Metabolism at a Glance

Metabolism at a Glance J.G.Salway Senior Lecturer in Medical Biochemistry School of Biological Sciences University of Surrey Guildford, UK

FOREWORD BY

D.K. Granner

SECOND EDITION

b

Blackwell Science

© 1994, 1999 by Blackwell Science Ltd Editorial Offices: Osney Mead, Oxford OX2 0EL 25 John Street, London WC1N 2BL 23 Ainslie Place, Edinburgh EH3 6AJ 350 Main Street, Maiden MA 02148 5018, USA 54 University Street, Carlton Victoria 3053, Australia 10, rue Casimir Delavigne 75006 Paris, France

Other Editorial Offices: Blackwell Wissenschafts-Verlag GmbH Kurfürstendamm 57 10707 Berlin, Germany Blackwell Science KK MG Kodenmacho Building 7-10 Kodenmacho Nihombashi Chuo-ku, Tokyo 104, Japan First published 1994 Reprinted 1995, 1996, 1998 Second edition 1999 Set by Oxford Designers & Illustrators, Oxford Printed and bound in Great Britain at the Alden Press Ltd, Oxford and Northampton The Blackwell Science logo is a trade mark of Blackwell Science Ltd, registered at the United Kingdom Trade Marks Registry

The right of the Author to be identified as the Author of this Work has been asserted in accordance with the 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 copyright owner. A catalogue record for this title is available from the British Library ISBN 0-632-05274-0 Library of Congress Cataloging-in-publication Data Salway, J.G. Metabolism at a glance/J.G. Salway—2nd ed. p. cm. Includes bibliographical references and index. ISBN 0-632-05274-0 1 Metabolism. I. Title QP171.S1185 1999 616.3'9—dc21 for Library of Congress 98-48798 CIP

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Contents 10 Metabolism of glucose to fat (triacylglycerol) 28 The importance of fat Chart 10.1: The flow of metabolites when glucose is converted to triacylglycerol Diagram 10.1: Insulin and fat synthesis

Foreword 8 Preface 9 1 Introduction to metabolic pathways 10 Metabolic charts Chart 1.1: Subcellular distribution of metabolic pathways 2 Biosynthesis of ATP I: ATP, the molecule that powers metabolism 12 How living cells conserve energy in a biologically useful form Chart 2.1: The biosynthesis of ATP The 'hydrogen carriers' NAD+ and FAD ATP/ADP translocase The ATP molecule has two phosphoanhydride bonds which provide the energy for life 3 Biosynthesis of ATP II: mitochondrial respiratory chain Proton extrusion Stoichiometry of ATP synthesis P/O ratios: 'traditional' integral and 'modern' non-integral values Inhibitors of the respiratory chain Interference with the flow of electrons Interference with the flow of protons (H+) Some other compounds which affect the respiratory chain

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4 The oxidation of cytosolic NADH+H+: the malate/aspartate shuttle and the glycerol phosphate shuttle 16 Oxidation of cytosolic NADH+ H+ 5 Metabolism of glucose to provide energy The importance of insulin in glucose transport

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6 Metabolism of one molecule of glucose yields 31 (or should it be 38?) molecules of ATP 20 Chart 6.1: Oxidation of glucose yields 38 ATP molecules assuming the traditional P/O ratios of 3 for NADH+H+ and 2 for FADH2 The net yield is 36 ATP molecules in insects Chart 6.2: Oxidation of glucose yields 31 ATP molecules assuming the 'modern' P/O ratios of 2.5 for NADH+H+ and 1.5 for FADH2 7 Metabolism of glucose to glycogen 22 Glycogen is stored in the fed state Chart 7.1: An overview of glycogen synthesis (glycogenesis) Glycogen as a fuel reserve Diagram 7.1: Glycogen, a molecule that is well designed for its function 8 Anaerobic metabolism of glucose and glycogen to yield energy as ATP 24 Anaerobic glycolysis Chart 8.1: Glucose is metabolized to lactate ATP yield by anaerobic metabolism Physiological and clinical relevance Diagram 8.1: The Cori cycle—muscle/liver The Cori cycle—red blood cells/liver 9 2,3-Bisphosphoglycerate (2,3-BPG) and the red blood cell 26 2,3-BPG helps to unload oxygen from haemoglobin Chart 9.1: The 2,3-BPG shunt in red blood cells (Rapoport-Luebering shunt) Physiological significance of 2,3-BPG Importance of 2,3-BPG in medicine Myoglobin Diagram 9.1: Transport of oxygen from the red blood cell to the mitochondrion for use in oxidative phosphorylation

11 Metabolism of glucose to fatty acids and triacylglycerol 30 Chart 11.1: Synthesis of triacylglycerols from glucose Diagram 11.1: Activation of acetyl CoA carboxylase by citrate in vitro 12 The pentose phosphate pathway and the production of NADPH+H+ 32 The pentose phosphate pathway Chart 12.1: The pentose phosphate pathway Regulation of the pentose phosphate pathway Glucose 6-phosphate dehydrogenase deficiency Favism 13 The pyruvate/malate cycle and the production of NADPH+H+ 34 The pyruvate/malate cycle Chart 13.1: The pyruvate/malate cycle The relative contributions of the pentose phosphate pathway and the pyruvate/malate cycle to the provision of NADPH+H+ for fatty acid synthesis 14 Mammals cannot synthesize glucose from fatty acids 36 Chart 14.1: In mammals, two molecules of carbon dioxide are evolved when acetyl CoA is oxidized in Krebs cycle Chart 14.2: The glyoxylate cycle enables germinating seeds to synthesize sugars from fat ß-Oxidation in plants 15 Metabolism of triacylglycerol to provide energy as ATP 38 Fatty acids are oxidized and ATP is formed Chart 15.1: The oxidation of fatty acids with energy conserved as ATP 16 The ornithine cycle for the production of urea: 'the urea cycle' 40 The origins of the nitrogen used for urea synthesis Chart 16.1: Nitrogen, in the form of ammonium ions or glutamate, is used for urea synthesis Regulation of the urea cycle Disorders of the urea cycle Creatine and creatinine The purine nucleotide cycle 17 Biosynthesis of the non-essential amino acids Tyrosine Serine, glycine and cysteine Aspartate and asparagine Glutamate, glutamine, proline and arginine

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18 Catabolism of amino acids I 44 Dietary protein as a source of energy in the fed state Metabolism of muscle protein during starvation or prolonged exercise Catabolism of the branched-chain amino acids (BCAAs) Chart 18.1: Formation of alanine and glutamine by muscle The ketogenic amino acids leucine and isoleucine as an energy source 19 Catabolism of amino acids II

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20 Metabolism of amino acids to glucose in starvation and during the period immediately after refeeding 48 In liver, the switch from gluconeogenic mode to glycolytic mode in the early fed state is a slow process Starvation The early fed state

21 Metabolism of protein to fat 50 Chart 21.1: Metabolism of amino acids to triacylglycerol Esterification of fatty acids to triacylglycerols 22 Disorders of amino acid metabolism Phenylketonuria Albinism Alkaptonuria Type I tyrosinaemia Nonketotic hyper glycinaemia Histidinaemia Maple syrup urine disease

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23 Amino acid metabolism, folate metabolism and the '1carbon pool' I: purine biosynthesis 54 The '1carbon pool' Amino acids and the '1carbon pool' Amino acid metabolism and purine synthesis Biosynthesis of purines Vitamin B12 and the 'methylfolate trap' 24 Amino acid metabolism, folate metabolism and the '1 carbon pool' II: pyrimidine biosynthesis 56 Amino acid metabolism and pyrimidine biosynthesis Conversion of UMP to UTP and GTP Formation of deoxycytidine triphosphate (dCTP) and deoxythymidine triphosphate (dTTP) Cancer chemotherapy Salvage pathways for the recycling of purines and pyrimidines LeschNyhan syndrome The antiviral drug AZT (azidothymidine) 25 Porphyrin metabolism, haem and the bile pigments 58 Haem biosynthesis Catabolism of haem to bilirubin 26 Glycogen metabolism I 60 The different roles of glycogen in liver and muscle The metabolic demands made on glycogen metabolism Glycogen metabolism: an overview Glycogen metabolism in liver Liver glycogen storage diseases 27 Glycogen metabolism II 62 Glycogen metabolism in skeletal muscle The glycogenolysis cascade Inactivation of glycogen synthesis Muscle glycogen storage diseases 28 Glycogen metabolism III: regulation of glycogen breakdown 64 Hormonal control: the role of adrenaline and glucagon in the regulation of glycogenolysis Diagram 28.1: Regulation of glycogenolysis Roles of protein kinase A in regulating glycogenolysis Phosphorylase kinase Properties of glycogen phosphorylase Protein phosphatase inhibitor1 29 Glycogen metabolism IV: regulation of glycogen synthesis 66 Hormonal control: the role of insulin in the regulation of glycogen synthesis Protein phosphatases Diagram 29.1: Regulation of glycogen synthesis Properties of glycogen synthase Role of glucose in the inhibition of phosphorylase in liver 30 Regulation of glycolysis 68 The regulatory mechanisms for glycolysis in liver and muscle are different Chart 30.1: The regulatory stages in glycolysis The 'Pasteur effect'

31 Regulation of Krebs cycle 70 Krebs cycle—the central junction of metabolism Regulation of the pyruvate dehydrogenase (PDH) complex Diagram 31.1: Regulation of PDH by phosphorylation and dephosphorylation Isocitrate dehydrogenase (ICDH) The purine nucleotide cycle Debating Forum. Krebs cycle: is it time to change the name of this bedrock of metabolism ? 32 Regulation of gluconeogenesis 72 Gluconeogenesis maintains the blood glucose concentration during fasting and starvation Chart 32.1: Regulation of gluconeogenesis Hormonal regulation of gluconeogenesis Regulatory enzymes 33 Regulation of fatty acid oxidation I: mobilization of fatty acids from storage in adipose tissue 74 Lipolysis in adipose tissue Mobilization of fatty acids: the triacylgfycerolfatty acid cycle 34 Regulation of fatty acid oxidation II: the carnitine shuttle 76 Transport of activated fatty acids into the mitochondrial matrix by the carnitine shuttle is inhibited by malonyl CoA in liver Availability of the coenzymes FAD and NAD+ for βoxidation The acyl CoA dehydrogenases Δ2enoyl CoA hydratases 3hydroxyacyl CoA dehydrogenases 3oxoacyl CoA thiolases (ketothiolases) Medium chain acyl CoA dehydrogenase (MCAD) deficiency Glutaric acidurias 35 The ketone bodies 78 The misunderstood 'villains' of metabolism Chart 35.1: Ketogenesis Diagram 35.1: Fatty acids are mobilized from adipose tissue for ketogenesis in the liver 36 Ketone body utilization 80 The ketone bodies are an important fuel for the brain during starvation ATP yield from the complete oxidation of D3hydroxybutyrate 37 βOxidation of unsaturated fatty acids Chart 37.1: βOxidation of linoleic acid What about the epimerase reaction? Fatty acid nomenclature

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38 Peroxisomal βoxidation 84 Mitochondria are not the only location for βoxidation Chart 38.1: Chainshortening of verylongchain fatty acids by peroxisomal βoxidation Peroxisomal βoxidation of unsaturated fatty acids and the 'trifunctional' enzyme Adrenoleukodystrophy and Lorenzo's Oil 39 Elongation and desaturation of fatty acids 86 Elongation of fatty acids by the endoplasmic reticulum pathway Desaturation of fatty acids Diagram 39.1: The desaturation of palmitoyl CoA to form palmitoleoyl CoA Elongation of shortchain fatty acids occurs in mitochondria Essential fatty acids Is there a Δ4desaturase? 40 Cholesterol, bile acids and the steroid hormones Cholesterol: friend or foe? Biosynthesis of cholesterol SmithLemliOpitz (SLO) syndrome The bile acids (salts) The steroid hormones

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41 Metabolism of ethanol 90 Ethanol is metabolized by three enzyme systems Metabolism of acetaldehyde The biochemical effects of ethanol 42 Sorbitol, galactitol, glucuronate and xylitol 92 Chart 42.1: Sorbitol, the dietary (exogenous) friend but endogenous foe Chart 42.2: Galactose and galactitol metabolism Chart 42.3: Glucuronate and xylitol metabolism 43 Fructose metabolism 94 Fructose does not need insulin to enter muscle cells Metabolism of fructose by the liver Metabolism of fructose by muscle Dangers of intravenous fructose Inborn errors of metabolism Fructose enhances glucose utilization by causing the translocation of glucokinase from the hepatocyte nucleus to the cytosol 44 Biochemistry of sport and exercise Anaerobic ATP production Aerobic ATP production

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45 Diabetes I: insulin-stimulated glycogen synthesis—signal transduction 98 A brief diversion into oncogenes and cancer Insulin-stimulated glycogen synthesis: PDK/PKB hypothesis Insulin-stimulated glycogen synthesis: MAP kinase hypothesis Insulin-stimulated glucose uptake 46 Diabetes II: metabolic changes in Type 1 diabetes Hyperglycaemia and ketoacidosis in diabetes Metabolism of triacylglycerol in diabetes Metabolism of protein and amino acids in diabetes Metabolism of glucose and glycogen in diabetes

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47 Diabetes III: Type 1 diabetes, Type 2 diabetes, MODY and pancreatic ß-cell metabolism 102 Type 1 diabetes Type 2 diabetes MODY (maturity-onset diabetes of the young) The biochemical aetiology of Type 2 diabetes ß-cell metabolism Candidate genes which may cause abnormal ß-cell metabolism resulting in diabetes 48 Diabetes IV: Type 2 diabetes and insulin resistance in muscle and adipose tissue 104 The insulin does not work properly Insulin resistance in skeletal muscle Insulin resistance in adipose tissue 49 Diabetes V: Type 2 diabetes and insulin resistance in liver 106 Insulin signalling Hyperlipidaemia Increased hepatic glucose output by liver Hypothesis for the pathogenesis of Type 2 diabetes Index

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Foreword Beauty itself doth of itself persuade The eyes of men without an orator. [W. Shakespeare, The Rape of Lucrece (1593-4)] Our forebears must have marvelled at how food and drink somehow sustained life. As science slowly evolved over the millenia it surely became apparent that Nature, when understood, has a special beauty and symmetry. This is nowhere more apparent than in the observation that one can now trace the metabolic fate of a certain substrate through numerous interrelated and carefully controlled pathways to its ultimate destination. The information base that enables one to take this journey certainly represents one of the great accomplishments of 20th century biological science. The study of metabolism reached its zenith one or two generations ago when scholars purified and characterized hundreds of enzymes using techniques so tedious, inefficient and sometimes dangerous that current students and scientists have difficulty believing these procedures even existed. The substrates and products of these enzymatic reactions were systematically defined, as were a variety of regulatory mechanisms that control the flux through the various pathways. It all seems so logical and straightforward now, but imagine the confusion that existed as the individual bits of data were presented and before enough was known to assemble the first 'metabolic chart.' Facts which at first seem improbable will, even on scant explanation, drop the cloak which has hidden them and stand forth in naked and simple beauty. [Galileo Galilei, Dialogues Concerning Two New Sciences (1638)] The study of metabolism has, perhaps, been eclipsed by other fields of endeavor that certainly attract more attention from students and investigators, better notice in the lay and scientific press and favoured research funding. This point was driven home to me a few years ago when I went searching for a metabolic chart for the purpose of making a series of introductory slides for a lecture. I conducted my own version of a futile cycle through numerous offices and laboratories in the vain quest. I saw many charts of oncogenes, signal transduction pathways and the organization of the murine and human genomes, but none of the metabolic pathway. Finally, a postdoctoral fellow came to the rescue when he recalled that he had a metabolic chart rolled up in a tube in a closet in his apartment. Beauty in things exists in the mind which contemplates them. [David Hume, Essays on Tragedy (1741-2)] Those who continue to explore the mysteries of metabolism, and new pieces of the puzzle are still being located and placed, lament a perceived lack of interest in the topic by students and young scientists and teachers. They (we) imagine that the inherent beauty of the system should suffice to attract attention. But science moves forward because new areas of interest

are defined and novel ways of exploring these topics are developed. New and unexplored terrain is always enticing, particularly to the young who are blessed with the neuronal plasticity necessary for rapid adaptation. In spite of the dire prediction that the advent of molecular biology heralded the end of serious science (a view shared by many physiologists and students of metabolism) quite the opposite has happened. Novel experimental techniques have led to the precise definition of the DNA mutations responsible for more than 500 human genetic diseases, and at least another 10 000 genes are likely to be associated with various maladies. The phenotypic manifestations of many of these mutations can only be understood through knowledge of metabolic pathways. The stunning ability to alter the genome of experimental animals by transgenic and gene knockout technology has led to the appearance of phenotypes that the molecular biologist often cannot predict in advance, or begin to explain after the fact. This has resulted, inevitably, in a resurgent need for people who understand metabolism. It is often difficult to find qualified senior collaborators in this area, and the supply pipeline is not bursting with young replacements. One reason for this is that, regrettably, this topic is not taught well at many institutions, if it is taught at all. It certainly is rare, in the US at least, to encounter an entering graduate student who has taken an undergraduate course in metabolism. Not unusual is the student well versed in immunology, molecular biology, oncology, neurobiology and genetics, to name a few subjects. There are, no doubt, several explanations for this, and not the least of these is the way the subject is taught. I suspect students asked to give a first response to the question 'What do you think of when you hear the word metabolism?' would quickly respond 'impenetrable charts'. The subject has not always been presented in a clear, exciting and relevant way in textbooks or classrooms. Metabolism at a Glance represents a career-long effort by J.G. Salway to make the subject of metabolism approachable, interesting and relevant to human disease. The book is successful on all accounts, and plays an important role as a supplemental text for students, and as a reference source for scientists and teachers. It is a mainstay in my laboratory. The fact that a new edition is required bespeaks the point that this is still a dynamic field, and efforts like this should help restore the discipline of metabolism to the position it so richly deserves. Beauty is in the eye of the beholder. [Margaret Wolfe Hungerford, Molly Brown (1878)] One final point, 1 hope to see the day when someone like George Lucas (LucasFilms) uses a 'Star Wars' cinematic approach to devise a tour through a four-dimensional, integrated representation of the metabolic, signal transduction and gene regulation pathways, perhaps as an interactive computer game. Imagine yourself starting as a glucose molecule starting on this journey. This is a trip that will attract people's attention and interest! D.K. Granner

Preface In the five years since the first edition was published I have been very encouraged by the response of readers. They have confirmed my premise that this work meets the need for a concise text to serve as a companion to the many excellent encyclopaedia-like textbooks on biochemistry. This simplified, cartographic approach is designed to guide students through the maze of metabolic pathways and to emphasize their interrelationships. The format should aid both tutorial teaching and individual revision. The book, like a geographical map, can be used at different levels of complexity. The reader can choose to zoom along the motorways of metabolism to gain an overview of the subject, or can focus on a particular interest. Some of the early chapters will be of interest to students of A-level biology and similar courses. Such students who progress to study the biological and medical sciences at university will grow into this book throughout their undergraduate studies. The book will also be a handy reference work for senior biological and medical scientists and for researchers who need to refresh 'at a glance' their knowledge and understanding of metabolic pathways. Over the past five years, numerous advances in our understanding of metabolism have dated the first edition. Also, it contained several omissions of subject material, which, notwithstanding the concise format, justify inclusion. Accordingly, Chapters 3 and 6 ('Respiratory Chain' and 'ATP yield from Glucose') have been altered to include the debate on integer/ non-integer values for P/O ratios. Chapter 34 (β-Oxidation) has been revised to include the recently discovered trifunctional enzyme and inborn errors of (β-oxidation. New chapters on 'Porphyrins and Bile Salts', 'Cholesterol and the Steroid Hormones' and 'Exercise Biochemistry' have been added. A principal feature is the inclusion of five chapters on diabetes. This is justified by the enormous progress in our understanding of the molecular mechanisms responsible for both insulin resistance in Type 2 diabetes; and for insulin secretion and MODY (maturity onset diabetes of the young). There is reason to believe that new antidiabetic drugs will be discovered using strategies which exploit our ever-increasing awareness of the molecular mechanisms involved both in glucose-stimulated insulin secretion, and of insulin signal transduction within target tissues such as muscle, adipose tissue and liver. Finally, a comment on nomenclature since there is considerable diversity from international convention in the famous companions this book seeks to serve. For example, 2-oxoglutarate (IUPAC approved) is rarely used and has yet to replace the traditional α-ketoglutarate. Because of this confusion, traditional nomenclature has been used to match the principal student biochemistry textbooks.

Acknowledgements I have been very encouraged by the alacrity with which so many people have responded to my requests for advice. On several occasions when I became bogged down with decision making over which subject matter to include, I sought guidance from Dr Loranne Agius whose broad knowledge and clarity of thought has been a major influence on many of the chapters. I am also

grateful to subject experts who reviewed and advised on specific sections, notably: Dr Darrio Alessi, Mr John Alien, Dr Stephen Ashcroft, Professor Kim Bartlett, Professor Stan Brown, Dr Ann Brown, Dr Ann Burchell, Professor Brian Cooke, Professor George Elder, Ms Anna Gloyn, Professor Eric Newsholme and Dr John Wrigglesworth. Amongst colleagues at the University of Surrey, I have been grateful to Mr Gordon Hartman for his advice and support on many occasions, and to many other colleagues for their specific advice but especially Dr Barry Gould, Dr Richard Hinton, Dr Susanna Hourani, Dr Margaret Murphy, and Dr John Wright. It is also a pleasure to acknowledge the help of students: Ms Raheela Ajmal, Ms Olivia Jepson and Ms Elizabeth Maurice who all appeared to relish the rolereversal which enabled them to criticise my writing for a change. I am also grateful to all at Blackwell Science, notably Dr Mike Stein the commissioning editor; and to Mr Jonathan Rowley, and Mr Edward Wales whose patience has endured through all the difficulties encountered during production. The artistic flair of Mr Sam Lynn and Ms Shazia Mahmood transposed my crude drawings of some of the signalling icons for finishing by Ms Elaine Leggett of Oxford Designers & Illustrators. Elaine's skill and patience throughout our collaboration with the artwork overcame the complexities inherent in this project. Much credit for the accuracy of the text is due to Mrs Rosemary James whose numerous hours of enthusiastic support enabled the project to meet production deadlines. Finally, the responsibility for any errors which have slipped through the net is mine, and advice and comments from readers would be appreciated. J.G. Salway University of Surrey E-mail: [email protected] April 1999

Further reading Devlin T.M. (Ed.) (1997) Textbook of Biochemistry with Clinical Correlations, Wiley-Liss, New York. Frayn K.N. (1996) Metabolic Regulation: A Human Perspective, Portland Press, London. Murray R.K., Granner D.K., Mayes P.A. & Rodwell V.W. (1996) Harper's Biochemistry, Appleton & Lange, Stamford. Newsholme E., Leech T. & Duester G. (1994) Keep on Running, John Wiley and Sons, New York. Pickup J.C. & Williams G. (1997) Textbook of Diabetes, 2nd edn, Blackwell Science, Oxford. Voet D. & Voet J.G. (1995) Biochemistry, John Wiley and Sons, New York. Shepherd P.R., Withers D.J. & Siddle K. (1998) Phosphoinositide 3-kinase: the switch mechanism in insulin signalling, Review article, Biochem J, 333, 471-90.

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Index Page numbers in italics refer to charts and figures; where text, tables, and figures co-exist, page numbers are given in roman. Page numbers in bold refer to tables. acetaldehyde, metabolism 90, 91 acetoacetate 79 in adenosine triphosphate biosynthesis 80, 81 biosynthesis 45,78, 79 acetoacetyl CoA, biosynthesis 78, 79 acetoacetyl CoA thiolase, catalysis 78, 79, 80, 81 acetone 78, 79 acetylcholine, insulin secretion stimulation 102,103 acetyl CoA biosynthesis 50, 51, 78, 79, 106 oxidation 36, 96, 97 roles 30,48 acetyl CoA carboxylase 28, 30 N-acetylglutamate (NAG), biosynthesis 40 N-acetylglutamate synthase, catalysis 40 acetyl transferase 70 acipimox, in Type 2 diabetes treatment 105 ackee fruit 77 ACP see acyl carrier protein (ACP) acyl carrier protein (ACP), roles, in fatty acid biosynthesis 30,31 acyl CoA dehydrogenases, localization 76 acyl CoA esters, transport 74 acyl CoA oxidase, catalysis 37, 84, 85 adenosine, biosynthesis 96 adenosine diphosphate (ADP), phosphorylation 12,54 adenosine monophosphate (AMP) deamination 96 phosphorylation 54 adenosine monophosphate deaminase, deficiency 70 adenosine monophosphate-dependent protein kinase, activation 74 adenosine triphosphate (ATP) aerobic, production 96-7 anaerobic, production 96 biosynthesis 10, 12-15, 24, 25, 38-9, 54, 80, 81 in glucose metabolism 18, 20-1 glycolysis inhibition 22,68,69 phosphofructokinase-1 inhibition 32 structure 12 as substrate 72 S-adenosylmethionine (SAM) biosynthesis 46 metabolism 54,55 adenylate kinase, catalysis 96 adenyi cyclase, activation 64 adenylosuccinase, deficiency 54,55 adipic acid see hexanedioic acid adipocytes fat production 28 free fatty acids 74, 75 lipoprotein lipase biosynthesis 105 triacylglycerol biosynthesis 100 adipose tissue fatty acid mobilization 75,78 free fatty acids 74 insulin resistance 105 triacylglycerol biosynthesis 28, 36 ADP see adenosine diphosphate (ADP) adrenaline biosynthesis 54,55 glycogenosis stimulation 60 glycolysis stimulation 24 hormone-sensitive lipase activation 38 roles 64,65,96 adrenoleukodystrophy (ALD), aetiology 85 Akt see protein kinase Β A L A see 5-aminolevulinic acid (ALA) alanine accumulation, in liver 106,107 biosynthesis, in muscle 44 catabolism 46,47 roles, as gluconeogenic precursor 48, 72, 73 alanine cycle, mechanisms 44 albinism, aetiology 52,53 alcohol, metabolism 90, 91 alcohol dehydrogenase, roles, in ethanol metabolism 90,9/ alcoholism, treatment 90 A L D see adrenoleukodystrophy (ALD) aldehyde dehydrogenase, deficiency 90 aldolase, deficiency 26 aldolase Β see fructose 1-phosphate aldolase aldose reductase catalysis 93 in diabetes mellitus 92 aldose reductase inhibitors 92

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aldosterone, biosynthesis 88 ALDP see peroxisomal membrane protein alkaptonuria, aetiology 52,53 amino acids branched-chain 44,45 catabolism 44-7 essential 42 gluconeogenesis from 49 in ketogenesis 78, 79 ketogenic 44 metabolism 48-9, 50-1, 52-3, 54-7, 100 non-essential, biosynthesis 42-3 in urea biosynthesis 40 5-aminolevulinic acid (ALA), biosynthesis 58, 59 5-aminolevulinic acid synthase, catalysis 58, 59 aminopterin 55,57 aminotransferase, catalysis 40 ammonia, incoiporation into glutamine 40 A M P see adenosine monophosphate (AMP) Amytal, electron transport inhibition 15 androstenedione, biosynthesis 88 Antabuse see disulfiram antimetabolites 56 antimycin A 14,15 antipurines, mechanisms 56 antipyrimidines, mechanisms 56 arachidonic acid, as eicosanoid hormone precursor 86 arachidonoyl CoA, biosynthesis 86 arginine biosynthesis 40,42,43 catabolism 46,47 argininosuccinate, biosynthesis 40 ascorbate, biosynmesis 92, 93 asparagine, biosynthesis 42,43 aspartate biosynthesis 17, 40, 42,43 catabolism 44 and purine biosynthesis 54,55 aspartate aminotransferase (AST), catalysis 40 AST see aspartate aminotransferase (AST) atorvastatin 89 ATP see adenosine triphosphate (ATP) ATP/ADP translocase inhibition 15 roles 12 ATP synthetase 14 ATP synthetase complex, proton transport 14 atractyloside 14, 15 axons 80 azaserine, inhibitory activity 56 azide, electron transport inhibition 15 azidothymidine (AZT), phosphorylation 56 azidothymidine triphosphate (AZTTP), inhibitory activity 56 AZT see azidothymidine (AZT) AZTTP see azidothymidine triphosphate (AZTTP) barbiturates, interactions with ethanol 90 BCAAs see branched-chain amino acids (BCAAs) B C K A D H see branched-chain cc-ketoacid dehydrogenase (BCKADH) betaine, and homocysteine metabolism 55 bifunctional enzyme, activity 84, 85 bile acids, biosynthesis 88-9 bile pigments, biosynthesis 58-9 bilirubin biosynthesis 58-9 glucuronate conjugates 92, 93 bilirubin diglucuronide, biosynthesis 58,59 biliverdin, biosynthesis 58, 59 biotin, as cofactor 28 2,3-bisphosphate phosphatase 26 1,3-bisphosphoglycerate, reduction 27, 92,93 2,3-bisphosphoglycerate (2,3-BPG), roles 26 bisphosphoglycerate mutase, deficiency 26 2,3-bisphosphoglycerate phosphatase, deficiency 26 blood glucose concentration, during fasting 72 blood transfusions, and 2,3-bisphosphoglycerate 26 bombesin, insulin secretion stimulation 103 bongkrekic acid 14, 15 2,3-BPG see 2,3-bisphosphoglycerate (2,3-BPG) brain, fuel requirements during starvation 80 branched-chain amino acids (BCAAs) catabolism 44, 45, 97 metabolism, disorders 52 branched-chain ct-ketoacid dehydrogenase (BCKADH), activity 44 branching enzyme, catalysis 60 calcium channels, voltage-dependent

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calmodulin-dependent protein kinase-2, activation 102,103 cancer chemotherapy 56 photodynamic dierapy 58 carbamoyl aspartate, biosynthesis 40 carbamoyl phosphate accumulation 40 biosynthesis 56,57 carbamoyl phosphate synthetase (CPS), catalysis 40 carbamoyl phosphate synthetase II (CPS II), catalysis 56,57 carbon dioxide, biosynthesis 36 carbon monoxide, electron transport inhibition 15 1 -carbon pool 54-7 carbonylcyanide-/j-trifluoroinethoxyphenylhydrazone (FCCP), proton transport inhibition 15 cardiovascular disease and cholesterol 88 and homocysteine 55 carnitine, deficiency 76, 77 carnitine/acyl-carnitine translocase, in carnitine shuttle 76, 77 carnitine conjugates, biosynthesis 76, 77 carnitine-palmitoy I -transferases (CPTs), in carnitine shuttle 76, 77 carnitine shuttle, mechanisms 76-7 casein kinases, glycogen synthase phosphorylation 66 catalase catalysis 90,91 in fatty acid oxidation 84, 55 cataracts, diabetic, polyol osmotic theory 92 cells, energy conservation 12 β-cells, metabolism 102,103 cerotic acid, accumulation 85 chemiosmotic theory 14 chenodeoxycholate, biosynthesis 88,89 chlorpropamide, aldehyde dehydrogenase inhibition 90 chlorpropamide alcohol flushing 90 cholate, biosynthesis 88, 89 cholecystokinin, insulin secretion stimulation 103 cholesterol, biosynthesis 88-9 citrate glycolysis inhibition 22

roles 30 citrate lyase, catalysis 30 citrate synthase, catalysis 78, 79 citric acid cycle see Krebs cycle citrulline, biosynthesis 40 cofactors, for pyruvate dehydrogenase catalysis 18 complexes I—IV mechanisms 15 proton transport 14 congenital adrenal hyperplasia, aetiology 88 congenital erythropoietic porphyria see Gunther's disease coproporphyria, hereditary, aetiology 59 coproporphyrinogens, biosynthesis 59 Cori cycle, mechanisms 24 Cori's disease, aetiology 61 Cortisol, biosynthesis 88 cot death see sudden infant death syndrome (SIDS) C peptide 103 CPS see carbamoyl phosphate synthetase (CPS) CPTs see carnitine-palmitoyl-transferases (CPTs) creatine, biosynthesis 41, 54, 96 creatine phosphate, biosynthesis 41 creatinine, biosynthesis 41 Crigler—Najjar syndrome, aetiology 59, 92, 93 cyanide, electron transport inhibition 15 cyclic AMP, biosynthesis 62 cyclic AMP-dependent protein kinase see protein kinase A cyclic A M P phosphodiesterase-3 accumulation 106,107 activation 66, 67, 105, 106 CYP family 58 cystathionine β-synthase, catalysis 55 cysteine biosynthesis 42,43 catabolism 46,47 cyt b see cytochrome b (cyt b) cyt c see cytochrome c (cyt c) cytochrome b (cyt b), in 'Q cycle' 15 cytochrome b5, localization 86,87 cytochrome b s reductase, localization 86, 87 cytochrome c (cyt c), electron transport 14,15 cytochrome P450 58 enzyme 90,91 cytosol adenosine triphosphate biosynthesis 39 metabolic pathways in 10-11

DAG see diacylglycerol (DAG) dATP see deoxyadenosine triphosphate (dATP) DCCD see dicyclohexylcarbodiimide (DCCD) dCTP see deoxycytidine triphosphate (dCTP) decanedioic acid, biosynthesis 76, 77 decanoyl carnitine, biosynthesis 77 cii-A4-decenoate, and medium-chain acyl CoA dehydrogenase deficiency 76, 77, 82, 83 ci.T-A4-decenoyI CoA, oxidation 82 7-dehydrocbolesterol, biosynthesis 89 dental decay treatment 92,94 xylitol-mediated 92 dental enamel, remineralization 92 deoxyadenosine triphosphate (dATP), biosynthesis 54 deoxycytidine triphosphate (dCTP), biosynthesis 56, 57 deoxyguanosine triphosphate (dGTP), biosynthesis 54 deoxythymidine monophosphate (dTMP), biosynthesis 56,57 deoxythymidine triphosphate (dTTP), biosynthesis 56,57 deoxyuridine (dUrd), as plasma marker 57 deoxyuridine monophosphate (dUMP), biosynthesis 56,57 desmolase, catalysis 88 desmosterol, biosynthesis 89 desmosterolosis, aetiology 88, 89 dGTP see deoxyguanosine triphosphate (dGTP) DHFsee dihydrofolate (DHF) DHP see dihydropyridine (DHP) DHT see dihydrotestosterone (DHT) diabetes mellitus aetiology 18 cataracts 92 dietary supplementation 86 ketone body detection 78 maturity-onset, of the young 102-3 metabolic processes in 100 and sorbitol 92, 93 see also Type 1 diabetes; Type 2 diabetes diacylglycerol (DAG) 75,103 diazo-oxo-norleucine (DON), inhibitory activity 56 diazoxide, insulin secretion inhibition 103 dicarboxylate carrier 10 dicarboxylic acids, biosynthesis 76, 77 dicyclohexylcarbodiimide (DCCD), proton transport inhibition 15 2,4-dienoyl CoA reductase, catalysis 82, 83, 84,55 dihomo-y-linolenic acid, as eicosanoid hormone precursor 86 dihomo-y-linolenoyl CoA, desaturation 86, 57 dihydrofolate (DHF) 55, 56,57 dihydrofolate reductase, catalysis 54, 55, 56, 57 dihydrolipoyl dehydrogenase 70 dihydropyridine (DHP), calcium channel opening 103 dihydrotestosterone (DHT), biosynthesis 88 dihydroxyacetone phosphate biosynthesis 94,95 reduction 16 2,4-dinitrophenol (DNP) 14, 15 2,3-diphosphoglycerate (2,3-DPG) see 2,3bisphosphoglycerate (2,3-BPG) disulfiram, in alcoholism treatment 90 DNA, biosynthesis 54 DNP see 2,4-dinitrophenol (DNP) dolichol, precursors 88, 59 DON see diazo-oxo-norleucine (DON) 2,3-DPG see 2,3-bisphosphoglycerate (2,3-BPG) drug metabolites, glucuronate conjugates 92, 93 dTTP see deoxythymidine triphosphate (dTTP) dUMP see deoxyuridine monophosphate (dUMP) dUrd see deoxyuridine (dUrd) eicosanoid hormones, precursors 86 eicosapentanoic acid, in fish oils 86 electron-transfer fiavoprotein (ETF), roles, in β-oxidation 76 electron transport inhibition 15

processes 14 endoplasmic reticulum and ethanol ingestion 90 fatty acid elongation 86, 87 glucose 6-phosphatase 10, 72 energy conservation, in cells 12 energy as ATP, via glucose metabolism 18-19, 22-3 energy storage, in fat 28 enoyl CoA hydratase, catalysis 84,55 A2-enoyl CoA hydratases, localization 76 3,2-enoyI CoA isomerase, catalysis 82, 5.Ϊ, 84, 55

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trans-A2~enoy\ CoA isomerase, catalysis 82, 83 enoyl CoA reductase, catalysis 86, 87 epinephrine see adrenaline ERK see mitogen-activated protein kinase (MAPK) ERK kinase see mitogen-activated protein kinase kinase (MAPKK) erythropoietic protoporphyria, aetiology 59 essential fatty acids, therapeutic benefits 86 essential fructosuria, aetiology 94, 95 essential pentosuria, aetiology 92 esterification and fatty acid biosynthesis 30 of fatty acids 74, 75 ETF see electron-transfer flavoprotein (ETF) ETF: ubiquinone oxidoreductase, roles, in carnitine shuttle 76, 77 ethanol, metabolism 90-1 evening primrose oil, therapeutic benefits 86 exercise biochemistry of 96-7 effects on muscle protein 44 exocytosis, regulatory mechanisms 102 FABP see fatty acid binding protein (FABP) FAD see flavin adenine di nucleotide (FAD) FADH 2 biosynthesis 38 oxidation 12, 16 phosphorylation 20 , P/O ratio 21 Fanconi—Bickel syndrome, aetiology 102 farnesyl isoprenoid groups, precursors 88, 89 farnesyl pyrophosphate (FPP) 59 fasting effects on muscle protein 44 and fat reserves 22 and gluconeogenesis 72 fat as energy store 28 sugar biosynthesis 37 fat cells, glucose transport 18 fatty acid binding protein (FABP), biosynthesis 97 fatty acids in adenosine triphosphate biosynthesis 38-9 biosynthesis 10, 30-1, 50-1 desaturation 86-7 esteriflcation, to triacylglycerols 50-1 as fuel reserves 96-7 and glucose biosynthesis, problems in mammals 36-7 14 C-Iabelled 36 metabolism, in diabetes mellitus 100 mobilization 74-5,78 nomenclature 82,84 β-oxidation 38, 72, 73, 74-7, 84, 105 re-esterification 74, 75 fatty acyl CoA desaturases, activity 86, 87 favism, aetiology 32 Fl,6-BPase see fructose 1,6-bisphosphatase (Fl,6BPase) FCCP see carbonylcyanide-ptrifluoromethoxyphenylhydrazone (FCCP) ferrochelatase, activity 58 fetal haemoglobin, affinity for 2,3bisphosphoglycerate 26 F o /F, particles, roles 10 FIGLU see W-formiminoglutamate (FIGLU) fish oils, therapeutic benefits 86 flavin adenine dinucteodde (FAD) availability 74,76 as hydrogen earner 12 "fight or flight'response 22,105 and glycogen biosynthesis 64 mechanisms 24 fluorouracil, inhibitory activity 56 folate, metabolism 54-7 folate antagonists, mechanisms 56 folinic acid, methotrexate toxicity mediation 56 W-formiminoglutamate (FIGLU) 46, 55 tf-formylkynurenine, biosynthesis 54, 55 Wl0-formyl tetrahydrofolate, biosynthesis 54, 55 FPP see farnesyl pyrophosphate (FPP) free fatty acids, biosynthesis 74 fructokinase, catalysis 94, 95 fructose, metabolism 94-5 fructose 1,6-bisphosphatase (Fl,6-BPase) deficiency 94,95 inhibition 106 regulatory mechanisms 72, 73 fructose 1,6-bisphosphate cleavage 20 pyruvate kinase activation 68,69 fructose 2,6-bisphosphate, biosynthesis 68,69 fructose 1-phosphate, biosynthesis 94, 95 fructose 1-phosphate aldolase, catalysis 94, 95 fructose transporters, Glu T5 94 fumarate, biosynthesis 40

fumarylacetoacetase, deficiency 52 fumarylacetoacetate, accumulation 52 gaiaclitol, metabolism 92 galactoklnase, deficiency 92 galactosaemia, aetiology 92 galactose, metabolism 92 galactose 1-phosphate uridyltransferase (Gal-1-PUT), deficiency 92 galanin, insulin secretion inhibition 103 Gal-l-PUTstfi* galactose 1-phosphate uridyltransferase (Gal-1-PUT) gene expression, insulin-regulated 104 George III, porphyria 58 geranyl isoprenoid groups, precursors 88,89 geranyl pyrophosphate (GPP) 89 Gilbert's syndrome, aetiology 59 GIP see glucose-dependent insulinotrophic polypeptide (GIP) GKRP see glucokinase regulatory protein (GKRP) GLP-I see glucagon-like peptide-1 (GLP-1) glucagon hormone-sensitive lipase activation 38 roies 60, 64, 65, 74 glucagon-like peptide-1 (GLP-1), insulin secretion stimulation 102 glucocorticoid see Cortisol glucokinase catalysis 68,69 localization 94 metabolic roles 10 translocation 95,95 in Type 2 diabetes 102 glucokinase regulatory protein (GKRP) mechanisms 68,69 as nuclear anchor 94, 95 gluconeogenesis acetyl CoA in 48 inhibition 90,91 in liver 24,100 precursors 44, 49,72, 73 regulatory mechanisms 72-3, 106,107 see also glucose biosynthesis glucose brain requirements 80 homeostasis, requirements 102 insulin-stimulated uptake 98 nerve cell delivery 80 oxidation 21 phosphorylation 20 roles, in liver phosphorylase inhibition 66 toxicity 106 utilisation 94 glucose biosynthesis from fatty acids, problems in mammals 36-7 in liver, and Type 2 diabetes 106 via amino acid metabolism 48-9 see also gluconeogenesis glucose-dependent insulinotrophic polypeptide (GIP), insulin secretion stimulation 102 glucose metabolism anaerobic 24-5 ATP production 20-1 in diabetes mellitus 100 for energy production 18-19 to fatty acids 30-1 to glycogen 22-3 to lactate 48 to triacylglycerols 28-9, 30-1 glucose 6-phosphatase deficiency 60,61 inhibition 106 localization 10,72 regulatory mechanisms 72, 73 in Type 2 diabetes 102 glucose 1-phosphate biosynthesis 62,63 reactions, with uridine triphosphate 60, 61 glucose 6-phosphate biosynthesis 60, 61, 62,63, 68, 69 glycolysis 20 glucose 6-phosphate dehydrogenase, catalysis 32 glucose transport insulin in 18 mechanisms 68,69 in triacylglycerol synthesis 28 glucose transporters G l u T l 96 GluT2 6/,68,102 GIuT4 28,68,74,75,96,100,105 Glu T5 94 roles 18,68 in skeletal muscle 96 translocation impairment 105 rx(l>6)-glucosidase, catalysis 60, 61 glucuronate, metabolism 92-3 glucuronate/xylulose pathway, mechanisms 92, 93

Glu T l , in skeletal muscle 96 GluT2 6/,68,102 GluT4 68 in adipose tissue 74, 75, 100, 105 in skeletal muscle 96, 105 translocation 28 Glu T5, fructose transport 94 glutamate biosynthesis 40, 42, 43 catabolism 46,47 roles 42,54 glutamate dehydrogenase, in urea biosynthesis 40 glutamine' biosynthesis 42,43,44 urea incorporation 40 glutamine antagonists, mechanisms 56 glutamine synthetase, catalysis 40 γ-gtutamylcysteinylglycine see glutathione glutarate, excretion 76 glutaric aciduria I, aetiology 76, 77 glutaric aciduria II, aetiology 76, 77 glutaryl CoA dehydrogenase, deficiency 76, 77 glutathione biosynthesis 32 structure 42 glyceraldehyde biosynthesis 95,95 insulin secretion stimulation 102 glyceraldehyde 3-phosphate biosynthesis 30, 50, 92, 93 oxidation 20 glyceraldehyde 3-phosphate dehydrogenase, catalysis 16,24 glycerol accumulation, in liver 106,107 biosynthesis 36, 38, 74, 75 metabolism, in diabetes mellitus 100 phosphorylation 36 roles, as gluconeogenic precursor 72, 73 glycerol 3-phosphate biosynthesis 16, 50, 92, 93 fatty acid re-esterification 74, 75 glycerol phosphate shuttle mechanisms 16,21 in Type 2 diabetes 102 glyceryl trierucate, discovery 85 glyceryl trioleate, discovery 85 glycinamide ribonucleotide (GAR), catalysis 54, 55 glycine accumulation, and neonates 52 biosynthesis 42,43, 54,55 catabolism 46,47 glycine cleavage enzyme, deficiency 52,53 glycine cleavage system 46, 47 glycine synthase, catalysis 42 glycogen as fuel reserve 22, 96-7 structure 22 glycogen biosynthesis 22-3 and 'fight or flight' response 64 in liver 60,61 mechanisms 22, 60, 63 regulatory mechanisms 66-7 in skeletal muscle 62, 63 and Type 2 diabetes 105 see also insulin-stimulated glycogen synthesis glycogen exhaustion, mechanisms 96 glycogenin 22 glycogen metabolism anaerobic 24-5 in diabetes mellitus 100 in liver 60-1 in muscle 62-3 regulatory mechanisms 64-7 glycogenosis mechanisms 60, 64, 65 in skeletal muscle 62, 63 glycogen phosphorylase, properties 64 glycogen storage 22 diseases 60, 61, 63 glycogen synthase catalysis 60, 61, 62 regulatory mechanisms 66,67 glycogen synthase kinase-3 (GSK-3) functions 98 glycogen synthase phosphorylation 66 glycolysis anaerobic 24 enzymes in 10 inhibition 22, 105 in liver 48 mechanisms 18, 20,63,68-9 reactions in 12 uncontrolled 94 glycolytic enzymes, deficiency 26 glycoproteins, biosynthesis 89 glycosyl transferase, catalysis 60, 61 glyoxylate cycle, mechanisms 37

glyoxysomes, roles, in germination 37 G M P see guanosine monophosphate (GMP) gout aetiology 60 and ethanol 90, 91 GPP see geranyl pyrophosphate (GPP) Grb-2 see growth-factor receptor bound protein-2 (Grb2) growth-factor receptor bound protein-2 (Grb-2), functions 98 GSK-3 see glycogen synthase kinase-3 (GSK-3) GTP see guanosine triphosphate (GTP) guanosine monophosphate (GMP), phosphorylation 54 guanosine triphosphate (GTP) biosynthesis 12,21,54 as substrate 72 L-gulonate, metabolism 92, 93 Gunther's disease, aetiology 59 haem, biosynthesis 58-9 haem oxygenase, catalysis 58, 59 hepatic nuclear factor I -a (HNF 1 -a), mutations 102 hepatic nuclear factor 4-ct (HNF 4-oc), mutations 102 hepatocytes, glucokinase 94 hereditary fructose intolerance, aetiology 94, 95 Hers' disease, aetiology 60, 61 hexadecanoate see palmitate hexanedioic acid, biosynthesis 76, 77 hexanoyl carnitine, biosynthesis 77 hexanoylglycine, biosynthesis 76, 77 hexokinase catalysis 68, 69, 94, 95 deficiency 26 hexose monophosphate shunt pathway see pentose phosphate pathway histidase, deficiency 52 histidinaemia, aetiology 52, 53 histidine, catabolism 46, 47 HMGCoA see 3-hydroxy-3-melhylglutaryl-CoA (HMGCoA) HNF 1-ct see hepatic nuclear factor 1-a (HNF 1-cf) HNF 4-a see hepatic nuclear factor 4-a (HNF 4-a) homocysteine, and cardiovascular disease 55 homocysteine methyltransferase. catalysis 46 homogentisate 1,2-dioxygenase, deficiency 52 hormone-sensitive lipase (HSL) activation 38, 105 inhibition 105, 106 regulatory mechanisms 74, 75 roles, in ketone body biosynthesis 78 HSL see hormone-sensitive lipase (HSL) hydrogen carriers 12 L-3-hydroxyacyl CoA dehydrogenase, catalysis 84, 55 3-hydroxyacyl CoA dehydrogenases, roles, in β-oxidation 76 3-hydroxyanthranilate, biosynthesis 46 D-3-hydioxybutyrate biosynmesis 78, 79 oxidation 80,81 D-3-hydroxybutyrate dehydrogenase, catalysis 80, 5/ 3-hydroxy CoA epimerase, issues 82 7-a-hydroxylase, regulatory mechanisms 88, 89 21-hydroxylase, catalysis 88 hydroxymethylbilane, biosynthesis 58,59 3-hydroxy-3-methylglutaryI-CoA (HMGCoA), biosynthesis 78, 79, 89 3-hydroxy-3-methylglutaryl-CoA reductase, catalysis 88, 59 3-hydroxy-3-methylglutaryI-CoA synthase, catalysis 78. 79 4-hydroxyphenylpyruvate dioxygenase, inhibition 52 hyperammonaemia, aetiology 40-1 hypercholesterolaemia, treatment 88 hyperglycaeinia aetiology 18, 102, 104, 106 and fatty acid oxidation 105 see also persistent hyperinsulinaemic hyperglycaemia of infancy (PHHI) hyperglycinaemia, non-ketotic, aetiology 52,53 hyperinsulinaemia, aetiology 104 hyperlactataemia aetiology

24

and ethanol 90, 91 hyperlipidaemia, aetiology 105,106 hypoglycaemia aetiology 18,22,94,95 and ethanol 90, 91 prevention 44 hypoglycin A, metabolism 77 hypophosphatemia, and diabetic ketoacidosis 26 IAPP see islet amyloid polypeptide (IAPP) ICDH see isocitrate dehydrogenase (ICDH) IDDM see Type 1 diabetes IMP see inosine monophosphate (IMP)

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inner membrane, composition 10 inosine monophosphate (IMP) biosynthesis 55,96 as precursor 54 inositol trisphosphate, biosynthesis 103 insects, glucose metabolism 20-1 insulin gene transcription stimulation 106 glucose uptake stimulation 98 molecular abnormalities 104 phosphoenolpyruvate carboxykinase inhibition 50 pleiotropic effects 98 roles 18,28,66,(57,104,106 signal transduction 98-9,104,105, 106 insulin-dependent diabetes mellitus (IDDM) see Type 1 diabetes insulinomas 18 insulin-promoting factor-1 (IPF-1), mutations 102 insulin receptor defective 102, 104 functions 98 insulin receptor substrate-1 (IRS-1), functions 98 insulin resistance in adipose tissue 105 in liver 106-7 in skeletal muscle 104-5 and Type 2 diabetes 104-5 insulin secretion, metabolism 102,103 insulin-stimulated glycogen synthesis, mechanisms 98-9 insulin-stimulated protein kinase (ISPK) see ribosomal S6 kinase (p90*) intermembrane space 10 IPF-1 see insulin-promoting factor-1 (IPF-1) IPP see tsopentenyl pyrophosphate (IPP) iron/sulphur complexes, electron transport 15 IRS-J see insulin receptor substrate-1 (IRS-1) islet amyloid polypeptide (IAPP), polymerisation 103 isocitrate, oxidation 90, 91 isocitrate dehydrogenase (ICDH), inhibition 30, 70, 72 isocitrate lyase, in glyoxylate cycle 37 isoleucine catabolism 96,97 oxidation 44,45 isopentenyladenosine, biosynthesis 89 isopentenyl pyrophosphate (IPP), biosynthesis 89 isoxazolidinediones, as insulin sensitizers 105 ISPK see ribosomal S6 kinase (p90"k) Jamaican vomiting sickness (JVS) 77 ' JTT-50i, as insulin sensitizer 105 juvenile-onset diabetes see Type 1 diabetes JVS see Jamaican vomiting sickness (JVS) kernicterus, aetiology 92, 93 α-ketoacid dehydrogenase, branched-chain, deficiency 52 ketoacidosis, diabetic 26, 100 3-ketoacyl CoA transferase, catalysis 80, 81 α-ketoadipate, biosynthesis 46 ketogenesis, mechanisms 78, 79 α-ketoglutarate, biosynthesis 40, 90, 91 ct-ketoisocaproate, insulin secretion stimulation 102 ketone bodies biosynthesis 78,79 utilization 80-1 ketosis, regulatory mechanisms 78, 79 ketothiolases see 3-oxoacyl CoA thiolases Krebs cycle acetyl CoA oxidation 36,78, 79, 80,81,96, 97 in adenosine triphosphate biosynthesis 38 catalytic mechanisms 12 in fatty acid oxidation 38 in glucose metabolism 18, 20, 21 inhibition 90,91 in mitochondrion 10 regulatory mechanisms 70-1 Krebs Henseleit ornithine cycle see ornithine cycle kynureninase, catalysis 46 kynurenine, biosynthesis 54,55

lactate accumulation, in liver 106,107 biosynthesis 24, 48, 90, 91 roles 72, 73 lactate dehydrogenase, catalysis 24, 84, 85 lactic acid, excessive production 94 lactic acidosis, aetiology 24, 94 lactonase, catalysis 32 lanosterol, biosynthesis 89 lathosterol, biosynthesis 89 L C A D see long-chain acyl CoA dehydrogenase (LCAD)

110

L C H A D see long-chain hydroxyacyl CoA dehydrogenase (LCHAD) leprechaunism, aetiology 104 leptin 103,107 Lesch—Nyhan syndrome, aetiology 56 leucine catabolism 97 insulin secretion stimulation 102 oxidation 44,45 leucovorin see folinic acid ligandin, bilirubin transport 58, 59 Ugnoceric acid accumulation 85 β-oxidation, peroxisomal 84, 85 linoleic acid as eicosanoid hormone precursor 86 β-oxidation 82,83 γ-linolenic acid, elongation 86, 87 lipolysis in adipose tissue 74, 75 signalling defects 105 lipoprotein lipase, biosynthesis 105 liver fatty acid transport inhibition 76, 77 fructose metabolism 94—5 gluconeogenesis in 24,100 glucose biosynthesis 36, 106 glycogen biosynthesis 60, 61 glycogen metabolism 60-1 glycogen storage 22 glycolysis 48,68 insulin resistance 106-7 ketogenesis in 78 Krebs cycle inhibition 90, 91 phosphorylase inhibition 66 liver cells, fat production 28 London Underground, map 10 long-chain acyl CoA dehydrogenase (LCAD), localization 76 long-chain acyl CoA synthetase, catalysis 38 long-chain hydroxyacyl CoA dehydrogenase (LCHAD), specificity 76 Lorenzo's Oil, studies 85 lovastatin 89 Lowenstein's cycle see purine nucleotide cycle LY294002, inhibitory activity 99 lysine, catabolism 46, 47 lysophosphatidate, biosynthesis 74, 75

McArdle's disease, aetiology 63 M A D D see glutaric aciduria Π malate biosynthesis 90,91 decarboxylation 34 malate/aspartate shuttle 16, 20 mechanisms 17,21 in Type 2 diabetes 102 malate dehydrogenase catalysis 12 in oxaloacetate reduction 17 malate dehydrogenase, decarboxylating see malic enzyme malate synthase, in glyoxylate cycle 37 malic enzyme, malate decarboxylation 34, 50 malonate 14, 15 malonyl ACP, biosynthesis 30 malonyl CoA catalysis 30, 86, 87 fatty acid transport inhibition 76 and insulin secretion 102 mammals amino acid biosynthesis 42 glucose biosynthesis from fatty acids, problems 36-7 mannose, insulin secretion stimulation 102 M A P K see mitogen-activated protein kinase (MAPK) M A P K A P kinase see ribosomal S6 kinase (p9ff*) M A P kinase kinase kinase ( M A P K K K ) see Ras activated factor (Raf) M A P K K see mitogen-activated protein kinase kinase (MAPKK) M A P K K K see Ras activated factor (Raf) maple syrup urine disease, aetiology 52 M A R C K S see myristoylated alanine-rich C kinase substrate (MARCKS) maturity-onset diabetes see Type 2 diabetes maturity-onset diabetes of the young (MODY), aetiology 102-3 M C A D see medium-chain acyl CoA dehydrogenase (MCAD) M C P A see mediylenecyclopropylalanine (MCPA) medium-chain acyl CoA dehydrogenase (MCAD), deficiency, and ci"i-A4-decenoate 76, 77, 82, 83 M E K see mitogen-activated protein kinase kinase (MAPKK)

MEOS see microsomal ethanol-oxidizing system (MEOS) mercaptopurine, inhibitory activity 56 metabolic charts, overview 10-11 metabolic fuel hypothesis, for insulin secretion 102 metabolic pathways, subcellular distribution 10-11 metabolites, accumulation 22 /Vs,W°-methenyl tetrahydrofolate, biosynthesis 55 methionine catabolism 46,47 metabolism 54,55 methionine salvage pathway 54, 55 methotrexate 55,57 inhibitory activity 56 Af-methyl-D-aspartate (NMDA) receptor, activation 52 methylenecyclopropylalanine (MCPA), metabolism 77 /V^V'-methylene tetrahydrofolate biosynthesis 54,55 oxidation 56,57 methylene tetrahydrofolate reductase, deficiency 55 'methyl—folate trap', and vitamin B | 2 54,55 ^-methyl tetrahydrofolate, biosynthesis 55 mevalonate 89 mevastatin 89 microsomal ethanol-oxidizing system (MEOS), roles, in ethanol metabolism 90,91 milk, galactose 92 mineralocorticoid see aldosterone mitochondrion adenosine triphosphate biosynthesis 39 metabolic pathways in 10-11 oxygen transport 26-7 respiratory chain 14—15 mitogen-activated protein kinase (MAPK) functions 98 pathway 99 mitogen-activated protein kinase activated protein kinase (MAPKAP) see ribosomal S6 kinase (p90rak) mitogen-activated protein kinase kinase (MAPKK), functions 98 mobilizing lipase see hormone-sensitive lipase M O D Y see maturity-onset diabetes of the young (MODY) monoacylglycerol lipase, catalysis 74, 75 multiple acyl CoA dehydrogenase deficiency (MADD) see glutaric aciduria Π muscle cells, glucose transport 18 muscle protein, metabolism 44 muscles contraction 96-7 fructose metabolism 94-5 glucose metabolism 48 glycogen metabolism 62-3 glycogen storage 22 glycolysis, regulatory mechanisms 68, 69 insulin resistance 104-5 red 74,96-7 wasting 80 white 24,96-7 myoadenylate deaminase see adenosine monophosphate deaminase myoglobin, roles, in oxygen transport 26 myristoylated alanine-rich C kinase substrate (MARCKS) 103 myxothiazol 14, 15 NAD* see nicotinamide adenine dinucleotide (NAD*) NAD*+H*, availability 74 NADH+H* biosynthesis 38 oxidation 12, 16-17 P/O ratio 21 reoxidation 84,85 NADP*, NADPH+H* biosynthesis 30 NADPH+H* biosynthesis 30 and pentose phosphate pathway 32-3, 50, 51 and pyruvate/malate cycle 34-5, 50,51 N A G seetf-acetylglutamate(NAG) neonates and glycine accumulation 52 insulin receptor defects 104 nerve cells, delivery systems 80 nicotinamide adenine dinucleotide (NAD*) availability 76 as hydrogen carrier 12 nicotinic acid, hormone-sensitive lipase inhibition 75, 105 NIDDM see Type 2 diabetes nitric oxide, occurrence 42 nitrogen, in urea biosynthesis 40,41 2-(2-mtro-4-trifluoro-methylbenzoyl)-l,3cyclohexanedione (NTBC), in type I tyrosinaemia treatment 52

N M D A receptor see N-methyl-D-aspartate (NMDA) receptor non-insulin-dependent diabetes mellitus (NIDDM) see Type 2 diabetes noradrenaline, methylation 54, 55 NTBC see 2-(2-nihO-4-trifluoro-methylbenzoy!)-l .3cyclohexanedione (NTBC) nucleoside diphosphate kinase, catalysis 12 5' -nucleotidase, catalysis 96 obesity, and tumor necrosis factor-α 104 octanedioic acid, biosynthesis 76, 77 octanoyl carnitine, biosynthesis 77 oestradiol, biosynthesis 88 oligomycin, proton transport inhibition 15 OMP see orotidine monophosphate (OMP) oncogenes, encoding 98 ornithine, reactions, with carbamoyl phosphate 40 ornithine cycle discovery 71 mechanisms 40-1 ornithine transcarbamoyiase (OTC), deficiency 40-1 orotate, biosynthesis 41 orotate phosphoribosyl transferase, catalysis 56, 57 orotidine monophosphate (OMP), biosynthesis 56, 57 OTC see ornithine transcarbamoyiase (OTC) outer membrane, composition 10 ovaries, sex hormone biosynthesis 88 oxaloacetate biosynthesis 30,90, 91 in Krebs cycle 71,78, 79 reduction 17 β-oxidation in adenosine triphosphate biosynthesis 38 fatty acids 38, 74-7, 84 linoleic acid 82,83 in mitochondrion 10' peroxisomal 84—5 in plants 37 unsaturated fatty acids 82-3 ω-oxidation, metabolism 76, 77 3-oxoacyl CoA thiolases, localization 76 oxygen transport, in red blood cells 26-7

p85, functions 98 p90rak see ribosomal S6 kinase (p90"*) palmitate adenosine triphosphate biosynthesis, net yields 38, 39 biosynthesis 28, 29, 38,74, 75 palmitoleoyl CoA, biosynthesis 86, 87 palmitoyl CoA biosynthesis 76,77 desaturation 86,87 PAO see phenylarsine oxide (PAO) Pasteur effect 24, 68 PBR see peripheral benzodiazepine receptor (PBR) PD98058, as M A P K K inhibitor 98 PDH see pyruvate dehydrogenase (PDH) PDK-1 see phosphoinosiride-dependent kinase-1 (PDK-1) PDK/PKB pathway 99 PDT see photodynamic therapy (PDT) pentose phosphate pathway enzymes in 10 in fatty acid biosynthesis 30 and NADPH+H* biosynthesis 32-3, 50, 51 in red blood cells 32 regulatory mechanisms 32 PEPCK see phosphoenolpyruvate carboxykinase (PEPCK) peripheral benzodiazepine receptor (PBR), and cholesterol uptake 88 peroxisomal membrane protein encoding 85 roles 84,55 peroxisomal β-oxidation, of lignoceric acid 84-5 peroxisomes, proliferation 84 persistent hyperinsulinaemic hypcrglycaemia of infancy (PHHI), aetiology 103 PFK-1 seephosphofructokinase-l (PFK-I) phenylalanine monooxygenase, deficiency 52 phenylarsine oxide (PAO), as protein-tyrosine phosphatase inhibitor 104, 105 phenylketonuria, aetiology 52, 53 PHHI see persistent hyperinsulinaemic hyperglycacmia of infancy (PHHI) phlorizin 103 phorbol esters 103 phosphatidate, as intermediate 75 phosphatidylcholine, biosynthesis 54 phosphatidylethanolamine, methylation 54 phosphatidylinositol-3 kinase (PI-3 kinase) catalysis 98 stimulation 104

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phosphatidyl inositol 4,5-bisphosphate, metabolism 99 phosphatidylinositol 3,4,5-trisphosphate, biosynthesis 98,99 phosphocreatine, adenosine triphosphate production 96 phosphoenolpyruvate carboxykinase (PEPCK) inhibition 50, 106 regulatory mechanisms 72, 73, 106, 107 phosphofructokinase, deficiency 26 phosphofructokinase-1 (PFK-1) inhibition 30,32 metabolic roles 10 stimulation 68,69 phosphofructokinase-2 (PFK-2), catalysis 68, 69 6-phosphogluconate dehydrogenase, catalysis 32 phosphoglucose isomerase, deficiency 26 2-phosphoglycerate, biosynthesis 48 phosphoglycerate kinase, in glycolysis 12, 20 phosphoinositide-dependent kinase-1 (PDK-1), functions 98 phosphoribosyl pyrophosphate (PRPP) 56,57 biosynthesis 54,55 phosphoribosyl transferases (PRTs), catalysis 56, 57 phosphorylase kinase activation 62, 64, 65 glycogen synthase phosphorylation 66 phosphorylases binding 106 catalysis 60, 61, 62, 63 inhibition 66 properties 64 phosphorylation glucose 68,69 oxidative 12, 14,39 substrate-level 12,39 photodynamic therapy (PDT), cancer treatment 58 piericidin, electron transport inhibition 15 PI-3 kinase see phosphatidylinositol-3 kinase (PI-3 kinase) Pima Native Americans, Type 2 diabetes studies 104 P K A see protein kinase A PKB see protein kinase Β PKC see protein kinase C plants, β-oxidation in 37 pleckstrin homology domain, binding 98 P/O ratios, integral vs. non-integral values 15, 20, 21 porin, in outer membrane 10 porphobilinogen (PBG), biosynthesis 58,59 porphobilinogen deaminase, deficiency 58 porphobilinogen synthase deficiency 59 inhibition 52 porphyria cutanea tarda, aetiology 59 porphyrias acute intermittent 59 aetiology 58 porphyrin, metabolism 58-9 potassium channels, adenosine triphosphate sensistive 102,103 PP-1 see protein phosphatase-1 (PP-1) PP-2A see protein phosphatase-2A (PP-2A) pravastatin 89 pregnenolone, biosynthesis 88 prenylated proteins 89 preproinsulin, metabolism 103 progesterone, biosynthesis 88 proinsulin, metabolism 103 proline biosynthesis 42,43 catabolism 46,47 proline oxygenase, catalysis 46 propionyl CoA carboxylase, deficiency 52,53 prostaglandins, precursors 86 protein, as source of energy 44 protein kinase A activation 102 glycogen synthase phosphorylation 66, 67 release 62 roles 64,65, 74 protein kinase B, functions 98 protein kinase C activation 93 stimulation 102,103 protein metabolism in diabetes niellitus 100 to acetyl CoA 50, 51 to fatty acids 50-1 protein phosphatase-1 (PP-1) inactivation 64, 65, 66, 67 regulatory mechanisms 106 protein phosphatase-2A (PP-2A) phosphorylase kinase dephosphorylation 64, 65 roles, in glycogen biosynthesis regulation 66, 67 protein phosphatase inhibitor-1, activity 64, 65 protein-tyrosine phosphatase, increased activity 104 proton channels 14 proton extrusion 14

proton transport inhibition 15 processes 14 protoporphyrin IX, biosynthesis 59 protoporphyrinogen IX, biosynthesis 59 PRPP see phosphoribosyl pyrophosphate (PRPP) PRTs see phosphoribosyl transferases (PRTs) purine nucleotide cycle 41,54 and Krebs cycle 70, 71 purinergic agonists, insulin secretion stimulation 103 purines, biosynthesis 32, 54-5, 56,57 pyrirnidines, biosynthesis 32, 56-7 pyruvate biosynthesis 18, 24 reduction 90,91 pyruvate carboxylase catalysis 50 regulatory mechanisms 72, 73 stimulation 72, 106 pyruvate dehydrogenase (PDH) catalysis 50 co factors 18 inhibition 72, 96, 97, 106 metabolic roles 10, 70 phosphorylation 70 regulatory mechanisms 70, 71 pyruvate kinase deficiency 26 in glycolysis 12,68,69 pyruvate/malate cycle, and NADPH+H* biosynthesis 34-5,50,51 'Q cycle', mechanisms

15

Rabson—Mendenhall syndrome, aetiology 104 Rad protein, Ras protein inhibition 104 Raf functions 98 Rapoport—Luebering shunt 26, 27 Ras activated factor see Raf functions Ras proteins 98 inhibition 104 red blood cells oxygen transport 26-7 pentose phosphate pathway 32 respiratory chain in fatty acid oxidation 38 hydrogen transport 18 in mitochondrion 10, 14-15 ribose 5-phosphate, in purine biosynthesis 54, 55, 60, 61 ribosomal S6 kinase (ρθΟ™11) activity 66,67 functions 98 ribulose 5-phosphate, biosynthesis 32 Rieske protein, electron transport 15 RNA, biosynthesis 54 rotenone, electron transport inhibition 15

S A M see 5-adenosylmethionine (SAM) sarco(endo)plasmic reticulum calcium ATPase (SERCA), catalysis 103 SCAD see short-chain acyl CoA dehydrogenase (SCAD) SCHAD see short-chain hydroxyacyl CoA dehydrogenase (SCHAD) sebacic acid see decanedioic acid seeds, sugar biosynthesis 37 SERCA see sarco(endo)plasmic reticulum calcium ATPase (SERCA) serine biosynthesis 42,43 catabolism 46,47 as glycine precursor 54,55 serine hydroxymethyltransferase, catalysis 42, 54,55 sex hormones, biosynthesis 88 short-chain acyl CoA dehydrogenase (SCAD), localization 76 short-chain fatty acids, elongation 86, 87 short-chain hydroxyacyl CoA dehydrogenase (SCHAD), specificity 76 SIDS see sudden infant death syndrome (SIDS) signal transduction, insulin 98-9 simvastatin 89 singlet oxygen, biosynthesis 59 skeletal muscle glucose transporters 96 glycogenosis 62,63 insulin resistance 104-5 skin tumours, treatment 58 Smith—Lemli—Opitz (SLO) syndrome, aetiology 88, 89 sorbinil, as aldose reductase inhibitor 92, 93 sorbitol, metabolism 92-3 sorbitol dehydrogenase, catalysis 93

sport, biochemistry of 96-7 squalene, biosynthesis 89 squalestatin 89 StAR see steroid acute regulatory protein (StAR) starllower oil, therapeutic benefits 86 starvation amino acid metabolism 48-9 brain requirement during 80 and gluconeogenesis 72 stercobilin, biosynthesis 58,59 steroid acute regulatory protein (StAR), regulatory mechanisms 88 steroid hormones, biosynthesis 88 steroids, glucuronate conjugates 92,93 Streptococcus mutatis, and xylitol 92 suberic acid see octanedioic acid suberylglycine, biosynthesis 76, 77 succinate dehydrogenase catalysis 12 inhibition 15 roles, in respiratory chain 10 succinic acid esters, and insulin secretion 103 succiny I acetone, porphobilinogen synthase inhibition 52,59 succinyl CoA biosynthesis 36, 90, 91, 96, 97 condensation 58,59 succinyl CoA synthetase, catalysis 12,54 sucrose, average daily intake 94 sudden infant death syndrome (SIDS), aetiology 76, 77 sugars, biosynthesis, from fats 37 sulphonylurea receptor, potassium channel closure 103 sulphonylureas 103 synaptotagmin, as calcium sensor 102,103

testes, sex hormone biosynthesis 88 testosterone, biosynthesis 88 tetrahydrobiopterin, biosynthesis, impaired 52 tetrahydrofolate (THF), biosynthesis 54,55, 56, 57 tetramethyl-p-phenyldiamine (TMPD), in respiratory chain studies 15 thenoyltrifiuoroacetone, electron transport inhibition 15 thermogenin, and proton transport 15 THF see tetrahydrofolate (THF) thiamine deficiency, and hyperlactataemia 24 threonine, catabolism 46, 47 thymidylate synthase, catalysis 56,57 TMPD see tetramethyl-p-phenyldiamine (TMPD) TNF-ct see tumor necrosis factor-α (TNF-cc) transamination route, urea biosynthesis 40 transdeami nation route, urea biosynthesis 40 triacylglycerol—fatty acid cycle, mechanisms 74, 75, 76 triacylglycerol lipase see hormone-sensitive lipase triacylglycerols biosynthesis 28-9, 30-1, 36, 50-1 ketogenesis 78, 79 lipolysis 74, 75 metabolism 38-9, 100 tricarboxylic acid cycle see Krebs cycle trifunctional enzyme localization 76,77 β-oxidation 84,85 triglycerides see triacylglycerols trimethoprim 55,57 triose kinase, catalysis 94, 95 those phosphates, biosynthesis 20 tripalmitin, hydrolysis 38, 74, 75 triparanol 89 tryptophan catabolism 46,47 oxidation 54,55 tryptophan dioxygenase, catalysis 46 tryptophan pyrrolase see tryptophan dioxygenase tumor necrosis factor-α (TNF-α), and obesity 104 Type 1 diabetes aetiology 102-3 metabolic changes in 100-1 Type 2 diabetes aetiology 102-7 genetic influences 106 and insulin resistance in liver 106-7 in muscle and adipose tissue 104—5 lifestyle influences 106 type I glycogen storage disease see von Gierke's disease type V glycogen storage disease see McArdle's disease type VI glycogen storage disease see Hers' disease type VII glycogen storage disease, aetiology 63 type XI glycogen storage disease see Fanconi—Bickel syndrome tyrosinaemia, type I, aetiology 52,53

tyrosine biosynthesis 42,43 deficiency 52,53 tyrosine kinase, suppression 104 tyrosine residues, autophosphorylation

104

ubiquinol, biosynthesis 14, 15 ubiquinone precursors 88,89 reduction 14, 15 UDP see uridine diphosphate (UDP) UDP glucuronate see uridine diphosphate glucuronate UMP see uridine monophosphate (UMP) unsaturated fatty acids, β-oxidation 82-3, 84, 85 urea biosynthesis 40-1 urea cycle see ornithine cycle uric acid, and gout 60 uridine diphosphate (UDP), phosphorylation 56,57 uridine diphosphate glucose (UDP-glucose), biosynthesis 60,61 uridine diphosphate glucuronate, biosynthesis 92, 93 uridine monophosphate (UMP), biosynthesis 56, 57 uridine triphosphate (UTP) biosynthesis 56,57 reactions, with glucose 1-phosphate 60, 61 urobilin, biosynthesis 58, 59 urobilinogen, biosynthesis 58, 59 uroporphyrinogen I, biosynthesis 58, 59 uroporphyrinogen III, biosynthesis 58, 59 UTP see uridine triphosphate (UTP) valine catabolism 96,97 oxidation 44,45 vanadate, as protein-tyrosine phosphatase inhibitor 104, 105 variegate porphyria, aetiology 59 very-long-chain acyl CoA dehydrogenase (VLCAD), roles, in carnitine shuttle 76, 77 very-long-chain acyl CoA synthetase catalysis 84,55 deficiency 85 very-long-chain fatty acids, chain-shortening 84, 85 very-low-density lipoproteins (VLDLs) secretion 106 triacylglycerol transport 28 Viciafava, toxicity 32 vitamin B 6 , and homocysteine catabolism 55 vitamin Β |2 46 and 'methyl—folate trap' 54,55 vitamin C see ascorbate vitamin D, precursors 88,89 V L C A D see very-long-chain acyl CoA dehydrogenase (VLCAD) VLDLs see very-low-density lipoproteins (VLDLs) von Gierke's disease, aetiology 60, 61 wortmannin, inhibitory activity 98 xanthine monophosphate (XMP), amination 54 X M P see xanthine monophosphate (XMP) xylitol biosynthesis 92,93 dental decay mediation 92 metabolism 92-3 xylulose 5-phosphate, biosynthesis 92, 93 L-xylulose reductase, deficiency 92, 93 Zellweger syndrome, aetiology 88 zona fasciculate, Cortisol biosynthesis 88 zona glomemlosa, aldosterone biosynthesis 88 zona reticularis, Cortisol biosynthesis 88 zymosterol, biosynthesis 89