003.qxd 12 10 / 21/ 08 4: 51 PM Page 12 CHAPTER TABLE 3 -1 NUMERICAL RELATIONSHIPS BETWEEN ⌬G0؅ AND KEQ AT 37؇C ⌬G0؅ Keq ϩ4255 ϩ2837 14 18 14 18 Ϫ2837 Ϫ4255 Ϫ7092 0.0 01 0. 01. .. LWW-WILCOX-08-07 01- 003.qxd 16 10 / 21/ 08 4: 51 PM Page 16 CHAPTER A + Competitive inhibitor B + Noncompetitive inhibitor 1/ v 1/ v No inhibitor No inhibitor Y-intercept = 1/ Vmax X-intercept = 1/ Km 1/ [S] C