Medical biochemistry with STUDENT CONSULT online access (medial biochemistry)

Medical Biochemistry FOURTH EDITION John W Baynes, PhD Carolina Distinguished Professor Emeritus, Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA Marek H Dominiczak, MD (Dr Hab Med) FRCPath FRCP (Glas) Professor of Clinical Biochemistry and Medical Humanities, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom Docent in Laboratory Medicine, University of Turku, Finland Consultant Biochemist, Clinical Biochemistry Service, National Health Service (NHS) Greater Glasgow and Clyde,, Gartnavel General Hospital, Glasgow, United Kingdom Table of Contents Instructions for online access Cover image Title page Copyright Preface Contributors Dedication Acknowledgments Abbreviations Chapter 1: Introduction Biochemistry and clinical medicine The entire biochemistry on two pages What this book is – and isn't Chapter 2: Amino Acids and Proteins Introduction Amino acids Buffers Peptides and proteins Purification and characterization of proteins Analysis of protein structure Summary Chapter 3: Carbohydrates and Lipids Introduction Carbohydrates Lipids Structure of biomembranes Summary Chapter 4: Blood and Plasma Proteins Introduction Formed Elements of Blood Plasma Proteins The Acute Phase Response and C-Reactive Protein Clinical Tests: Biomarkers Summary Chapter 5: Oxygen Transport Introduction Characteristics of mammalian globin proteins Allosteric Modulation of the Oxygen Affinity of Hemoglobin Selected Topics Summary Chapter 6: Catalytic Proteins – Enzymes Introduction Enzymatic Reactions Enzyme Kinetics Use of the Lineweaver–Burk and Eadie–Hofstee plots Mechanism of Enzyme Action Enzyme Inhibition Regulation of Enzyme Activity Enzymatic Measurement of Blood Glucose Summary Chapter 7: Hemostasis and Thrombosis Introduction Hemostasis The vessel wall Platelets and platelet-related bleeding disorders Coagulation Fibrinolysis Summary Chapter 8: Membranes and Transport Introduction Types of transport processes Examples of transport systems and their coupling Summary Chapter 9: Bioenergetics and Oxidative Metabolism Introduction Oxidation as a source of energy Free energy Conservation of energy by coupling with adenosine triphosphate Mitochondrial synthesis of adenosine triphosphate from reduced coenzymes The mitochondrial electron transport system Transfer of electrons from NADH into mitochondria Synthesis of adenosine triphosphate – the chemiosmotic hypothesis Inhibitors of oxidative metabolism Regulation of oxidative phosphorylation Summary Chapter 10: Digestion and Absorption of Nutrients: The Gastrointestinal Tract Introduction Water and electrolyte handling in the gastrointestinal tract Digestion Digestion and absorption of carbohydrates Digestion and absorption of lipids Digestion and absorption of proteins Summary Chapter 11: Vitamins and Minerals Introduction Fat-soluble vitamins: A, D, E, K Water-soluble vitamins B, C Minerals Trace elements Summary Chapter 12: Anaerobic Metabolism of Glucose in the Red Blood Cell Introduction The erythrocyte Glycolysis The splitting stage of glycolysis The yield stage of glycolysis – synthesis of ATP by substrate-level phosphorylation Fermentation Regulation of glycolysis in erythrocytes Characteristics of regulatory enzymes Synthesis of 2,3-bisphosphoglycerate (2,3-BPG) The pentose phosphate pathway Summary Chapter 13: Carbohydrate Storage and Synthesis in Liver and Muscle Introduction Structure of glycogen Pathway of glycogenesis from blood glucose in liver Pathway of glycogenolysis in liver Hormonal regulation of hepatic glycogenolysis Mechanism of action of glucagon Mobilization of hepatic glycogen by epinephrine Glycogenolysis in muscle Regulation of glycogenesis Gluconeogenesis Summary Chapter 14: The Tricarboxylic Acid Cycle Introduction Functions of the tricarboxylic acid cycle Pyruvate carboxylase The pyruvate dehydrogenase complex Enzymes and reactions of the tricarboxylic acid cycle Energy yield from the tricarboxylic acid cycle Anaplerotic (‘building up’) reactions Regulation of the tricarboxylic acid cycle Summary Chapter 15: Oxidative Metabolism of Lipids in Liver and Muscle Introduction Activation of fatty acids for transport into the mitochondrion Oxidation of fatty acids Ketogenesis – a metabolic pathway unique to liver Summary Chapter 16: Biosynthesis and Storage of Fatty Acids Introduction Fatty acid synthesis Fatty acid elongation Desaturation of fatty acids Essential fatty acids Storage and transport of fatty acids: synthesis of triacylglycerols Regulation of total body fat stores Summary Chapter 17: Biosynthesis of Cholesterol and Steroids Introduction The Cholesterol Molecule Free and esterified cholesterol Intestinal absorption of cholesterol Biosynthesis of cholesterol Bile acids Steroid hormones Vitamin D3 Summary Chapter 18: Lipoprotein Metabolism and Atherogenesis Introduction signal cascades, 543, 544f secretory granules, 86 seizures, 85b selected reaction monitoring (SRM), 480 selectins, 505 selenium, 139–140, 491b selenocysteine, 249b, 491 self-antigens, 508 self-tolerance, 500 sensor kinases, 580 sepsis, muscle loss during, 255b serine, 7, 12 serine proteases, 59–60, 60f serotonin (5-hydroxytryptamine), 71, 560, 560b serum, chemical measurements performed on, 31 serum calcium, 345 serum creatinine, 317 serum electrophoresis, 39 serum urea measurements, 239b, 317 short-chain fatty acids (SCFA) produced in large bowel from undigested carbohydrates, 121b reabsorption, combined with bicarbonate secretion, 115 sialic acid, 362 synthesis with amino sugars, 362f sickle cell disease (SCD), 51 anemia, 442b, 613b vasoocclusive crises, 52b signaling cascades amplification of signals initiated by receptor binding, 543, 544f cell cycle, 574–577 signal transduction, 1–2 SILAC labeling, quantitative mass spectrometry, 482f single nucleotide polymorphisms (SNPs), 471 sinusoids, 393 sitosterolemia, 88 skeletal system, 343 muscle, 253t, 256f sliding filament model, muscle contraction, 255, 256f small bowel, 115, 348 Smith–Lemli–Opitz syndrome, 211b smoking, 491 snake venoms, 89 sodium, 135–136 co-transporters, 113 distribution, 321f electroneutral and electrogenic transport, 113 homeostasis, 328 maintenance of gradients across cell membrane, 321 osmolality, 323–324 reabsorption, 311, 313f See also Na+/K+–ATPase sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), 14f, 16 sodium-potassium ATPase, Na+/K+–ATPase (sodium-potassium adenosine triphosphatase) somatostatin, 531–532 SOS (guanine nucleotide exchange factor), 575–577 specializd functions of, tissues, serotonin specific reuptake inhibitors (SSRIs), 558 spectrin, 29 sphingolipidoses, 372b sphingolipids, 27, 372–374 sphingomyelin, 373–374 sphingosine, structure and biosynthesis, 373–374 spironolactone, 313 spleen, 504 enlargement, 72 spongiform encephalopathy, 19 squalene, 203, 203f stamina, 259 starch, 21, 116–118 Stargardt disease, 88 starvation, gluconeogenesis in, 186–188 statins, 207, 208b, 234 steatorrhea, 124 steatosis, liver, 400f See also fatty liver stereochemistry, amino acids, steroid hormones, 209–212 actions in female, 530–531 actions in male, 528–530 androgens, 211 biosynthesis, 210–211, 525f cell membranes, traversing, 536 corticosteroids, 211 elimination, 212 estrogens, 212 intracellular receptors, 212, 538 local metabolism, 516 mechanism of action, 212 structure and nomenclature, 210f See also cholesterol steroidogenesis, 210–211 steroid receptors, 457–459 gene family, 460b organization, 459 similarity between, 459f thyroid hormone receptors, 460b steroids, 24 See also steroid hormones steroid secretion disorders, 531 steroid synthesis abnormalities, 212b sterol-regulated transcription factors, 207f sterol regulatory element-binding proteins (SREBPs), 205–207 stomach digestive function, 115b electrolytes secreted by, 111–115 protein digestion, 123 proton pump in, 90, 91b strength training, 262 stress hyperglycemia induced by, 277b metabolism during, 275–276, 277f subcutaneous fat, 305 substance P, 562–563 substrate-level phosphorylation, 145–147 adenosine triphosphate synthesis by, 145–147 succinate, 100 succinate dehydrogenase, 178 succinyl-CoA, 186f succinyl-CoA synthetase, 177–178 sugars attached to specific amino acids in proteins, 353–355, 354f cyclization of, 22 dietary, 357–358 examples, found in human tissues, 24f and glucose, 357 See also glucose interconversions, 357–358 nucleoside metabolism pathways, 359–362 simple, nomenclature and structure, 21–22 sulfate donors, lipid synthesis, 371f sulfite oxidase deficiency, 13 sulfonamides, 33 sulfonylureas, 288–289 sulfur-containing amino acids, superoxide, formation, 488f sympathetic nervous system (SNS), 557 symport transport processes, 87 synaptic transmission, 567–571 catecholamine, 568–569 cholinergic, 568 GABA-ergic, 570 glutamatergic, 569–570 ion channels, 570–571 types of synapse, 568 syndrome of inappropriate antidiuretic hormone secretion (SIADH), 329 systemic lupus erythematosus (SLE), 508 T Tangier disease, 88 target analysis, metabolite, 484 Tay–Sachs disease, 375t T cells and antigen-presenting cells, 504–505 CD4 T helper sub sets, 506 cytotoxic T cells, and CD8+, 507 response, 506–507 T cell antigen receptor (TCR), 501–502 TH1 and TH2 cells, 506–507 TH17 cells, 507 T lymphocytes, 504 T regulatory (T Reg) cells, 507 telomeres, 421–422, 599b testes, 210 actions of FSH and LH on, 528 testosterone biochemical actions in male, 528 clinical disorders of secretion in male, 528–530 deficiency, 528 mechanism of action, 529f tetrodotoxin, 89 β-thalassemia, 50 thiamine (vitamin B1), 130 deficiency, 130, 173 thiazide, 313 thiazolidinediones, 289 thiokinase, 183f threonine, 7, 12 thrombin, 31, 77–79 antithrombin deficiency, 79b and atherosclerosis, 232 formation, 68–70 generation, 76 generation curve, 78f hemostasis, role in, 77 inhibitors, 77–78 prevention of excessive formation, 78–79 thrombin clotting time (TCT), 74, 77 thrombocytes See platelets thrombocytopenia, 72 thromboelastography (TEG), 76 thromboelastography trace, 76f thrombosis antithrombotic treatment, 80b arterial, 68, 71–72 clinical relevance, 68 deep vein thrombosis, 80b prevention, 78–79 venous, 68 See also hemostasis thromboxane A2, 71, 71b thromboxane synthase inhibitors, 72 thymic education, 500 thymidylate synthase, 415b thymine dimer, 425f thyroid gland clinical disorders of function, 523 thyroid hormones biochemical actions, 522–523 biosynthesis, 522f intracellular receptors, 538 regulation of oxidative phosphorylation, 110 resistance syndromes, 523b thyroxine (T4), 521–522 transporters, 523b tri-iodothyronine (T3), 521–522 See also hormones thyrotropin-releasing hormone (TRH), 520–521 thyrotropin-stimulating hormone (TSH), 521 thyroxine (T4), 521–522 thyroxine-binding globulin (TBG), 39 ticlopidine, 72 TIM (translocase in inner mitochondrial membrane), 98 tissue engineering and extracellular matrix, 391b and muscle replacement, 260–261 tissue factor, 75–77 tissue factor pathway inhibitor (TFPI), 79 tissues hormone action, 515–516 specialized functions, vitamins stored in, 126 tissue-type plasminogen activator (tPA), 79–80 titin, 253–254 Tolerable Upper Intake Level (UL), 305 Toll-like receptors (TLR), 499 ligands and cellular distribution, 500t TOM (translocase in outer mitochondrial membrane), 98 tooth decay, and glycolysis, 148b total parenteral nutrition, 303 trace elements, 2, 126, 137–140, 300 transaldolase, 152 transaminases, 401 abnormal, 402b transamination, amino acids, 238 transcription, ribonucleic acid, 432–435, 433f transcription factors gene expression, 456–457 gene induction, 270 sterol-regulated, 207f transcriptome studies, 466, 475 transcriptomics, and gene expression, 471–473 transfer proteins, and enzymes, 218–219 transferrin, 33, 39, 137 transfer RNAs (tRNAs), 429–430, 430f transketolase, 152 transmembrane proteins, 28–29 trans-methylglutaconate shunt, 205b transport proteins, 33t, 133b transthyretin, 39 triacylglycerols (triglycerides), 24–26, 121, 197–198, 214, 264 fatty acids, storage and transport, 197–198 tricarboxylic acid cycle (TCA), 2, 170–181, 242f amphibolic nature, 171f anaplerotic (‘building up’ reactions), 179 energy yield, 179 and enzymes, 175–178 functions, 170–172 interconversion of fuels and metabolites, 170 malonate block, 178b metabolic defects, 172 regulation, 180–181 tricyclic antidepressants (TCAs), 558 triglycerides, 24, 222, 235 See also triacylglycerols tri-iodothyronine (T3), 521–522 trimeric proteins, 13 trioses, structure, 21f tropomyosin, 253 troponins, 253 trypanosomes, variable surface antigens, 373b trypsin, 18, 55f, 60, 63 tryptophan, 6–7, 12, 245, 560 tuberous sclerosis complex (TSC), 588 tumor cells, glycolysis in, 149b tumor necrosis factor (TNF), 497 2D-differential gel electrophoresis (DIGE), 18 two-dimensional gel electrophoresis (2D-PAGE), 16–19, 478–479 type I diabetes, 278, 279t, 287–288 type II diabetes, 278–279, 279t drug therapy, 288–289 obesity, 278–279, 303 tyrosine, 6–7, 12 tyrosine hydroxylase, 559b U ubiquitin, 395, 450f ubiquitination, 477 ubiquitin-proteasome system, protein degradation, 395 UDP galactose 4-epimerase, 358 uridine diphosphoglucuronic acid (UDP-GlcUA), 359–360 ulceration, stomach, 115 ultraviolet radiation aromatic amino acids, 7f and vitamin D synthesis, 345–346 uncouplers/uncoupling proteins (UCPs), 106, 107f uniport transport processes/uniporters, 84–85, 87 uniquinone See coenzyme Q10 unsaturated fatty acids, 24, 185, 297 urea cycle and ammonia, 395 enzymes, 242t regulation, 243–244 sources of nitrogen atoms in, 240f and tricarboxylic acid cycle, 242f urea synthesis, 242t uric acid excess of, causing gout, 414b metabolism, 408–411 sources and disposal, 408–410 uridine diphosphate (UDP), 397 uridine monophosphate (UMP), 411 uridine triphosphate (UTP), 357–358 urinary steroids metabolites, alteration in pattern, 212b separation, mass spectrometry, 213f urinary-type plasminogen activator (uPA), 80 urine alkaptonuria (black urine disease), 248–249 calcium excretion, 348 creatinine concentration, dilution, assessment, 260b formation, 310–311 glucose in, 286–287 ketone bodies in, 188b maple syrup urine disease (MSUD), 249 urine protein electrophoresis, 39 V vaccination, 509–511 valine, 6, 51 valinomycin, 83 vanadium, 140 varicella-zoster (VZV), 64 vascular endothelial growth factor (VEGF), 439, 545 vascular injury coagulation factors, activating, 68–70 diabetes mellitus, 276–278 platelet-fibrin plug formation, 70–71 vascular wall, 230 vasoconstriction/vasodilatation, chemical mediators, 71b vasoocclusive crises, sickle cell, 52b vasopressin, 329–330, 329f V-ATPase, 86 voltage-dependent Ca2+ channels (VDCCs), 88, 89f, 90 ventilation, 336–337 verapamil, 89 very low-density lipoprotein (VLDL), 197, 219–220, 224 visceral fat, 305 vision mechanism, 571–572 Vitamin A conversion to retinol, 127 deficiency, presentation as night blindness, 127 storage in liver, 127 structure, metabolism and function, 127f toxicity, 128 vitamin B1 (thiamine), 130 vitamin B2 (riboflavin), 56, 130 vitamin B3 (niacin), 41–42, 130–131 vitamin B6 (pyridoxine), 131 vitamin B12 (cobalamin), 131–133, 132f deficiency, causing pernicious anemia, 132–133 and folate, 133–134 heme structure, 131 intrinsic factor requirement, 131–132 supplementation, 134 transport proteins, 133b vitamin C deficiency effects, 71–72, 134–135 structure and synthesis, 134f supplementation, 135 vitamin D disorders of metabolism, 350 calcidiol as main liver storage form, 346 calcitriol, as active form, 346–347 deficiency effects, 128 metabolism, 348f, 350 requirement for, 128 synthesis, 345–346 toxicity, 128, 350 vitamin D3, 212 vitamin D-binding protein (DBP), 345–346 vitamin E (tocopherol) as antioxidant, 128, 492f malabsorption, 128–129 structure, 128f vitamin K antagonists, 76 blood clotting, necessary for, 129 carboxylation of glutamate residues, 129f deficiency, causing and bleeding disorders, 76–77, 129 inhibitors of action, 130 oral antagonists, 77 in premature infants, 129 vitamins biotin, 131 fat-soluble, 126–130 folate See folic acid/folate measurement, 300 and metabolism, panthothenic acid, 134 storage in tissues, 126 supplementation, 134–135 toxic in excess, 126, 128 water-soluble, 126, 130–135 See also minerals Vmax (maximum velocity of an enzymatic reaction) of an enzyme estimating, 58–59 voltage-dependent Ca2+ channels (VDCCs), 88, 89f, 90 vomiting fluid and electrolyte loss, 113b metabolic alkalosis, 341b Von Gierke's disease, 157b von Willebrand disease, 72 vWF (ligand), 73b W warfarin, 33 wasting syndromes, muscle, 260b water daily balance, 325f excess and deficit, 330 reabsorption, 311 renal handling, 313f and sodium metabolism, 330f water and electrolyte homeostasis, 320–331 body water compartments, 320–323 integration of water and sodium homeostasis, 329–331 oncotic and hydrostatic pressures, 324f osmolality, 323–324 potassium, 325 renin–angiotensin system, 325–329 water redistribution caused by changes in osmolality, 321f water and electrolytes causes of loss, 113b handling of in gastrointestinal tract, 111–115 homeostasis See water and electrolyte homeostasis transport of in intestine, mechanisms, 113–115 weight loss programs, 188b, 303, 304b See also low-carbohydrate diets Wilson's disease, 34b, 88b, 405 work, mobilization of fuels during, 188 X X-chromosome inactivation, 464b X-ray crystallography, 12, 19 xylulose-5-phosphate, 152 Y yeast, anaerobic glycolysis in, 148f Z Zellweger syndrome, 88, 185 zinc, 137–138 zinc finger motif, gene expression, 457–459 Zollinger–Ellison syndrome, 124 zymogens, 63 in hemophilia, 64b in digestion, 116 Instructions for online access Thank you for your purchase Please note that your purchase of this Elsevier eBook also includes access to an online version Please click here (or go to http://ebooks.elsevier.com) to request an 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Biochemistry and Medical Humanities, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom Docent in Laboratory Medicine, University of Turku, Finland Consultant Biochemist,... Clinical Biochemistry and Medical Humanities College of Medical, Veterinary and Life Sciences, University of Glasgow, UK Docent in Laboratory Medicine University of Turku, Finland Consultant Biochemist