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Dedication In memory of Gordon Hartman (1936–2004), friend and colleague whose enthusiasm and encyclopaedic knowledge were an asset to all who knew him. ������������������� ������������� ������� ������������� Mitochondrion Inner membrane Outer membrane Intermembrane space urocanate histidine ��� ��������� ��������� ��� � 4-imidazolone- 5-propionate �2� ����������� ���������� FIGLU N 5-formimino -THF glutamate NADPH+H+ ATP ADP+Pi ���������������� NADH+H+ ��������� g������������� ������������� glutamate g-semialdehyde (P 5-C) ����������� proline FADH2 FAD ����������������� ��������� ornithine ���������������� NH4 + N 5,N 10 -methenyl-THF folate cycle THF ��������� �������������������� NAD+ NADP+ NADPH+H+ NADP+ 4H+ 10H+ 4H+ 4H+ 2H+ 4H+ 4H+ H+ Pi H+ Q C NAD+ ADP ��� NADH+H+ ATP ATP Complex �� Complex ��� Complex � H2O Pi –O2 1 2 2H+ FO F1 Respiratory chain ATP ADP H2O a-ketoglutarate glutamate aspartate alanine cysteine serine glycine pyruvate ���������������� ���������������� NAD+ NADH+H+ �������� ������ pyruvate oxaloacetate lactate malate ������ ������������� GTP GDP CO2 phosphoenolpyruvate 2-phosphoglycerate ������� 3-phosphoglycerate ���������������� ������ ���������������� ������ NADH+H+ NAD+ H2O Pi �������� ���������������� ��������� ATP ADP dihydroxyacetone phosphate ATP ADP glucose �������������� ��������� ATP ADP 1,3-bisphosphoglycerate fructose 1,6-bisphosphate fructose 6-phosphate glucose 6-phosphate ������� ������������� Pi Pi Endoplasmic reticulum Cytosol Pi a-ketoglutarate glutamate NAD+ NADH+H+ H2O ������������� ������� �������������������������� ������������� Complex �� 4H+ 2H+ 2H+ 3H+ 6H+ Complex �� H+ F1 FADH2 ATP ATP Pi Pi H+ 4H+ H2O –O2 1 2 Complex ��� 4H+ Q C FO ADP Pi H+ NADH+H+ malate oxaloacetate isocitrate a-ketoglutarate succinyl CoA succinate fumarate ������ ������������� �������� ��������� ������������� a�������������� ������������� ��������� ������� �������� CoASH H2O citrate [cis-aconitate] CoASH FAD acetyl CoA �������� ������� ADP+Pi ATP CoASH HCO3 – ��������� ������������ ���������� GTP GDP CoASH CO2 CO2 pyruvate NAD+ NAD+ NADH+H+ H2O Pi H+ NADH+H+ NAD+ NADH+H+ NAD+ CO2 H2O H2O ����������������������������� ADP ATP ����������� GTP GDP FADH2 glutamate NH4+ NADH+H+ FADH2 myristoyl CoA (C14) C12 C10 C8 C6 C4 (8) acetyl CoA palmitoylcarnitine palmitoyl Co A 2 Pi ��������������� C14 acetoacetyl CoA �������� CoASH “Ketone bodies" acetoacetyl CoA CoASH hydroxymethyl glutaryl CoA (HMGCoA) acetoacetate 3-hydroxybutyrate acetyl CoA CoASH NADH+H+ FADH2 NADH+H+ FADH2 NADH+H+ FADH2 NADH+H+ FADH2 NADH +H+ FADH2 acetyl CoA acetyl CoA H2O NAD+ NADH+H+ CoASH b-Oxidation Ketogenesis glycogen ������������������ a (1Æ4) glucose oligosaccharide (n+1 residues) ������������������ ����������������������� �����a���Æ������������� ��������� ������ uridine diphosphate glucose ����������������������������� PPi UTP a (1Æ4) glucose oligosaccharide primer (n residues) glycogen (n–1 residues) glucose 1-phosphate 2 Pi ��������������� Pi UDP NADP+ NADPH+H+ 6-phosphogluconate 6-phosphoglucono- d-lactone ������������� ������������� ������������� ������������� ������������� glyceraldehyde 3-phosphate sedoheptulose 7-phosphate erythrose 4-phosphate fructose 6-phosphate fructose 6-phosphate glucose 6-phosphate NADP+ NADPH+H+ ��������� ������������������ ������������� glyceraldehyde 3-phosphate fructose 6-phosphate glucose 6-phosphate glyceraldehyde 3-phosphate H2O CO2 ���� Pentose phosphate pathway (hexose monophosphate shunt) NADP+ NADPH+H+ b������������� �������� ������������������� b������������� �������� ������������������� enoyl ACP HCO3–+ATP H++ADP+Pi ��������������� ������������ CoASH malonyl ACP CoASH C6 malonyl CoA acetyl CoA acyl ACP C4 acetoacetyl ACP b������������� ��������� acetoacetyl ACP ���������� ������������ malonyl CoA cysteine–SH group of condensing enzyme hydroxymethyl glutaryl CoA (HMGCoA) acetoacetyl CoA mevalonate cholesterol many intermediates acetyl CoA NADP+ NADPH+H+ H2O D-3-hydroxybutyryl ACP ��������� ��������� NADP+ NADPH+H+ H2O NADH+H+ NAD+ NADP+ NADPH+H+ citrate �������������� ������� ������ ������������� oxaloacetate ADP+Pi CoASH ������������� ����� ������ ATP malate CO2 acyl carrier protein CO2 CoASH b��������������� ������������� CO2 O2 ��������������� tetrahydrobiopterin dihydrobiopterin ���������������� ��������� NADP+ NADPH+H+ a-ketoglutarate glutamate �������� ���������������� 4-hydroxyphenylpyruvate ����������� homogentisate ��������������� 4-maleylacetoacetate ��������� fumarylacetoacetate ������������������� acetoacetate phenylalanine tyrosine fumarate oxidised by extrahepatic tissues L-DOPA dopamine noradrenaline S-adenosyl- methionine S-adenosyl- homocysteine adrenaline H2O O2 CO2 O2 H2O O2 CO2 H2O ��������������������������� Glycolysis Krebs cycle ���������������������� �������������������� ���������������������� ��������������������������� ������� ��������� ������������������������ ����������������� ��������������������� �������� ������������������ ����������� ���������� �������� ������������� ������� ����������� ������������� Regulatory enzyme glutamine-PRPP amidotransferase carbamoyl phosphate synthetase II palmitoyl CoA (C16) acyl CoA dehydrogenase FAD FADH2 enoyl CoA hydratase L-3-hydroxyacyl CoA dehydrogenase L-3-hydroxyacyl CoA thiolase 3-ketoacyl CoA CoASH acetyl CoA carnitine (3) palmitate ATP CoASH PPi+AMP trans-D2-enoyl CoA long chain acyl CoA synthetase H2O NADH+H+ NAD+ pyrophosphatase inner CPT outer CPT ribulose phosphate 3-epimerase ribose 5-phosphate isomerase ribulose 5-phosphate xylulose 5-phosphate ribose 5-phosphate transketolase (thiamine PP) H2O C16 C14 C12 C10 C8 acyl carrier protein ATP ADP glycerol kinase (not in white adipose tissue) glycerol tripalmitin (triacylglycerol) palmitate esterification CO2 CO2 CO2 CO2 CO2 glycerol 3-phosphate CoASH CoASH CoASH CoASH CoASH palmitoyl ACP thio- esterase 3 H2O lypolysis hormone sensitive lipase (adipose tissue) Fatty acid synthesis CoASH CO2 NAD+ NADH+H+ HCO3 – acetyl CoA CoASH CO2 dehydrogenase CoASH NAD+ CO2 CoASH argininosuccinate lyase synthetase citrulline ornithine transcarbamoylase 2ADP+Pi 2ATP arginine urea isovaleryl CoA isobutyryl CoA methylmalonate semialdehyde propionyl CoA a-methylbutyryl CoA D-methylmalonyl CoA L-methylmalonyl CoA succinyl CoA acetyl CoA acetyl CoA CoASH dehydrogenase glutaryl CoA propionyl CoA dehydrogenase dehydrogenase acetyl CoA THF Vitamin B12 Odd numbered fatty acids ornithine NADH+H+ NAD+ CO2 CO2 CoASH NADH+H+ NAD+ CO2 NAD+ NADH+H+ NADH+H+ Pi carbamoyl phosphate NH4+ AMP+PPi ATP aspartate fumarate mutase acetoacetate carnitine shuttle carnitine shuttle arginase dehydrogenase a-ketoisocaproate a-ketoisovalerate aminotransferase aminotransferase aminotransferase a-keto-b-methylvalerate isoleucine valine leucine a-ketobutyrate threonine glycine lysine saccharopine 2 aminoadipate semialdehyde 2-aminoadipate amino- transferase a-ketoadipate carnitine shuttle N5, N10 -methylene THF Urea cycle H2O H2O CO2 H2O H2O CO2 glutamate IMP AIR PRPP fumarate aspartate ADP+Pi ATP AMP ATP ribose 5-phosphate b-5-phosphoribosylamine glycinamide ribonucleotide (GAR) formylglycinamide ribonucleotide (FGAR) FAICAR AICAR SAICAR CAIR formylglycinamidine ribonucleotide (FGAM) N10-formyl THF glycine glutamate glutamine glutamine carbamoyl phosphate carbamoyl aspartate dihydroorotate orotate OMP (orotidine monophosphate) aspartate UMP (uridine monophosphate) UDP UTP FMNH2 2ATP glutamate FMN bicarbonate GDP GTP RNA ADP ATP DNA dGTP dATP dTTP dCTP UTP CTP CDP dCDP dCMP dUMP dTMP dTDP UTP UTP THF THF N 5, N10-methenyl THF DHF ATP ADP+Pi ATP ADP+Pi ATP ADP+Pi N10-formyl THF glutamine 2ADP+Pi PPi ADP+Pi ATP N 5, N10-methenyl THF DHF (dihydrofolate) folate THF (tetrahydrofolate) N 5, N10--methylene THF N10-formyl THF N5-methyl THF H2O NADPH+H+ NADP+ NADPH+H+ NADP+ NADPH+H+ NADP+ NADPH+H+ NADP+ methionine methyl group transferred to acceptor SAM (S-adenosylmethionine) methyl transferase S-adenosylhomocysteine homocysteine cystathionine homoserine cysteine vitamin B6 homocysteine methyltransferase N5-methyl THF THF homocysteine vitamin B12 Folate cycle Methionine salvage pathway N-formylkynurenine kynurenine 3-hydroxykynurenine 3-hydroxyanthranilate 2-amino-3-carboxymuconate semialdehyde 2-aminomuconate semialdehyde 2-aminomuconate tryptophan alanine xanthurenate (yellow) NAD+ and NADP+ synthesis NH4+ formate a-ketoadipate carbamoyl phosphate synthetase I –CH3 methyl SAM Medical Biochemistry at a Glance Companion website This book is accompanied by a companion website which contains interactive Multiple-Choice Questions: www.ataglanceseries.com/medicalbiochemistry Medical Biochemistry at a Glance Dr J. G. Salway School of Biomedical and Molecular Sciences University of Surrey Guildford Surrey, UK Third edition A John Wiley & Sons, Ltd., Publication This edition first published 2012 © 2012 by John Wiley & Sons, Ltd. Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s global Scientific, Technical and Medical business with Blackwell Publishing. 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. First edition published 1996 Second edition published 2006 Second edition translations: Chinese Translation 2007 Taiwan Yi Hsien Publishing Co. Ltd Japanese Translation 2007 Medical Sciences International Ltd, Tokyo Korean Translation 2007 E*PUBLIC KOREA Co. Ltd Polish Translation 2009 Górnicki Wydawnictwo Medyczne 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. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. 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 physicians 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 Salway, J. G. Medical biochemistry at a glance. – 3rd ed. / J.G. Salway. p. ; cm. – (At a glance) Includes bibliographical references and index. ISBN-13: 978-0-470-65451-4 (pbk. : alk. paper) ISBN-10: 0-470-65451-1 (pbk. : alk. paper) 1. Biochemistry–Outlines, syllabi, etc. 2. Clinical biochemistry–Outlines, syllabi, etc. I. Title. II. Series: At a glance series (Oxford, England) [DNLM: 1. Biochemical Phenomena. QU 34] QP514.2.G76 2012 612'.015–dc23 2011024248 A catalogue record for this book is available from the British Library. Set in 9 on 11.5pt Times by Toppan Best-set Premedia Limited 1 2012 Contents 5 Contents 32 Regulation of glycolysis and Krebs cycle 72 33 Oxidation of fatty acids to produce ATP in muscle and ketone bodies in liver 74 34 Regulation of lipolysis, β-oxidation, ketogenesis and gluconeogenesis 76 Part 6 Lipids and lipid metabolism 35 Structure of lipids 78 36 Phospholipids I: phospholipids and sphingolipids 80 37 Phospholipids II: micelles, liposomes, lipoproteins and membranes 82 38 Metabolism of carbohydrate to cholesterol 84 39 VLDL and LDL metabolism I: “forward” cholesterol transport 86 40 VLDL and LDL metabolism II: endogenous triacylglycerol transport 88 41 HDL metabolism: “reverse” cholesterol transport 90 42 Absorption and disposal of dietary triacylglycerols and cholesterol by chylomicrons 92 43 Steroid hormones: aldosterone, cortisol, androgens and oestrogens 94 Part 7 Metabolism of amino acids and porphyrins 44 Urea cycle and overview of amino acid catabolism 96 45 Non-essential and essential amino acids 98 46 Amino acid metabolism: to energy as ATP; to glucose and ketone bodies 100 47 Amino acid disorders: maple syrup urine disease, homocystinuria, cystinuria, alkaptonuria and albinism 102 48 Phenylalanine and tyrosine metabolism in health and disease 104 49 Products of tryptophan and histidine metabolism 106 50 Haem, bilirubin and porphyria 108 Part 8 Vitamins 51 Fat-soluble vitamins I: vitamins A and D 110 52 Fat-soluble vitamins II: vitamins E and K 112 53 Water-soluble vitamins I: thiamin, riboflavin, niacin and pantothenate 114 54 Water-soluble vitamins II: pyridoxal phosphate (B6) 116 55 Water-soluble vitamins III: folate and vitamin B12 118 56 Water-soluble vitamins IV: biotin and vitamin C 120 Part 9 Molecular biology 57 The cell cycle 122 58 Pyrimidine metabolism 124 59 Purine metabolism 126 60 Structure of DNA 128 61 The “central dogma” of molecular biology 130 62 Organisation of DNA in chromosomes 132 63 Replication of DNA (part 1) 134 64 Replication of DNA (part 2) 136 65 DNA damage and repair 138 66 Transcription of DNA to make messenger RNA (part 1) 140 67 Transcription of DNA to make messenger RNA (part 2) 142 Preface to the third edition 7 Acknowledgements to the third edition 7 Figure key 8 SI/mass unit conversions 9 Part 1 Acids, bases and pH 1 Acids, bases and hydrogen ions (protons) 10 2 Understanding pH 12 3 Production and removal of protons into and from the blood 14 4 Metabolic alkalosis and metabolic acidosis 16 5 Respiratory alkalosis and respiratory acidosis 18 Part 2 Structure of amino acids and proteins 6 Amino acids and the primary structure of proteins 20 7 Secondary structure of proteins 22 8 Tertiary and quaternary structure and collagen 24 Part 3 Formation of ATP: oxidation and reduction reactions 9 Oxidation/reduction reactions, coenzymes and prosthetic groups 26 10 Anaerobic production of ATP by substrate-level phosphorylation, from phosphocreatine and by the adenylate kinase (myokinase) reaction 28 11 Aerobic production of ATP 30 12 Biosynthesis of ATP by oxidative phosphorylation I 32 13 Biosynthesis of ATP by oxidative phosphorylation II 34 14 What happens when protons or electrons leak from the respiratory chain? 36 15 Free radicals, reactive oxygen species and oxidative damage 38 16 Aerobic oxidation of glucose to provide energy as ATP 40 17 Anaerobic oxidation of glucose by glycolysis to form ATP and lactate 42 18 Anaerobic glycolysis in red blood cells, 2,3-BPG (2,3-DPG) and the Bohr effect 44 Part 4 Carbohydrates 19 Carbohydrates 46 20 Absorption of carbohydrates and metabolism of galactose 48 21 Fate of glucose in liver: glycogenesis and lipogenesis 50 22 Fructose metabolism 52 23 Glucose homeostasis 54 24 Glucose-stimulated secretion of insulin from β-cells 56 25 Regulation of glycogen metabolism 58 26 Glycogen breakdown (glycogenolysis) and glycogen storage diseases 60 27 Insulin signal transduction and diabetes mellitus 62 28 Diabetes mellitus 64 29 Alcohol metabolism: hypoglycaemia, hyperlactataemia and steatosis 66 Part 5 Enzymes and regulation of pathways 30 Enzymes: nomenclature, kinetics and inhibitors 68 31 Regulation of enzyme activity 70 6 Contents 68 Transcription of DNA to make transfer RNA 144 69 Transcription of DNA to make ribosomal RNA 146 70 Translation and protein synthesis 148 71 Comparison of DNA replication, DNA transcription and protein synthesis in eukaryotes and prokaryotes 150 Part 10 Diagnostic clinical biochemistry 72 Diagnostic clinical biochemistry (with Dr J. W. Wright FRCP, MRCPath) 152 Index 154 Companion website This book is accompanied by a companion website which contains interactive Multiple-Choice Questions: www.ataglanceseries.com/medicalbiochemistry Preface to the third edition The subject matter in Medical Biochemistry at a Glance is selected from the biochemistry content of First Aid for the USMLE Step 1 : the most popular guide used by students preparing for examinations. As such, it is written for medical students, but is equally accessible to students of the biomedical sciences such as biochemists, medical labo- ratory scientists, veterinary scientists, dentists, pharmacologists, phys- iologists, physiotherapists, nutritionists, food scientists, nurses, medical physicists, microbiologists and students of sports science. This book aspires to present medical biochemistry in the concise two - page format of the “ At a Glance ” series. Students who study biochemistry as a subsidiary part of their course are frequently overwhelmed by the complexity and huge amount of detail involved. Lecturers will be familiar with the anxious expression of students as they complain “ How much of this do we need to know? ” or “ Do we need to memorise all the structural formulae and the chemi- cal reactions? ” In fairness, biochemistry is a complex and heavily detailed subject. Students should have two objectives: (i) to study and understand biochemical concepts and reactions but not necessarily memorise the structural details, (ii) to prepare for examinations by determining the amount of detail required by intelligent perusal of lecture notes and past examination papers. Medical Biochemistry at a Glance is written with these two objec- tives in mind. Judicious study of the back inside cover featuring a metabolic chart including formulae and the enzymes catalysing the reactions plus the comprehensive chart on the front inside cover will enable an understanding of metabolic biochemistry. The enzymes which regulate metabolic pathways are indicated in both charts and throughout the book. In the text of the book, complex detail is subju- gated to a faint background so as to emphasise the most important aspects of the topic. However, students must familiarise themselves with the requirements of their particular examination board to deter- mine how much should be trusted to memory. Finally, the inspiration for Medical Biochemistry at a Glance has developed from my book Metabolism at a Glance . The latter is a more advanced book but the similarity of style between these two books facilitates progression to a higher level by students specialising in metabolism and disorders of metabolism. Preface and acknowledgements 7 Acknowledgements to the third edition Following discussion with my editor, it was clear this new, third edition must include a section on “Molecular Biology”: not my strong- est subject. So the start of this book was marked by a four-day trip to Cheshire visiting my friends Dr Peter Barth and his wife Jane. Peter has dedicated his career to molecular biology and so I was most for- tunate when he offered to update me in this fascinating subject. Jane provided excellent food and warm hospitality in their beautiful house. Peter’s patient, clear and authoritative tuition defined the structure of the chapters. We also made time for recreation, and together they gave me a most enjoyable, productive and unforgettable visit. Peter’s support, advice and encouragement continued through to the last moments of the final proofs. This book would not have been possible without Peter’s invaluable help. Once again I have been very fortunate to work with Elaine Leggett of Oxford Designers & Illustrators and the facilities provided by Mr Richard Corfield and his team. Elaine’s first task was to update the artwork colour scheme from the second edition to full colour. Then, with her customary aplomb and talent she rose to the challenge of interpreting my sketches for the new Molecular Biology section. At a Christmas drinks party, I met my old colleague Professor Peter Goldfarb. Inspired with Yuletide spirit, he offered help and generously gave his time, wise advice with characteristic attention to detail and constructive criticism. I am very grateful to readers who have emailed to report errors and to friends and colleagues for expert advice, especially Dr Kimberly Dawdy, Dr Lucy Elphick, Dr Anna Gloyn, Professor Keith Frayn, Mrs Rosemary James, Professor Gary John, Professor George Kass, Dr Lisa Meira, and Dr Helen Stokes. Also, I wish again to record my gratitude to those who contributed to the second edition of this book, namely: Professor Loranne Agius, Dr Wynne Aherne, Dr Beatrice Evans, Dr Martyn Egerton, Professor George Elder, Dr Janet Brown, Dr Geoffrey Gibbons, Dr Barry Gould, Dr Bruce Griffin, Professor Stephen Halloran, Professor Chris O’Callaghan, Dr Anna Saada, and Mrs Marie Skerry. Many reviewers commented on the excellent index compiled by Philip Aslett for the second edition, so I was very pleased when he agreed to help once more. My editor Martin Davies has been exceptionally supportive. He has replied to my emails with extraordinary promptness and provided every facility requested to ensure efficient completion of the work. Also, it has been a great pleasure to work with other members of a most pro- fessional Wiley-Blackwell team, especially Heather Addison, Lesley Aslett, Helen Harvey, Karen Moore, Laura Murphy, and Beth Norton. Regrettably, omissions and errors will have occurred and I would be most grateful to have these drawn to my attention. Finally, I am grateful to my wife Nicky once again for her support, and for tolerating the intrusion of publication deadlines into our social programme; also the accumulation of documents and papers associ- ated with writing this book. J. G. Salway Surrey, UK

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