Medical biochemistry with STUDENT CONSULT online access (medial biochemistry)

Dominiczak, MD Dr Hab Med FRCPath FRCP GlasProfessor of Clinical Biochemistry and Medical Humanities, College of Medical, Veterinary and Life Sciences, University of Glasgow, United King

Marek H Dominiczak, MD (Dr Hab Med) FRCPath FRCP (Glas)

Professor of Clinical Biochemistry and Medical Humanities, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom

Docent in Laboratory Medicine, University of Turku, Finland

Consultant Biochemist, Clinical Biochemistry Service, National Health Service (NHS) Greater Glasgow and Clyde,, Gartnavel General Hospital, Glasgow, United Kingdom

The entire biochemistry on two pages

What this book is – and isn't

Chapter 2: Amino Acids and Proteins

Introduction

Amino acids

Buffers

Peptides and proteins

Purification and characterization of proteins

Analysis of protein structure

Chapter 5: Oxygen Transport

Introduction

Characteristics of mammalian globin proteins

Allosteric Modulation of the Oxygen Affinity of Hemoglobin Selected Topics

Regulation of Enzyme Activity

Enzymatic Measurement of Blood Glucose

Summary

Chapter 7: Hemostasis and Thrombosis

Introduction

Hemostasis

The vessel wall

Platelets and platelet-related bleeding disorders

Coagulation

Fibrinolysis

Summary

Chapter 8: Membranes and Transport

Introduction

Types of transport processes

Examples of transport systems and their coupling

Conservation of energy by coupling with adenosine triphosphate

Mitochondrial synthesis of adenosine triphosphate from reduced coenzymes The mitochondrial electron transport system

Transfer of electrons from NADH into mitochondria

Synthesis of adenosine triphosphate – the chemiosmotic hypothesis

Inhibitors of oxidative metabolism

Regulation of oxidative phosphorylation

Digestion and absorption of carbohydrates

Digestion and absorption of lipids

Digestion and absorption of proteins

The splitting stage of glycolysis

The yield stage of glycolysis – synthesis of ATP by substrate-level phosphorylation Fermentation

Regulation of glycolysis in erythrocytes

Characteristics of regulatory enzymes

Structure of glycogen

Pathway of glycogenesis from blood glucose in liver

Pathway of glycogenolysis in liver

Hormonal regulation of hepatic glycogenolysis

Mechanism of action of glucagon

Mobilization of hepatic glycogen by epinephrine

The pyruvate dehydrogenase complex

Enzymes and reactions of the tricarboxylic acid cycle

Energy yield from the tricarboxylic acid cycle

Anaplerotic (‘building up’) reactions

Regulation of the tricarboxylic acid cycle

Summary

Chapter 15: Oxidative Metabolism of Lipids in Liver and Muscle

Introduction

Activation of fatty acids for transport into the mitochondrion

Oxidation of fatty acids

Ketogenesis – a metabolic pathway unique to liver

Summary

Chapter 16: Biosynthesis and Storage of Fatty Acids

Introduction

Fatty acid synthesis

Fatty acid elongation

Desaturation of fatty acids

Essential fatty acids

Storage and transport of fatty acids: synthesis of triacylglycerols Regulation of total body fat stores

Summary

Chapter 17: Biosynthesis of Cholesterol and Steroids

Introduction

The Cholesterol Molecule

Free and esterified cholesterol

Intestinal absorption of cholesterol

Lipoprotein receptors

Enzymes and LIPID transfer proteins

Pathways of lipoprotein metabolism

Dyslipidemias

Atherosclerosis, atherogenesis and atherothrombosis

THE Assessment of cardiovascular risk

Summary

Chapter 19: Biosynthesis and Degradation of Amino Acids

Introduction

Metabolism of dietary and endogenous proteins

Amino acid degradation

Metabolism of the carbon skeletons of amino acids

Biosynthesis of amino acids

Inherited diseases of amino acid metabolism

Summary

Chapter 20: Muscle: Energy Metabolism and Contraction

Introduction

Muscle structure

The contractile process

Muscle energy metabolism

Tissue engineering and replacement of muscle

Effect of exercise

Summary

Chapter 21: Glucose Homeostasis and Fuel Metabolism: DiabetesMellitus

Introduction

Insulin

The feed–fast cycle

Metabolism during stress

Regulation of food intake

Regulation of energy balance

Nutrigenomics

Main classes of nutrients

Definitions in nutrition science

Essential (limiting) nutrients

Assessing nutritional STATUS

Malnutrition

Obesity

Healthy eating and dietary prevention of disease

Summary

Chapter 23: Role of Kidneys in Metabolism

Body water compartments

Osmolality: osmotic and oncotic pressures

Handling of bicarbonate by the kidneys

Disorders of the acid–base balance

Calcium homeostasis

Disorders of calcium metabolism

Metabolic bone disease

Summary

Chapter 27: Complex Carbohydrates: Glycoproteins

Introduction

Structures and linkages

Interconversions of dietary sugars

Other pathways of sugar nucleotide metabolism

Noncollagenous proteins in the extracellular matrix

Structure of the liver

Liver and carbohydrate metabolism

Liver and protein metabolism

Heme synthesis

Bilirubin metabolism

Drug metabolism

Pharmacogenomics

Biochemical tests of liver function

Classification of liver disorders

Genomics of liver disease

Chapter 32: Deoxyribonucleic Acid

Introduction

Structure of deoxyribonucleic acid

The cell cycle in eukaryotes

Messenger ribonucleic acid: transcription

Post-transcriptional processing of ribonucleic acids Selective degradation or inactivation of ribonucleic acid Summary

Chapter 34: Protein Synthesis and Turnover

Introduction

The genetic code

The machinery of protein synthesis

The process of protein synthesis

Protein folding and endoplasmic reticulum (ER) stress Protein targeting and post-translational modifications Summary

Chapter 35: Regulation of Gene Expression: Basic Mechanisms

The inertness of oxygen

Reactive oxygen species and oxidative stress

Reactive nitrogen species and nitrosative stress

The nature of oxygen radical damage

Innate immune response

Adaptive immune response

T and B lymphocytes

Molecules involved in antigen recognition

Major histocompatibility complex

Principles of hormone action

Biochemical assessment of hormone action

Major types of endocrine pathology

The hypothalamo–pituitary regulatory system

The hypothalamo–pituitary–thyroid axis

The hypothalamo–pituitary–adrenal axis

The hypothalamo–pituitary–gonadal axis

The growth hormone axis

The prolactin axis

Chapter 40: Membrane Receptors and Signal Transduction

Introduction

Types of hormone and monoamine receptors

Receptor coupling to intracellular signal transduction

Brain and peripheral nerve

Cells of the nervous system

Cell cycle

Cytokine receptor signaling

Regulation of cell cycle

Genetic models of increased lifespan

Anti-aging interventions – what works and what doesn't

Summary

Appendix A1: Selected Clinical Laboratory Reference Ranges

Appendix A2: The Fundamentals of Recombinant DNA Technology:Molecular hybridization and DNA cloning

Index

SAUNDERS, an imprint of Elsevier Limited

© 2014, Elsevier Limited All rights reserved

First edition 1999

Second edition 2005

Third edition 2009

Fourth edition 2014

The right of John W Baynes and Marek H Dominiczak to be identified

as authors of this work has been asserted by them in accordance withthe Copyright, Designs and Patents Act 1988

No part of this publication may be reproduced or transmitted in anyform or by any means, electronic or mechanical, including

photocopying, recording, or any information storage and retrievalsystem, without permission in writing from the publisher Details onhow to seek permission, further information about the Publisher'spermissions policies and our arrangements with organizations such asthe Copyright Clearance Center and the Copyright Licensing Agency,

This book and the individual contributions contained in it are

protected under copyright by the Publisher (other than as may benoted herein)

Notices

Knowledge and best practice in this field are constantly

changing As new research and experience broaden our

understanding, changes in research methods, professional

practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on theirown experience and knowledge in evaluating and usingany information, methods, compounds, or experimentsdescribed herein In using such information or methodsthey should be mindful of their own safety and the safety

of others, including parties for whom they have a

professional responsibility

With respect to any drug or pharmaceutical productsidentified, readers are advised to check the most currentinformation provided (i) on procedures featured or (ii) bythe manufacturer of each product to be administered, toverify the recommended dose or formula, the method andduration of administration, and contraindications It is theresponsibility of practitioners, relying on their own

experience and knowledge of their patients, to make

diagnoses, to determine dosages and the best treatmentfor each individual patient, and to take all appropriatesafety precautions

To the fullest extent of the law, neither the Publisher northe authors, contributors, or editors, assume any liabilityfor any injury and/or damage to persons or property as amatter of products liability, negligence or otherwise, orfrom any use or operation of any methods, products,

instructions, or ideas contained in the material herein

ISBN: 978-1-4557-4580-7

e-book ISBN: 978-1-4557-4581-4

Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1

We now present the 4th edition of Medical Biochemistry Our aim

remains, as before, to provide biochemical foundation for the study ofclinical medicine – with down-to-earth practical relevance

A textbook is a snapshot of a field as it exists at the time of writing.Such ‘photographic’ metaphor is appropriate here, becausebiochemistry undergoes constant change; in the period since thepublication of the 3rd edition it has probably changed faster than everbefore

While core metabolic pathways remain largely unchanged, ourunderstanding of underlying regulatory mechanisms is better, thanks

to the progress in identifying signaling pathways In many instances,these pathways have become targets for drugs, and underpin theimpressive therapeutic progress in fields such as oncology

Since completion of the Human Genome Project, genome-wideassociation studies and bioinformatic analyses have allowed us to puttogether a new picture of genetic regulation, the hallmarks of whichare interactions between multiple, heterogeneous transcription factorsand gene promoters, and the emerging field of epigenetics

Behind this are, as had happened many times before in the history

of science, major advances in methodology, including rapidlyexpanding genetic screening The common denominator betweenmethodologies now employed in genetic research laboratories andhospital clinical labs has been the advent of robotics andbioinformatics, and therefore the ability to process – and interpret – anever-increasing amount of data

This edition has again been substantially updated We haverewritten the chapters on lipids, glucose homeostasis, nutrition and

biochemical endocrinology, and added a section on the effects ofexercise on muscle development and cardiovascular health Thechapter on the -omics incorporates new directions in proteomics,metabolomics and recombinant DNA technology.

This edition also benefits from the expertise of new authors whohave shared their perspectives on signaling, fat and glycoconjugatemetabolism, exercise biochemistry, nutrition, and blood coagulationprocesses

We have expanded the chapter on the GI tract as an importantinterface between the organism and the environment, and now have aseparate short chapter on kidney function In both we provide moreinformation on membrane transport systems We remain convincedthat the biochemistry of water and electrolyte balance is as importantfor future clinicians as the key metabolic pathways – and deservemore emphasis in the biochemistry curricula

We have updated literature and web references throughout thetextbook At the same time we were able to eliminate some web links

in this edition, because search engines and websites such as Wikipediaand YouTube now provide quick access to so many rapidly evolvingresources

Throughout the text we strive to explain complex issues as simply

as possible, but try hard not to become superficial Unfortunately, newfields come with new terminologies and numerous additions toscientific slang The discovery of new genes and new signalingpathways means new names and acronyms We identify them herenot as material to be committed to memory, but to help build aknowledge framework without oversimplification The fact that somechapters may seem complex to the uninitiated may also reflect thetrue state of knowledge – the complexity, or even a touch ofconfusion, often present before a coherent picture emerges

The Question Bank (Self-Assessment) and many more resources are

the reader is referred Student Consult also provides links to otherElsevier biomedical textbooks which integrate and build onknowledge of medical biochemistry There is also a companion

publication, Medical Biochemistry Flash Cards, which provides meansfor quick revision.

As before, we welcome comments, criticisms and suggestions fromour readers Many of these suggestions are incorporated in this 4thedition There is no better way to continue the improvement of thistext

Gary A Bannon, PhD, Director

Section on Protein Analytics

Regulatory Division

Monsanto

St Louis, MO, USA

John W Baynes, PhD, Carolina Distinguished Professor Emeritus

Department of Pharmacology, Physiology and Neuroscience

University of South Carolina School of Medicine

Columbia, SC, USA

Graham Beastall, Formerly Consultant Clinical Scientist

Department of Clinical Biochemistry

Royal Infirmary

Glasgow, UK

Hanna Bielarczyk, PhD, Assistant Professor

Head of Department of Laboratory Medicine

Department of Laboratory Medicine

Medical University of Gda sk

Wayne E Carver, PhD, Professor of Cell Biology and Anatomy

Department of Cell Biology and Anatomy

University of South Carolina School of Medicine

Columbia, SC, USA

Marek H Dominiczak, MD Dr Hab Med FRCPath FRCP (Glas), Hon Professor of Clinical Biochemistry and Medical Humanities

College of Medical, Veterinary and Life Sciences, University of Glasgow, UK

Docent in Laboratory Medicine

University of Turku, Finland

Consultant Biochemist

Clinical Biochemistry Service

National Health Service (NHS) Greater Glasgow and Clyde,

Gartnavel General Hospital

Glasgow, UK

†Alan D Elbein, PhD, Professor and Chair

Department of Biochemistry and Molecular Biology

University of Arkansas for Medical Sciences

Little Rock, AR, USA

†Alex Farrell, FRCPath, Consultant Immunologist

Formerly Head of Department of Immunology and Immunopathology

Histocompatibility and Immunogenetics

Western Infirmary

Glasgow, UK

William D Fraser, BSc MD MRCP FRCPath, Professor of Medicine

Norwich Medical School

University of East Anglia

Norwich, UK

Norma Frizzell, PhD, Assistant Professor

Department of Pharmacology, Physiology and Neuroscience

University of South Carolina School of Medicine

Columbia, SC, USA

Junichi Fujii, PhD, Professor of Biochemistry and Molecular Biology

Graduate School of Medical Science

Yamagata University

Yamagata, Japan

Helen S Goodridge, BSc PhD, Research Scientist

Immunobiology Research Institute

Cedars-Sinai Medical Center

Los Angeles, CA, USA

J Alastair Gracie, PhD BSc (Hons), Senior University Teacher

School of Medicine

College of Medical, Veterinary and Life Sciences

University of Glasgow

Glasgow, UK

Alejandro Gugliucci, MD PhD, Director of Research and Sponsored Programs

Associate Dean of Research

Professor of Biochemistry

Touro University California

College of Osteopathic Medicine

Vallejo, CA, USA

Margaret M Harnett, BSc(Hons) PhD, Professor of Immune Signalling

Division of Immunology, Infection and Inflammation

Glasgow Biomedical Research Centre

University of Glasgow

Glasgow, UK

Simon J.R Heales, PhD FRCPath, Professor of Clinical Chemistry

Department of Chemical Pathology

Great Ormond Street Hospital

London, UK

George M Helmkamp, Jr., PhD, Emeritus Professor of Biochemistry

Department of Biochemistry and Molecular Biology

University of Kansas School of Medicine

Kansas City, KS, USA

Koichi Honke, MD PhD, Professor of Biochemistry

Department of Biochemistry

Kochi University Medical School

Kochi, Japan

D Margaret Hunt, BA PhD, Emeritus Professor

Department of Pathology, Microbiology and immunology

University of South Carolina School of Medicine

University of Arkansas for Medical Sciences

Research Career Scientist

Central Arkansas Veterans Healthcare System

Little Rock, AR, USA

W Stephen Kistler, PhD, Professor of Biochemistry

Department of Chemistry and Biochemistry

University of South Carolina

Columbia, SC, USA

Walter Kolch, MD FRSE, Director

Systems Biology Ireland

Pittsburgh, PA, USA

Utkarsh V Kulkarni, MBBS MD MRCP DipRCPath, Senior Research Fellow Centre for Obesity Research and Epidemiology

The Robert Gordon University

Gordon D.O Lowe, DSc MD FRCP, Emeritus Professor

Institute of Cardiovascular & Medical Sciences

University of Glasgow

Glasgow, UK

Masatomo Maeda, PhD, Professor of Molecular Biology

Department of Molecular Biology

Laboratory of Food and Regulation Biology

School of Agriculture

Tokai University Kawayou, Minamiaso

Kumamoto, Japan

Jeffrey R Patton, PhD, Associate Professor

Department of Pathology, Microbiology, and Immunology

University of South Carolina School of Medicine

Columbia, SC, USA

Verica Paunovi , Postdoctoral Researcher

Institute of Microbiology and Immunology

School of Medicine, University of Belgrade,

Belgrade, Serbia

Andrew R Pitt, BSc DPhil, Professor of Pharmaceutical Chemistry and Chemical Biology Aston University

Birmingham, UK

Matthew Priest, MbChB FRCP(Glas), Consultant Gastroenterologist

Gartnavel General Hospital

Glasgow, UK

Allen B Rawitch, PhD, Professor of Biochemistry and Molecular Biology

Vice Chancellor for Academic Affairs

Dean of Graduate Studies

University of Kansas Medical Center

Kansas City, KS, USA

Ian P Salt, BSc PhD, Senior Lecturer in Molecular Cell Biology

Institute of Cardiovascular & Medical Sciences

Mirosława Szczepa ska-Konkel, PhD, Professor of Clinical Biochemistry

Department of Clinical Chemistry

Medical University of Gda sk

Gda sk, Poland

Andrzej Szutowicz, MD PhD, Professor

Department of Laboratory Medicine

Medical University of Gda sk

Poland

Naoyuki Taniguchi, MD PhD, Group Director, Systems Glycobiology Group

RIKEN Advanced Science Institute

Wako, Saitama, Japan

Yee Ping Teoh, FRCPATH MRCP MBBS, Consultant in Chemical Pathology and Metabolic Medicine

Wrexham Maelor Hospital

Robert Thornburg, PhD, Professor of Biochemistry

Department of Biochemistry, Biophysics and Molecular Biology

Iowa State University

Ames, IA, USA

†A Michael Wallace, BSc MSc PhD FRCPath, Professor,

University of Strathclyde

Consultant Clinical Scientist

Department of Clinical Biochemistry

Royal Infirmary

Glasgow, UK

To inspirational academics

Inquisitive students And all those who want to be good doctors

First of all, we wish to thank our contributors for sharing theirexpertise with us and for fitting the writing – again – into their busyresearch, teaching and clinical schedules In the 4th edition, wewelcome several new contributors: Catherine Bagot, Norma Frizzel,Koichi Honke, Fredrik Karpe, Matthew Kostek, Jennifer Logue, AlisonMichie, Matthew Priest, Ryoji Nagai and Ian Salt We are delightedthat they have joined us

We were saddened by the death of our good friends andcontributors to previous editions, A Michael Wallace and Alan D.Elbein

As in the previous editions, we greatly valued the excellentsecretarial assistance of Jacky Gardiner in Glasgow

We are very grateful to students and academics from universitiesaround the world who continue to provide us with comments,criticisms and suggestions

The key to the whole project has been, of course, the Elsevier team.Our thanks go to Nani Clansey, Senior Development Editor, whoenthusiastically steered the project through, and also to Meghan K.Ziegler and Madelene Hyde who formulated the strategy We are verygrateful to the production staff, Anne Collett, Samuel Crowe andAndrew Riley who gave the book its final form

Our inspiration to change and improve this text comes also from

‘the field’ – from the issues, questions and decisions that arise in oureveryday clinical practice, in the outpatient clinics and duringwardrounds Therefore a final thank you goes to all our clinicalcolleagues and doctors in training

ACP acyl carrier protein

ACTase aspartate carbamoyl transferase

ANP atrial natriuretic peptide

APC adenomatous polyposis coli (gene)

apoA, B, etc. apolipoprotein A, B, etc

APRT adenosine phosphoribosyl transferase

APTT activated partial thromboplastin time

AQP aquaporin

ARDS acute respiratory distress syndrome

ARE antioxidant response element

AST aspartate aminotransferase

ATF activation transcription factor

ATM ataxia telangiectasia-mutated gene

ATP adenosine triphosphate

AVP arginine-vasopressin (same as antidiuretic hormone)

AZT azido-2′,3′-dideoxythymidine

Bcl-2 B cell lymphoma protein 2

BMI body mass index

BMR basal metabolic rate

BNP brain natriuretic peptide

CDG congenital disorders of glycosylation

CDGS carbohydrate-deficient glycoprotein syndromes

CGRP calcitonin gene-related peptide

CML chronic myeloid leukemia

CMP cytidine monophosphate

CNS central nervous system

COAD chronic obstructive airways disease (synonym: COPD)

COMT catecholamine-O-methyl transferase

COPD chronic obstructive pulmonary disease (synonym: COAD)

COX-1 cyclooxygenase-1

CK creatine phosphokinase (also CPK)

CPK creatine phosphokinase (also CK)

CPS I, II carbamoyl phosphate synthetase I, II

CPT I, II carnitine palmitoyl transferase I, II

CREB cAMP-response element-binding protein

CRGP calcitonin-related gene peptide

DPPC dipalmitoyl phosphatidyl choline

DVT deep vein thrombosis

EF-1, 2 elongation factor-1,2

EFAs essential fatty acids

EGF epidermal growth factor

eIF-3 eukaryotic initiation factor 3

EMSA electrophoretic mobility shift assay

ENaC epithelial sodium channel

ER endoplasmic reticulum

ERK extracellular signal-regulated kinase

ESR erythrocyte sedimentation rate

FACIT fibril-associated collagen with interrupted triple helicesFAD flavin adenine dinucleotide

FADD a ‘death domain’ accessory protein

FAICAR 5-formylaminoimidazole-4-carboxamide ribonucleotideFAP familial adenomatous polyposis

Fas apoptosis signaling molecule: a ‘death domain’ accessoryprotein (CD95)

FBPase fructose bisphosphatase

FDP fibrin degradation product

FGAR formylglycinamide ribonucleotide

FGF fibroblast growth factor

FHH familial hypocalciuric hypercalcemia

GHRH growth hormone-releasing hormone

GIP glucose-dependent insulinotropic peptide

GlcUA D-glucuronic acid

HBOC Hb-based oxygen carrier

HCM hypercalcemia associated with malignancy

Hct hematocrit

HDL high-density lipoprotein

HGF-R hepatocyte growth factor receptor

HGP Human Genome Project

HGPRT hypoxanthine-guanine phosphoribosyl transferaseHIV human immunodeficiency virus

HLA human leukocyte antigen (system)

HLH helix-loop-helix (motif)

HMG hydroxymethylglutaryl

HMWK high-molecular-weight kininogen

HNPCC hereditary nonpolyposis colorectal cancer

hnRNA heteronuclear ribonucleic acid

HPLC high-performance liquid chromatography

HPT hyperparathyroidism

HRT hormone replacement therapy

HTGL hepatic triglyceride lipase

HTH helix-turn-helix (motif)