Functional Biochemistry in Health and Disease E-Book

Eric Newsholme

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1499

Veröffentlichungsjahr: 2011

Beschreibung

Functional Biochemistry in Health and Disease provides a clear and straightforward account of the biochemistry that is necessary to understand the physiological functions of tissues or organs essential to the life of human beings. Focusing on the dynamic aspects of biochemistry and its application to the basic functions of the body, the book bridges the gap between biochemistry and medical practice.

Carefully structured within five sections, each biochemical, physiological or medical subject that is covered in the book is presented in one complete chapter. Consequently, each subject can be read and studied in isolation although cross-sectional links between the subjects are included where necessary. Background material, both biochemical and medical, that is necessary for an understanding of the subject, is included at the start of each chapter and clear, relevant diagrams enhance students' understanding.
* Focuses on medically relevant aspects of biochemistry written from a physiological rather than a chemical perspective.
* Clear presentation that minimises the use of jargon.
* Each chapter contains boxes on related topics, relevant diagrams and a brief glossary.
* Coverage includes athletic performance, apoptosis and the immune system.
* Key historical developments are included to show how modern biochemistry has evolved.

By linking biochemistry, medical education and clinical practice this book will prove invaluable to students in medical and health sciences, biomedical science and human biology taking an introductory biochemistry course. In addition it will appeal to biochemistry and biology students interested in clinical applications of biochemistry.

Leseprobe

Contents

Preface

Abbreviations

Acknowledgements

I: INTRODUCTION

1 The Structural and Biochemical Hierarchy of a Cell and a Human

Cell structure

Tissues

The whole human

The biochemical hierarchy

II: ESSENTIAL TOPICS IN DYNAMIC BIOCHEMISTRY

2 Energy: In the Body, Tissues and Biochemical Processes

Energy transformations in the whole body

Energy transformations in tissues and organs

Energy transformation in biochemical reactions and pathways

Adenosine triphosphate: its role in the cell

3 Enzymes: Activities, Properties, Regulation and Physiology

Nomenclature and classification

Basic facts

Mechanisms by which an enzyme enhances the rate of a reaction

Cofactors and prosthetic groups

Factors that change the activity of an enzyme

Allosteric inhibition

The physiological signicance of Km and Vmax values

Enzymes as tools

Enzymes in diagnosis

Enzymes as therapeutic agents

Enzymes as targets for therapy

Kinetic structure of a biochemical pathway

Regulation of enzyme activity

4 Transport into the Body: The Gastrointestinal Tract, Digestion and Absorption

Gross structure of the gastrointestinal tract

Biochemistry of cooking and food preparation

Digestion and absorption

The gastrointestinal tract and disease

5 Transport into the Cell: Particles, Molecules and Ions

Structure of the plasma membrane

Diffusion through membranes

Active transport

Primary active transport

Endocytosis and exocytosis

Physiological importance of some transport systems

III: ESSENTIAL METABOLISM

6 Carbohydrate Metabolism

Glyco lysis

The biochemical and physiological importance of anaerobic glycolysis

Regulation of the 9ux through glycolysis

Glycogen synthesis

Synthesis of fructose and lactose

The pentose phosphate pathway

Gluconeogenesis: glucose formation from non-carbohydrate sources

The physiological pathway of gluconeogenesis

Role of the liver in the regulation of the blood glucose concentration

Hormones and control of gluconeogenesis

Regulation of glycolysis and gluconeogenesis by ATP/ADP concentration ratio in the liver

Hypoglycaemia

Hyperglycaemia

7 Fat Metabolism

Fats in nutrition

Fat fuels

Physiological importance of fat fuels

Limitations or drawbacks of fats as a fuel

Genetic defects in fatty acid oxidation

Pathological concentrations of fat fuels

8 Amino Acid and Protein Metabolism

Introduction

Sources of amino acids

Protein and ami no acid requirements

Fate of amino acids

Central role of transdeamination

Amino acid metabolism in different tissues

Glutamine: an amino acid of central importance

Urea ‘salvage’

9 Oxidation of Fuels and ATP Generation: Physiological and Clinical Importance

The Krebs cycle

The electron transfer chain

Oxidative phosphorylation

Coupling of electron transfer with oxidative phosphorylation

Transport into and out of mitochondria

‘Energy’ transport in the cytosol: the creatine/phosphocreatine shuttle

Regulation of fluxes

The physiological importance of mitochondrial ATP generation

The effect of ageing on ATP generation

10 Metabolism of Ammonia and Nucleic Acids

Roles of ammonia

Urea synthesis

Degradation of nucleic acids, nucleotides, nucleosides and bases: the generation of ammonia

Ammonia toxicity

Deficiencies of urea cycle enzymes

11 Synthesis of Fatty Acids, Triacylglycerol, Phospholipids and Fatty Messengers: The Roles of Polyunsaturated Fatty Acids

Synthesis of long-chain fatty acids

Unsaturated fatty acids

Essential fatty acids

Phospholipids

Fatty messenger molecules

Fatty acids in neurological and behavioural disorders

12 Hormones: From Action in the C to Function in the Body

Endocrine hormones: traditional and novel

The action, effects and functions of a hormone

Action of hormones

The biochemical and physiological effects of a hormone

Pheromones

Kinetic principles that apply to hormone action

IV: ESSENTIAL PROCESSES OF LIFE

13 Physical Activity: In Non-Athlet Athletes and Patients

The mechanical basis of movement by skeletal muscle

Structure of muscle

Proteins involved in muscle action

Mechanism of contraction: the cross-bridge cycle

Regulation of contraction

Fuels for various athletic events and games

Fatigue

Fatigue in patients

Physical training

Health bene1ts of physical activity

Health hazards of physical activity

Skeletal muscle diseases

14 Mental Activity and Mental Illness

Mental activity

Electrical communication

Chemical communication

Fuels and energy metabolism in the brain

Mental illnesses: biochemical causes

Recreational drugs

15 Nutrition: biochemistry, physiology and pathology

Basic information required for discussion of some biochemical aspects of nutrition

Vitamins

Minerals

A healthy diet

Nutrition for speci:c activities or conditions

Overnutrition

Malnutrition

Functional foods and nutraceuticals

Nutrition for patients with genetic disorders

Vegetarian diets

Eating disorders

16 Starvation: Metabolic Changes, Survival and Death

Mechanisms for the regulation of the blood glucose concentration

Metabolic responses to starvation

Sequence of metabolic changes from intermediate starvation to death

Progressive decrease in protein degradation in starvation

17 Defence Against Pathogens: Barriers, Enzymes and the Immune System

When the physical barrier is breached

The immune system

Adaptive immunity

Cytokines

Mechanisms for killing pathogens

Killing of in trace llular bacteria and large parasites in the extracellular 1uid

Allergy

Fuels and generation of ATP in immune cells: consequences for a patient

Essential fatty acids and proliferation

The lymph nodes

Tolerance

Chronic inflammation and autoimmunity

Immunosuppressive agents

Conditions that reduce the effectiveness of the immune system

Factors that increase the effectiveness of the immune system

Return of the ‘old’ infectious diseases

New infectious diseases

Defence in the intestine

18 Survival After Trauma: Metabolic Changes and Response of the Immune System

Physiological and metabolic responses: the ebb & flow phases

Nutrition

Mobilisation of triacylglycerol and protein in trauma

Metabolic changes in trauma and in starvation

Fever

Summary of the effects of trauma on the immune system and the whole body

19 Sexual Reproduction

Male reproductive system

Female reproductive system

The menstrual cycle

Ovulation

Chemical communication in male and female reproduction

Coitus and the sexual response in the male and female

Fertilisation

Pregnancy

Parturition

Contraception

The menopause

Sexually transmitted diseases

20 Growth and Death of Cells and Humans: The Cell Cycle, Apoptosis and Necrosis

Introduction to cell proliferation

The cell cycle

Death

V: SERIOUS DISEASES

21 Cancer: Genes, Cachexia and Death

Basic information

Oncogenes and proto-oncogenes

Proteins expressed by oncogenes

Processes by which proto-oncogenes can be activated or converted to oncogenes

Tumour suppressor genes

Telomeres and telomerase in tumour cells

Metastasis

Metabolic changes in cancer patients

Overview of cancer

Cancer-causing agents or conditions

Chemotherapy

Radiotherapy

22 Atherosclerosis, Hypertension and Heart Attack

Atherosclerosis

Hypertension

Heart attack (myocardial infarction)

Index

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Library of Congress Cataloguing-in-Publication Data

Newsholme, E. A.

Functional biochemistry in health and disease / Eric Arthur Newsholme and Tony R. Leech.

p. cm.

Includes bibliographical references and index.

ISBN 978-0-471-98820-5 (cloth) - ISBN 978-0-471-93165-2 (pbk.) 1. Biochemistry. 2. Metabolism. I. Leech, A. R. II. Title. QP514.2.N48 2009 612′.015–dc22

2009007437

ISBN: 978 0 471 98820 5 (HB) and 978 0 471 93165 2 (PB)

A catalogue record for this book is available from the British Library.

Set in 10/12 pt Times by SNP Best-set Typesetter Ltd., Hong Kong Printed in Singapore by Markono Print Media Pte. Ltd.

First printing 2010

To

Pauline Newsholme and Barbara Leech for patience, encouragement and a willingness to share their husbands

with biochemistry.

Preface

This text attempts to provide a clear and straightforward account of the biochemistry underlying the physiological functions of different cells, tissues or organs essential for human life. The approach highlights the contribution that functional biochemistry makes to health and, when it is disturbed, to ill health and disease. It attempts to link biochemistry, medical education and clinical practice. Structural biochemistry and molecular biology are kept to a minimum in favour of a focus on the dynamic aspects of biochemistry and its immediate importance for health.

Unfortunately, in many medical or biomedical pro grammes, biochemical education has been reduced to the presentation of basic facts. It is the aim of this book to provide the link between these facts and medical practice to achieve a more complete biochemical education. Each topic is presented in one complete section or one chapter, which can be studies independently, unencumbered by extraneous material. Nonetheless, cross-references between topics are emphasised to help the student appreciate the common biochemical principles underlying health and disease.

Both authors and the editorial assistant have collabo rated on each chapter; there have been no other contribu tors. Since the authors are not expert in all areas, much research in journals, reviews and books has been under taken. The challenge faced has therefore been the same as that faced by every student entering a field for the first time and for this reason the authors hope to have been better placed to clarify the biochemistry which underlies physiology and pathology.

Background material necessary to tackle the core of each topic is provided in the introduction to each section or chapter. Students, including graduates, who are entering courses in medicine or the biomedical sciences, and who have limited knowledge of biochemistry, physiology or pathology, should find these introductions of particular value. Our approach should also help students who are taking courses which involve problem-based learning or who are preparing seminars. We hope, too, that it might be of use to physicians, surgeons and academics in under standing the biochemical background of illness and disease and help them to prepare lectures, reports and grant applications.

The manner in which biochemical and physiological knowledge and ideas are presented should help the student to develop the skills of critical analysis, debate issues and even challenge some of the dogmas in biomedicine. Such opportunities are not always available when there is over-dependence on electronic sources of information.

The topics covered in this book are presented in five Sections:

IntroductionEssential topics in dynamic biochemistryEssential metabolismEssential processes of lifeSerious diseases

Problems of ill health are discussed in most of these Sec tions, including fatigue, allergies, nutritional deficiencies, AIDS, chronic fatigue syndrome, Creutzfeldt-Jacob disease, malaria, neurological and eating disorders, tuberculosis, cancer and the deadly trio: atherosclerosis, hyper tension and heart attack. The conditions of obesity, diabetes mellitus and disorders of fat metabolism are included in the on-line Appendices to allow full discussion and the clarification (and correction) of important aspects. The Appendices can be found on the companion website for the book – visit www.wiley.com/go/newsholme/biochemistry The reader will also find here a compilation of the book’s figures and a full list of the References referred to throughout the text.

Eric A. Newsholme Tony R. Leech

Acknowledgements

The authors wish to thank Professor Craig Sharp, Professor Philip Newsholme and Lindy Castell for their considerable help in providing much helpful information and for reading and constructively criticising the chapters relevant to their own fields. We also wish to thank Lindy Castell for carry ing out literature searches and for introducing us to many of her clinical and physiological colleagues who were willing to answer specific queries.

Despite it being the age of the computer, the first drafts of all chapters were written by hand so we owe an enormous debt of gratitude to our typist, Judith Kirby, Fellows’ Secretary at Merton College, Oxford. She miraculously transformed barely legible scribblings into immaculate electronic documents and then coped uncomplainingly with numerous further alterations.

We are exceedingly grateful for the way in which Ruth Swann was able to improve the proofs by detecting lack of clarity in places and by suggesting organisational improvements. She accepted what were sometimes quite substantial handwritten changes with good humour and executed them with deft professionalism.

We wish to identify three books which provided useful information on topics which were not otherwise easily available or accessible:

Modern Nutrition in Health and Disease (2006) by Maurice Shils, Moshe Shike, Catharine Ross, Benjamin Caballero & Robert Cousins. Lippincott Williams & Wilkins.The Encyclopedia of Molecular Biology (1994) edited by John Kendrew. Blackwell Science.The Fats of Life (1998) by Caroline Pond. Cambridge University Press.

A further three books provided valuable information which extended the coverage of a number of topics which were not specifically biochemical:

The Faber Book of Science (1995) edited by John Carey. Faber & Faber (London).Drug Discovery: the Evolution of Modern Medicines (1995) by Walter Sneader. John Wiley & Sons, Ltd. (Chichester).The Oxford Medical Companion (1994) edited by John Walton, Jeremiah Barondess and Stephen Lock, Oxford University Press.

Abbreviations

acetyl-CoA

acetyl-coenzyme-A

ACE

angiotensin-converting enzyme

ACP

acyl carrier protein

ACTH

adrenocorticotropic hormone

ADH

antidiuretic hormone

ARDS

adult respiratory distress syndrome

ALT

alanine aminotransferase

AMP

adenosine monophosphate

APC

antigen-presenting cell

APP

amyloid precursor protein

AST

aspartate aminotransferase

ATP

adenosine triphosphate

BMR

basal metabolic rate

BCAA

branched-chain amino acid

BMI

body mass index

cAMP

cyclic AMP (cyclic 3’,5’-adenosine monophosphate)

CHD

coronary heart disease

CJD

Creutzfeldt-Jacob Disease

CNS

central nervous system

CPS-I

carbamoyl phosphate synthetase

CoA

coenzyme A

CoASH

reduced coenzyme A

COX-1 and

cyclooxygenase enzyme

COX-2

DAG

diacylglycerol

DTH

delayed-type hypersensitivity

DIC

disseminated intravascular coagulation

DNA

deoxyribonucleic acid

EFA

essential fatty acid

ELISA

enzyme-linked immunoabsorbent assay

FABP

fatty acid binding protein

FAD

flavin adenine dinucleotide

FFA

free fatty acid

FSH

follicle-stimulating hormone

G1P

glucose 1-phosphate

G6P

glucose 6-phosphate

GABA

gamma-aminobutyrate

GALT

gut-associated lymphoid system

GDP

guanosine diphosphate

GIP

glucose-dependent insulinotrophic polypeptide

GMP

guanosine monophosphate

GnRH

gonadotrophin-releasing hormone

GLP

glucagon-like peptide

GOT

glutamate-oxaloacetate transaminase

GPCR

G-protein coupled receptor

GPT

glutamate-pyruvate transaminase

GTP

guanosine triphosphate

HK

hexokinase

HRT

hormone replacement therapy

HDL

high density lipoprotein

IRS

insulin receptor substrate

IMP

inosine monophosophate

IP3

inositol trisphosphate

IRS

insulin-receptor substrate

IRP

iron-regulating protein

Km

Michaelis constant

kDa

kilodalton

LCAT

lecithin-cholesterol acyl transferase

LH

luteinising hormone

LO

lipoxygenase

LGIC

ligand-gated ion channel

LDL

low density lipoproteins

LSD

lysergic acid diethylamide

Mmolar

(mol/litre)

mM

millimolar (mmol/litre)

MDA

methylene dioxyamphetamine

MODY

maturity onset diabetes in the young

mol

mole

mmol

millimole

MOF

multiple organ failure

MSF

multiple systems failure

MW

molecular weight

mV

millivolt(s)

ME

myalgic encephalomyelitis

MLCK

myosin light chain kinase

mRNA

messenger RNA

NAD+

nicotinamide adenine dinucleotide

NADH

reduced nicotinamide adenine dinucleotide

NADP+

nicotinamide adenine dinucleotide phosphate

NADPH

reduced nicotinamide adenine dinucleotide phosphate

NAGS

N-acetylglutamate synthetase

NEFA

non-esterifi ed fatty acids

NSAIDs

non-steroidal anti-infl ammatory drugs

OGDH

oxoglutarate dehydrogenase

PAF

platelet activating factor

PAH

phenylalanine hydroxylase

PEM

protein-energy defi ciency

Pi

phosphate ion

PIP2

phosphatidylinositol bisphosphate

PKU

phenylketonuria

PPi

pyrophosphate ion

PTH

parathyroid hormone

PUFAs

polyunsaturated fatty acids

ROS

reactive oxygen species

REE

Resting energy expenditure

RDA

recommended daily allowance

SAM

S-adenosyl methionine

SR

sarcoplasmic reticulum

SIRS

systemic infl ammatory response syndrome

TNF

tumour necrosis factor

TAG

triacylglycerol

UDP

uridine diphosphate

UDPG

UDP-glucose

VLDL

very low density lipoprotein

v-onc

viral oncogene

Vmax

maximal velocity

VFA

volatile fatty acids

I

INTRODUCTION

1

The Structural and Biochemical Hierarchy of a Cell and a Human

There is no magician’s mantle to compare with skin in its diverse roles of waterproof overcoat, sunshade, suit of armor and refrigerator, sensitive to the touch of a feather, to temperature and to pain, withstanding wear and tear of three score years and ten, and executing its own running repairs.

(Lockhartet al., 1959)

It is conventional to describe the structure of an organism in hierarchical terms: organelles make cells; cells make tissues; tissues make organs; organs make people. It is also possible to consider biochemistry in the same way. The biochemistry in the organelles contributes to that of the cell, which contributes to that of the tissues and organs and, eventually, they all contribute to the biochemistry and physiology that constitute the processes of life of a human. Indeed, the normal functioning of this hierarchy provides the basis for health and, when any component fails, the basis of disease.

In 1665, Robert Hooke examined thin slices of cork under his very simple microscope and discovered small, box-like spaces which he named cells. A few years later the Italian anatomist Marcello Malpighi described similar structures in animal tissues, which he called vesicles or utricles and, in 1672, the English botanist Nehemiah Grew published two extensively illustrated volumes greatly extending Hooke’s findings. The concept of the cell as a unit of structure in the plant and animal kingdoms was launched, but it was two centuries later before scientists generally accepted the idea of the cell as the fundamental structural unit of living organisms. The ‘cell theory’ attributed to Matthias Schleiden & Theodor Schwann, was proposed in 1838: the cell is the smallest component of life that can exist independently. All living organisms are composed of cells and, as concluded by Rudolf Virchow in 1855, cells can arise only from pre-existing cells. Multicellular organisms develop from one cell (a fertilised egg), which differentiates into many different cell types. The number of cells in a multicellular organism varies greatly from one organism to another. The average human comprises approximately 100 million million (1014) cells.

Most human cells have diameters in the range 10–20 ilm. A spherical cell of diameter 15 μm would have a volume of 1.8 × 10–9 mL and contain around 2.5 × 109 molecules of protein and 4.5 × 1013 molecules of water. A single drop of blood (0.05 mL) contains around 2.25 × 108 red blood cells.

Cell structure

The detailed knowledge of the structure and function of cells is largely due to the introduction of the electron microscope in the 1940s and the subsequent development of biochemical and cell biological techniques.

All cells are surrounded by a thin lipid membrane. This is a selective barrier, allowing some substances to pass across it and excluding others in order to maintain a relatively constant internal environment. Some of the different proteins that are embedded in the cell membrane transport compounds and ions across the membrane, whereas others act as receptors that respond to factors in the external environment and initiate responses within the cell, and still others provide a mechanism for cells to interact and communicate with each other.

Subcellular structures (organelles) are present in the cell. Each one has its own characteristic activities and properties that work together to maintain the cell and its functions. The remainder of the cell is the gel-like cytoplasm, known as cytosol (Figure 1.1). The largest organelle in the cell is the nucleus: it contains the genetic material, deoxyribonucleic acid (DNA). Through the information contained in a coded form within its chemical structure, DNA determines to a large extent, but not completely, the specifi c morphological and biochemical characteristics of each type of cell.

Figure 1.1Diagrammatic representation of cell organelles as seen under an electron microscope.

Figure 1.2Diagrammatic representation of the plasma membrane. Arrangement of integral and peripheral membrane proteins with the molecular layer of phospholipids is shown.