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Biochemistry And Molecular Biology

by: Elliott, William H.; Elliott, Daphne C.

Biochemistry And Molecular Biology

by: Elliott, William H.; Elliott, Daphne C.

ISBN 13:
9780199271993
ISBN 10:
0199271992
Edition: 3rd
Format: Paperback
Copyright: 02/03/2005
Publisher: Oxford University Press
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Summary

An understanding of biochemistry and molecular cell biology opens the door to an understanding of life itself. Biochemistry and Molecular Biology is perfectly suited to opening up this subject to the widest range of students, giving insights into this fascinating area with which everybiological and biomedical science student should be familiar. Biochemistry and Molecular Biology takes students from the fundamentals of cell biology and biochemistry to the latest advances in genomics and proteomics, maintaining a wonderful clarity, enriched by carefully layered explanations and vivid illustrations throughout. New Organisation The third edition has undergone substantial re-structuring to facilitate its use by students with little prior understanding of the subject area. New Pedagogy - Summaries at the end of each chapter which highlight the key concepts presented and aid revision. - Boxed applications illuminate the concepts being introduced, describing medical examples and health-related issues. - More problems at the end of each chapter. Supplementary resources The companion web site will contain illustrations from the book, Web links, course outlines as PowerPoint slides, checklists of key concepts, discussion points and questions for each chapter, plus answers to the discussion points, questions, and problems in the textbook.

Preface

Acknowledgements

List of abbreviations

xxxi

Part 1 Basic concepts of life

The basic molecular themes of life

(12)

Unity of life at the molecular level

(1)

Living cells obey the laws of physics and chemistry: the energy cycle in life

(1)

ATP (adenosine triphosphate) is the universal energy currency in life

(1)

Types of molecule found in living cells

(1)

Small molecules

(1)

The macromolecular constituents of cells

(1)

Proteins

(2)

Catalysis of reactions by enzyme proteins is central to the existence of life

(2)

Evolution of proteins

(1)

Development of new genes

(1)

DNA (deoxyribonucleic acid)

(3)

DNA can direct its own replication

(1)

Junk DNA

(1)

Molecular recognition by proteins

(1)

Noncovalent or weak chemical bonds

(1)

How did it all start?

(2)

The RNA world

(1)

The new `omics' phase of biochemistry and molecular biology

(1)

Summary

(1)

Further reading

(1)

Cells and viruses

(12)

Cells are the units of all living systems

(1)

Classification of organisms

(5)

Prokaryotic cells

(1)

Cell division in prokaryotes

(1)

Eukaryotic cells

(3)

Eukaryotic cell growth and division

(1)

Stem cells

(3)

Mitosis and cell division in eukaryotic cells

(1)

Meiosis

(2)

Viruses

(2)

Genetic material of viruses

(1)

Some examples of viruses of special interest

(1)

Retroviruses

(1)

Summary

(1)

Further reading

(1)

Problems

(1)

Energy considerations in biochemistry

(20)

What determines whether a chemical reaction is possible?

(1)

Reversible and irreversible reactions and ΔG values

(1)

The importance of irreversible reactions in the strategy of metabolism

(1)

Why is this metabolic strategy used in the cell?

(1)

How are ΔG values obtained?

(1)

Standard free-energy values and equilibrium constants

(1)

Given that a reaction has a negative ΔG value, what determines whether it actually takes place at a perceptible rate in the cell?

(1)

How is food breakdown in cells coupled to drive energy-requiring reactions?

(6)

The high-energy phosphate compound

(1)

What is a `high-energy phosphate compound'?

(1)

What are the structural features of high-energy phosphate compounds?

(2)

What transports the --P around the cell?

(1)

How does ATP perform chemical work?

(1)

Calculation of ΔG value

(1)

How does ATP drive other types of work?

(1)

A note on the relationship between AMP, ADP, and ATP

(1)

Covalent and noncovalent bonds

(2)

What causes weak bond formation and breakage?

(1)

The vital role of weak bonds in molecular recognition

(1)

Appendix: Buffers and pKa values

(3)

pKa values and their relationship to buffers

(2)

Summary

(1)

Further reading

(1)

Problems

(5)

Part 2 Structure and function of proteins and membranes

The structure of proteins

(27)

The primary structure of proteins

(5)

What is a native protein?

(1)

What are the basic considerations which determine the folded structure of a protein?

(1)

Structures of the 20 amino acids

(1)

Hydrophobic amino acids

(1)

Hydrophilic amino acids

(1)

Amino acids for special purposes

(1)

Ionization of amino acids

(1)

Symbols for amino acids

(1)

The different levels of protein structure---primary, secondary, tertiary, and quaternary

(5)

Secondary structure of proteins

(1)

The α helix

(1)

The β-pleated sheet

(1)

Connecting loops

(1)

Tertiary structure of proteins

(1)

How do the three motifs--the α helix, the β-pleated sheet, and connecting loops--make up a protein?

(1)

What forces hold the tertiary structure in position?

(1)

Where do the disulphide or S--S covalent bonds come into protein structure?

(1)

Quaternary structure of proteins

(1)

Protein homologies and evolution

(1)

Protein domains

(1)

Domain shuffling

(1)

The problem of protein folding

(1)

Membrane proteins

(1)

Conjugated proteins

(1)

Extracellular matrix proteins

(13)

Structure of collagens

(2)

Genetic diseases of collagen

(1)

Structure of elastin

(1)

Structure of proteoglycans

(2)

Adhesion proteins of the extracellular matrix

(1)

Integrins are important signalling proteins

(1)

Myoglobin and haemoglobin--an illustration of how protein structure is related to function

(1)

Myoglobin

(1)

Structure of haemoglobin

(1)

Binding of oxygen to haemoglobin

(1)

How is the sigmoidal oxygen saturation curve achieved?

(1)

Theoretical models to explain protein allosterism

(1)

Mechanism of the allosteric change in haemoglobin

(1)

The essential role of 2:3-bisphosphoglycerate (BPG) in haemoglobin function

(1)

Effect of pH on oxygen binding to haemoglobin

(1)

Role of pH changes in oxygen and CO2 transport

(1)

Sickle cell anaemia and thalassaemias

(1)

pH buffering in the blood

(1)

Summary

(1)

Further reading

(1)

Problems

(2)

Methods in protein investigation

(16)

Purification of proteins

(4)

Column chromatography

(1)

SDS polyacrylamide gel electrophoresis

(1)

Immunological detection of proteins

(1)

Methods of protein sequencing

(1)

The role of databases in protein sequencing

(1)

Deduction of amino acid sequences of proteins from the base sequences of genes

(1)

Determination of the three-dimensional structure of proteins

(1)

X-ray diffraction

(1)

Nuclear magnetic resonance

(1)

Homology modelling

(1)

An exercise in obtaining a 3-D structure from a protein database

(1)

Analysis of proteins by mass spectrometry

(2)

Introduction

(1)

Mass spectrometers consist of three principal components

(1)

Ionization methods for protein and peptide MS

(1)

Types of mass analyser

(1)

Quadrupole (Q)

(1)

Time of flight (TOF)

(1)

Ion-trap

(1)

Types of mass spectrometer

(1)

Single-analyser mass spectrometers

(1)

Tandem mass spectrometers (MS/MS)

(1)

Identification of proteins using MS for peptide mass analysis (`fingerprinting') and database searching

(1)

Identification of proteins by limited sequencing and database searching

(1)

Sequencing a protein by MS

(1)

Molecular-weight determination of proteins

(1)

Analysis of posttranslational modification of proteins

(1)

Proteomics and MS

(1)

Bioinformatics and databases

(1)

A bioinformatics overview

(1)

Database website addresses

(1)

Appendix: An example of how the structure of a protein can be obtained from the protein data bank (PDB)

(2)

Summary

(1)

Further reading

(1)

Problems

(1)

Enzymes

(15)

Enzyme catalysis

(3)

The nature of enzyme catalysis

(1)

The induced-fit mechanism of enzyme catalysis

(1)

Enzyme kinetics

(2)

Hyperbolic kinetics of a `classical' enzyme

(2)

Allosteric enzymes

(1)

General properties of enzymes

(3)

Nomenclature of enzymes

(1)

Isozymes

(1)

Enzyme cofactors and activators

(1)

Effect of pH on enzymes

(1)

Effect of temperature on enzymes

(1)

Effect of inhibitors on enzymes

(1)

Reversible and irreversible inhibitors

(1)

Competitive and noncompetitive inhibitors

(1)

What are the structural features of enzyme proteins that confer catalytic activity on them?

(4)

Mechanism of the chymotryps in reaction

(1)

The catalytic triad of the active centre

(1)

The reactions at the catalytic centre of chymotrypsin

(2)

What is the function of the aspartate residue of the catalytic triad?

101

(1)

Other serine proteases

101

(1)

A brief description of other types of protease

101

(1)

Summary

102

(1)

Further reading

103

(1)

Problems

104

(1)

The cell membrane and membrane proteins

105

(25)

Basic lipid architecture of membranes

105

(7)

The polar lipid constituents of cell membranes

105

(1)

Glycerophospholipids

106

(1)

What are the polar groups attached to the phosphatidic acid?

107

(1)

Sphingolipids

108

(1)

Membrane lipid nomenclature

109

(1)

Why are there so many different types of membrane lipid?

110

(1)

The fatty acid components of membrane lipids

110

(1)

What is cholesterol doing in membranes?

111

(1)

The self-sealing character of the lipid bilayer

111

(1)

Permeability characteristics of the lipid bilayer

112

(1)

Membrane proteins and membrane design

112

(1)

Structures of integral membrane proteins

112

(3)

Anchoring of peripheral membrane proteins to membranes

114

(1)

Glycoproteins

114

(1)

Functions of membranes

115

(12)

Transport of substances in and out of the cell

115

(1)

Active transport

115

(1)

Calculation of energy required for transport

115

(1)

Mechanism of the Na+ /K+ pump

115

(1)

Cardiac glycosides

116

(1)

Symport systems

117

(1)

Antiport systems

117

(1)

Uniport systems

117

(1)

Passive transport or facilitated diffusion

118

(1)

Gated ion channels

118

(1)

Mechanism of the selectivity of the potassium channel

118

(2)

Nerve-impulse transmission

120

(1)

Cholinesterase inhibitors and Alzheimer's disease

121

(1)

The acetylcholine-gated Na+ /K+ channel or acetylcholine receptor

121

(1)

How does acetylcholine binding to a membrane receptor result in a nerve impulse?

121

(1)

How is the initial signal propagated along nerve axons?

122

(2)

Mechanism for ensuring that the nerve impulse only goes forward

124

(1)

Mechanism of control of the voltage-gated Na+ and K+ channels

124

(1)

Myelinated neurons permit more rapid nerve-impulse transmission

125

(1)

Why doesn't the Na+ /K+ pump conflict with the propagation of action potentials?

125

(1)

Role of the cell membrane in maintaining the shape of the cell

125

(1)

Cell--cell interactions--tight junctions, gap junctions, and cellular adhesive proteins

126

(1)

Membrane-targeted antibiotics

127

(1)

Summary

127

(1)

Further reading

128

(1)

Problems

129

(1)

Muscle contraction, the cytoskeleton, and molecular motors

130

(21)

Muscle contraction

130

(1)

A reminder of conformational changes in proteins

130

(1)

Types of muscle cell and their energy supply

130

(6)

Structure of skeletal striated muscle

131

(1)

Structure of the myofibril

131

(1)

How does the sarcomere shorten?

131

(1)

Structure and action of thick and thin filaments

132

(1)

How does the myosin head convert the energy of ATP hydrolysis into mechanical force on the actin filament?

133

(1)

Mechanism of the conformational changes in the myosin head

133

(1)

Muscular dystrophy

134

(2)

How is contraction in voluntary striated muscle controlled?

136

(2)

How does Ca2+ trigger contraction?

136

(2)

Malignant hyperthermia

138

(1)

How does smooth muscle differ in structure and control from striated muscle?

138

(1)

Control of smooth muscle contractions

138

(1)

How does Ca2+ control smooth muscle contraction?

138

(1)

The cytoskeleton

139

(1)

Molecular motors and movements in cells

139

(1)

The role of actin and myosin in nonmuscle cells

139

(2)

Structural role of actin and its involvement in cell movement

140

(1)

Mechanism of contraction in nonmuscle cells

140

(1)

The role of actin and myosin in intracellular transport of vesicles

141

(1)

Microtubules, cell movement, and intracellular transport

141

(2)

Microtubules and intracellular transport

142

(1)

Molecular motors: kinesins and dyneins

142

(1)

Role of microtubules in cell movement

143

(1)

Role of microtubules in mitosis

143

(1)

Intermediate filaments

143

(1)

Effects of drugs on the cytoskeleton

144

(1)

Summary

144

(1)

Further reading

145

(1)

Problems

146

(5)

Part 3 Metabolism

Food digestion, absorption, distribution to the tissues, and appetite control

151

(17)

Chemistry of foodstuffs

151

(1)

Digestion and absorption

152

(1)

Anatomy of the digestive tract

152

(1)

What are the energy considerations in digestion and absorption?

152

(1)

A major problem in digestion---why doesn't the body digest itself?

153

(1)

Zymogen or proenzyme production

153

(1)

Protection of intestinal epithelial cells by mucous

153

(1)

Digestion of proteins

153

(2)

HCl production in the stomach

153

(1)

Pepsin, the proteolytic enzyme of the stomach

153

(1)

Completion of protein digestion in the small intestine

154

(1)

Activation of the pancreatic proenzymes

154

(1)

Absorption of amino acids into the bloodstream

155

(1)

Digestion of carbohydrates

155

(2)

Digestion of starch

156

(1)

Digestion of lactose

156

(1)

Absorption of monosaccharides

157

(1)

Digestion and absorption of fat

157

(3)

Resynthesis of TAG in intestinal cells

158

(1)

Chylomicrons

158

(1)

Digestion of other components of food

159

(1)

Outline of fuel distribution and utilization by the different tissues of the body

160

(1)

Storage of food components in the body

160

(4)

How are the different food components stored in cells?

160

(1)

Glucose storage as glycogen

160

(1)

Storage of fat in the body

160

(1)

Are amino acids stored by the body?

161

(1)

Characteristics of different tissues in terms of energy metabolism

161

(2)

Overall control of fuel distribution in the body by hormones

163

(1)

Postprandial condition

163

(1)

Fasting condition

163

(1)

Prolonged fasting or starvation

163

(1)

The emergency situation--fight or flight

164

(1)

Regulation of food intake: appetite control

164

(1)

Hormones which control appetite

164

(1)

How do these hormones control appetite?

164

(1)

Can hormones be used therapeutically to control obesity?

165

(1)

Summary

165

(1)

Further reading

166

(1)

Problems

167

(1)

Biochemical mechanisms involved in transport, storage, and mobilization of dietary components

168

(16)

Glucose traffic in the body

168

(8)

Mechanism of glycogen synthesis

168

(1)

How is energy injected into the process?

169

(1)

G-1-P is converted to the activated form, UDPG

170

(1)

Adding branches to glycogen

170

(1)

Breakdown of glycogen to release glucose into the blood

171

(1)

Removing branches from glycogen

172

(1)

Key issues in the interconversion of glucose and glycogen

173

(1)

Why does liver have glucokinase and the other tissues hexokinase?

173

(1)

What happens to other sugars absorbed from the intestine?

173

(1)

Galactose metabolism

174

(1)

Uridyl transferase deficiency and galactosaemia

175

(1)

Amino acid traffic in the body (in terms of fuel logistics)

176

(1)

Fat and cholesterol traffic in the body

176

(4)

Uptake of fat from chylomicrons into cells

176

(1)

Logistics of fat and cholesterol movement in the body

176

(1)

An overview

176

(1)

Utilization of cholesterol in the body

177

(1)

Lipoproteins involved in fat and cholesterol movement in the body

178

(1)

Apolipoproteins

179

(1)

Mechanism of TAG and cholesterol transport from the liver and the reverse cholesterol transport in the body

179

(1)

The role of HDL in cholesterol transport

179

(1)

How does cholesterol exit cells to be picked up by HDL?

179

(1)

Cholesterol homeostasis in cells

180

(2)

Inhibitors of cholesterol synthesis

181

(1)

Release of FFA from adipose cells

181

(1)

How are FFA carried in the blood?

181

(1)

Summary

182

(1)

Further reading

182

(1)

Problems

183

(1)

Principles of energy release from food

184

(12)

Biological oxidation and hydrogen-transfer systems

184

(2)

NAD+ --an important electron carrier

185

(1)

FAD and FMN are also electron carriers

186

(1)

Energy release from glucose

186

(5)

The main stages of glucose oxidation

186

(1)

Stage 1 in the release of energy from glucose; glycolysis

186

(1)

Anaerobic glycolysis

186

(2)

Stage 2 of glucose oxidation: the citric acid cycle

188

(1)

How is pyruvate fed into the citric acid cycle?

188

(1)

What is coenzyme A?

188

(1)

Oxidative decarboxylation of pyruvate

189

(1)

Stage 3 of glucose oxidation: electron transport to oxygen

189

(1)

The electron transport chain--a hierarchy of electron carriers

189

(1)

Redox potentials

189

(1)

Determination of redox potentials

190

(1)

Electrons are transported in a stepwise fashion

190

(1)

Calculation of the relationship between the ΔG0' value and the E'0 value

191

(1)

Energy release from oxidation of fat

191

(1)

Energy release from oxidation of amino acids

192

(1)

The interconvertibility of fuels

192

(2)

A survey of vitamins

194

(1)

Summary

194

(1)

Problems

195

(1)

Glycolysis, the citric acid cycle, and the electron transport system: reactions involved in these pathways

196

(30)

Stage 1--glycolysis

196

(7)

Glucose or glycogen?

196

(1)

Why use ATP here at the beginning of glycolysis?

197

(1)

Why is glucose-6-phosphate converted to fructose-6-phosphate?

197

(1)

Splitting fructose bisphosphate to two C3 compounds

197

(1)

A note on the ΔG0 and ΔG values for the aldolase reaction

198

(1)

Interconversion of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate

199

(1)

Gyceraldehyde-3-phosphate dehydrogenase-- an oxidation linked to ATP synthesis

199

(1)

The final steps in glycolysis

200

(2)

The ATP balance sheet from glycolysis

202

(1)

Reoxidation of cytoplasmic NADH from glycolysis by electron shuttle systems

202

(1)

The glycerol phosphate shuttle

202

(1)

The malate--aspartate shuttle

202

(1)

Transport of pyruvate into the mitochondria

203

(1)

Conversion of pyruvate to acetyl-CoA--a preliminary step before the citric acid cycle

203

(2)

Components involved in the pyruvate dehydrogenase reaction

204

(1)

Stage 2--the citric acid cycle

205

(6)

The citric acid cycle as a water-splitting machine

205

(1)

A simplified version of the citric acid cycle

205

(1)

Mechanisms of the citric acid cycle reactions

206

(1)

The synthesis of citrate

206

(1)

Conversion of citrate to α-ketoglutarate

206

(1)

Citrate → isocitrate

206

(1)

Isocitrate dehydrogenase

207

(1)

The C4 part of the cycle

207

(1)

Generation of GTP coupled to splitting of succinyl-CoA

208

(1)

Conversion of succinate to oxaloacetate

208

(1)

What determines the direction of the citric acid cycle?

209

(1)

Stoichiometry of the cycle

209

(1)

Topping up the citric acid cycle

210

(1)

Biotin is the cofactor for CO2 activation

210

(1)

Stage 3--the electron transport chain that conveys electrons from NADH and FADH2 to oxygen

211

(12)

The electron transport chain

211

(1)

Where does it take place?

211

(1)

Nature of the electron carriers in the chain

211

(1)

Arrangement of the electron carriers

212

(1)

Oxidative phosphorylation---the generation of ATP coupled to electron transport

213

(1)

The chemiosmotic theory of oxidative phosphorylation

214

(1)

How are protons ejected?

214

(1)

The Q cycle in complex III ejects protons from mitochondria

215

(1)

Complex IV also creates a proton gradient

216

(1)

ATP synthesis by ATP synthase is driven by the proton gradient

216

(1)

Structure of ATP synthase

217

(1)

The F1 unit and its role in the conversion of ADP+Pi to ATP

217

(1)

Activities of the enzyme catalytic centres on the F1 subunit

217

(2)

Structure of the F0 unit and its role

219

(1)

Mechanism by which proton flow causes rotation of F0

219

(2)

Transport of ADP into mitochondria and ATP out

221

(1)

The balance sheet of ATP production by electron transport

222

(1)

Yield of ATP from the oxidation of a molecule of glucose to CO2 and H2O

222

(1)

Is ATP production the only use that is made of the potential energy in the proton-motive force?

222

(1)

Inhibitors of oxidative phosphorylation

223

(1)

Summary

223

(1)

Further reading

224

(1)

Problems

224

(2)

Energy release from fat

226

(7)

Mechanism of acetyl-CoA formation from fatty acids

227

(2)

`Activation' of fatty acids by formation of fatty acyl-CoA derivatives

227

(1)

Transport of fatty acyl-CoA derivatives into mitochondria

227

(1)

Conversion of fatty acyl-CoA to acetyl-CoA molecules inside the mitochondrion by β-oxidation

228

(1)

Energy yield from fatty acid oxidation

228

(1)

Oxidation of unsaturated fat

229

(1)

Is the acetyl-CoA derived from fat breakdown always directly fed into the citric acid cycle?

229

(1)

How is acetoacetate made from acetyl-CoA?

229

(1)

Otilization of acetoacetate

229

(1)

Oxidation of odd-numbered carbon-chain fatty acids

230

(1)

Peroxisomal oxidation of fatty acids

231

(1)

Where to now?

231

(1)

Summary

231

(1)

Further reading

232

(1)

Problems

232

(1)

The synthesis of fat and related compounds

233

(14)

Mechanism of fat synthesis

233

(4)

General principles of the process

233

(1)

Synthesis of malonyl-CoA

233

(1)

The acyl carrier protein (ACP) and the β-ketoacyl synthase

234

(1)

Mechanism of fatty acyl-CoA synthesis

234

(1)

Organization of the fatty acid synthesis process

234

(1)

The reductive steps in fatty acid synthesis

235

(1)

What is NADP+?

236

(1)

Where does fatty acid synthesis take place?

236

(1)

Synthesis of unsaturated fatty acids

237

(1)

Omega fatty acids and diet

238

(1)

Synthesis of TAG and membrane Lipids from fatty acids

238

(1)

Synthesis of new membrane lipid bilayer

238

(4)

Synthesis of glycerophospholipids

239

(2)

Synthesis of new membrane lipid bilayer

241

(1)

Synthesis of prostaglandins and related compounds

242

(3)

The prostaglandins and thromboxanes

242

(1)

Nonsteroidal anti-inflammatory drugs (NSAIDs)

243

(1)

Leukotrienes

244

(1)

Synthesis of cholesterol

244

(1)

Conversion of cholesterol to steroid hormones

244

(1)

Summary

245

(1)

Further reading

245

(1)

Problems

245

(2)

Synthesis of glucose (gluconeogenesis)

247

(8)

Mechanism of glucose synthesis from pyruvate

247

(6)

What are the sources of pyruvate used by the liver for gluconeogenesis?

248

(2)

Synthesis of glucose from glycerol

250

(1)

Effects of ethanol metabolism on gluconeogenesis

251

(1)

Effect of ethanol metabolism on the NADH/NAD+ ratio in the liver cell

251

(1)

Synthesis of glucose via the glyoxylate cycle

252

(1)

Summary

253

(1)

Further reading

253

(1)

Problems

253

(2)

Strategies for metabolic control and their application to carbohydrate and fat metabolism

255

(24)

Why are controls necessary?

255

(2)

The potential danger of futile cycles in metabolism

256

(1)

How are enzyme activities controlled?

257

(1)

Metabolic control by varying the amounts of enzymes is not instantaneous

257

(1)

Metabolic control by regulation of the activities of enzymes in the cell

257

(1)

Which enzymes in metabolic pathways are regulated?

257

(1)

The nature of control enzymes

258

(1)

Allosteric control of enzymes

258

(2)

The mechanism of allosteric control of enzymes

258

(1)

What causes the sigmoidal response of reaction velocity to substrate concentration?

259

(1)

Reversibility of allosteric control

259

(1)

Allosteric control is a tremendously powerful metabolic concept

259

(1)

Allosteric enzymes often have multiple allosteric modulators

260

(1)

Control of enzyme activity by phosphorylation

260

(1)

Protein kinases and phosphatases

260

(1)

Control by phosphorylation usually depends on chemical signals from other cells

261

(1)

General aspects of the hormonal control of metabolism

261

(2)

How do glucagon, epinephrine, and insulin work?

261

(1)

What is a second messenger?

261

(1)

The second messenger for glucagon and epinephrine is cyclic AMP (cAMP)

262

(1)

Control of carbohydrate metabolism

263

(13)

Control of glucose uptake into cells

263

(1)

Control of glycogen metabolism

264

(1)

Control of glycogen breakdown in muscle

264

(1)

Mechanism of muscle phosphorylase activation by cAMP

265

(1)

Control of glycogen breakdown in the liver

266

(1)

Reversal of phosphorylase activation in muscle and liver

266

(1)

Control of glycogen synthase

267

(1)

cAMP causes inactivation of glycogen synthase

267

(1)

Mechanism of insulin activation of glycogen synthase

267

(1)

How does insulin Inactivate GSK3?

267

(1)

Control of glycolysis and gluconeogenesis

268

(1)

Allosteric controls

268

(1)

Hormonal control of glycolysis and gluconeogenesis

269

(1)

Control of glycolysis and gluconeogenesis pathways by fructose-2:6-bisphosphate (F-2:6-BP)

269

(1)

Control of pyruvate kinase

270

(1)

Glucocorticold stimulation of gluconeogenesis

271

(1)

Control of pyruvate dehydrogenase, the citric acid cycle, and oxidative phosphorylation

271

(1)

Controls of fatty acid oxidation and synthesis

272

(1)

Nonhormonal controls

272

(1)

Hormonal controls on fat metabolism

273

(1)

Regulation of the cellular ATP level by AMP-activated protein kinase

273

(1)

Insulin and diabetes

274

(1)

A concluding note on metabolic control analysis

275

(1)

Summary

276

(1)

Further reading

277

(1)

Problems

278

(1)

Why should there be an alternative pathway of glucose oxidation? The pentose phosphate pathway

279

(6)

The oxidative section produces equal amounts of ribose-5-phosphate and NADPH

279

(4)

The nonoxidative section and its purpose

279

(1)

Conversion of surplus ribose-5-phosphate to glucose-6-phosphate

280

(1)

Glucose-6-phosphate to ribose-5-phosphate production without NADPH generation

281

(1)

Where does the complete oxidation of glucose come into all of this?

282

(1)

Why do red blood cells have the pentose phosphate pathway?

283

(1)

Summary

283

(1)

Further reading

284

(1)

Problems

284

(1)

Raising electrons of water back up the energy scale---photosynthesis

285

(10)

Overview

285

(1)

Site of photosynthesis---the chloroplast

286

(1)

The Light-dependent reactions of photosynthesis

286

(4)

The photosynthetic apparatus and its organization in the thylakoid membrane

286

(1)

How Is light energy captured?

287

(1)

Mechanism of light-dependent reduction of NADP+

288

(1)

Photosystem II

288

(1)

Photosystem I

288

(1)

The water-splitting centre of PSII

289

(1)

How is ATP generated?

289

(1)

An explanatory note

290

(1)

The `dark reactions' of photosynthesis

290

(3)

How is CO2 converted to carbohydrate?

290

(1)

Getting from 3-phosphoglycerate to glucose

290

(1)

3-Phosphoglycerate is formed from ribulose-1:5-bisphosphate

290

(1)

Where does the ribulose-1:5-bisphosphate come from?

291

(1)

Has evolution slipped up a bit?

291

(1)

The C4 pathway

292

(1)

Summary

293

(1)

Further reading

294

(1)

Problems

294

(1)

Amino acid metabolism

295

(17)

Nitrogen balance of the body

296

(1)

General metabolism of amino acids

296

(6)

Aspects of amino acid metabolism

296

(1)

Glutamate dehydrogenase has a central role in the deamination of amino acids

297

(1)

Mechanism of transamination reactions

298

(1)

Special deamination mechanisms for serine and cysteine

298

(1)

Fate of the keto acid or carbon skeletons of deaminated amino acids

299

(1)

Genetic errors in amino acid metabolism cause diseases

300

(1)

Phenylketonuria

300

(1)

Maple syrup disease

301

(1)

Alcaptonuria

301

(1)

Methionine and transfer of methyl groups

301

(1)

What are the methyl groups transferred to?

302

(1)

Synthesis of amino acids

302

(1)

Synthesis of glutamic acid

302

(1)

Synthesis of aspartic acid and alanine

302

(1)

Synthesis of serine

302

(1)

Synthesis of glycine

303

(1)

Haem and its synthesis from glycine

303

(2)

Destruction of haem

303

(1)

Acute intermittent porphyria

304

(1)

Synthesis of epinephrine and norepinephrine

304

(1)

The urea cycle

305

(5)

Mechanism of arginine synthesis

306

(1)

Conversion of citrulline to arginine

307

(1)

How is the amino nitrogen transported from extrahepatic tissues to the liver to be converted into urea?

308

(1)

Transport of ammonia in the blood as glutamine

308

(1)

Transport of amino nitrogen in the blood as alanine

309

(1)

Diseases due to urea cycle deficiencies

309

(1)

Alternatives to urea formation exist in different animals

309

(1)

Summary

310

(1)

Further reading

310

(1)

Problems

311

(1)

Enzymic protective mechanisms in the body

312

(12)

Blood clotting

312

(3)

What are the signals that clot formation is needed?

313

(1)

How does thrombin cause thrombus (clot) formation?

313

(1)

Keeping clotting in check

314

(1)

Rat poison, blood clotting, and vitamin K

315

(1)

Protection against ingested foreign chemicals (xenobiotics)

315

(2)

Cytochrome P450

316

(1)

Medical significance of P450s

316

(1)

Secondary modification--addition of a polar group to products of the P450 attack

316

(1)

The glucuronidation system

316

(1)

The glutathione S-transferase system

316

(1)

Multidrug resistance

317

(1)

Protection of the body against its own proteases

317

(1)

Protection against reactive oxygen species

318

(1)

Mopping up oxygen free radicals with vitamins C and E

319

(1)

Enzymic destruction of superoxide by superoxide dismutase

319

(1)

The glutathione peroxidase--glutathione reductase strategy

319

(1)

Protection against hypoxia (low oxygen levels)

320

(1)

Mechanism of the hypoxia response

320

(1)

Summary

321

(1)

Further reading

322

(1)

Problems

323

(1)

Nucleotide synthesis and metabolism

324

(17)

Structure and nomenclature of nucleotides

324

(2)

The sugar component of nucleotides

324

(1)

The base component of nucleotides

325

(1)

Nomenclature

325

(1)

Structure of the bases

325

(1)

Attachment of the bases in nucleotides

325

(1)

Synthesis of purine and pyrimidine nucleotides

326

(9)

Purine nucleotides

326

(1)

PRPP--the ribotidation agent

326

(1)

The de novo purine nucleotide synthesis pathway

327

(1)

The one-carbon transfer reaction in purine nucleotide synthesis

327

(2)

Where does the formyl group in N10-formyl FH4 come from?

329

(1)

How are ATP and GTP produced from AMP and GMP?

329

(1)

The purine salvage pathway

330

(1)

What is the physiological role of the purine salvage pathway?

331

(1)

Formation of uric acid from purines

331

(1)

Control of purine nucleotide synthesis

332

(1)

Synthesis of pyrimidine nucleotides

332

(1)

How are deoxyribonucleotides formed?

333

(1)

Thymidylate synthesis--conversion of dUMP to dTMP

333

(2)

Medical effects of folate deficiencies

335

(1)

Thymidylate synthesis is targeted by anticancer agents such as the antifolate, methotrexate

335

(1)

Vitamin B12 deficiency in cells and the folate methyl trap

335

(1)

Summary

336

(1)

Further reading

336

(1)

Problems

336

(5)

Part 4 Information storage and utilization

DNA and genomes

341

(15)

What are nucleic acids?

341

(1)

The primary structure of DNA

341

(7)

What are the bases in DNA?

342

(1)

Attachment of the bases to deoxyribose

342

(1)

The physical properties of the polynucleotide components

342

(1)

Structure of the polynucleotide of DNA

342

(1)

Why deoxyribose? Why not ribose?

343

(1)

The DNA double helix

344

(1)

Complementary base pairing

344

(2)

DNA chains are antiparallel; what does this mean?

346

(2)

How is the DNA packed into a nucleus?

348

(2)

How does the described structure of DNA correlate with the compact eukaryotic chromosomes visible in the light microscope?

349

(1)

The mitochondrial genome

350

(1)

What is a gene in molecular terms?

350

(3)

Some variations on the `standard' gene

351

(1)

Size and organization of genomes

351

(1)

Organization of the human genome

351

(1)

Repetitive DNA sequences

351

(1)

Transposon movement

352

(1)

Noncoding RNAs are challenging the basic dogma of molecular genetics

352

(1)

Discovery of microgenes for small noncoding RNAs

352

(1)

RNA interference (RNAi)

353

(1)

Where are we now?

353

(1)

Summary

353

(1)

Further reading

354

(1)

Problems

355

(1)

DNA synthesis, repair, and recombination

356

(24)

Overall principle of DNA replication

356

(1)

Control of initiation of DNA replication in E. coli

357

(1)

Initiation and regulation of DNA replication in eukaryotes

357

(1)

Unwinding the DNA double helix and supercoiling

358

(3)

How are positive supercoils removed ahead of the replicative fork?

359

(2)

The basic enzymic reaction catalysed by DNA polymerases

361

(1)

How does a new strand get started?

362

(1)

The polarity problem in DNA replication

362

(4)

Mechanism of Okazaki fragment synthesis

363

(1)

Enzyme complex at the replicative fork in E. coli

364

(1)

The DNA sliding clamp and the clamp loading mechanism

364

(1)

Processing the Okazaki fragments

364

(2)

How is fidelity achieved in DNA replication?

366

(3)

Exonucleolytic proofreading

368

(1)

Methyl-directed mismatch repair

368

(1)

Repair of DNA damage in E. coli

369

(2)

Repair of double-strand breaks

370

(1)

The machinery in the eukaryotic replicative fork

371

(2)

The problem of replicating the ends of eukaryotic chromosomes

371

(2)

How is telomeric DNA synthesized?

373

(1)

Telomere shortening correlates with ageing

373

(1)

DNA damage repair in eukaryotes

373

(1)

Is the mechanism described above the only way in which DNA is synthesized?

374

(1)

DNA synthesis by reverse transcription

374

(1)

Homologous recombination

375

(2)

Mechanism of homologous recombination in E. coli

375

(1)

Formation of cross-over junctions by single-strand invasion

376

(1)

Separation of the duplexes

376

(1)

Recombination in eukaryotes

377

(1)

Summary

377

(1)

Further reading

377

(1)

Problems

378

(2)

Gene transcription and control

380

(28)

Messenger RNA

380

(2)

The structure of RNA

380

(1)

How is mRNA synthesized?

380

(1)

Some general properties of mRNA

381

(1)

Some essential terminology

381

(1)

A note on where we go from here

382

(1)

Gene transcription in E. coli

382

(5)

What do we mean by the 5' end of a gene?

383

(1)

Phases of gene transcription

383

(1)

Initiation of transcription in E. coli

383

(1)

Separating the DNA strands

384

(1)

Termination of transcription

384

(1)

The rate of gene transcription initiation in prokaryotes

384

(1)

Control of transcription by different sigma factors

385

(1)

Gene control in E. coli: the lac operon

385

(1)

Structure of the E. coli lac operon

386

(1)

Gene transcription in eukaryotic cells

387

(2)

Capping the RNA transcribed by RNA polymerase II

387

(1)

Split genes

387

(1)

Mechanism of splicing

387

(2)

Ribozymes and self-splicing of RNA

389

(1)

What is the biological status of introns?

390

(1)

What is the origin of split genes?

390

(1)

Alternative splicing or two (or more) proteins for the price of one gene

390

(1)

Mechanism of initiation of eukaryotic gene transcription and its control

390

(7)

Unpacking of the DNA for transcription

390

(1)

A general overview of the differences in the initiation and control of gene transcription in prokaryotes and eukaryotes

391

(1)

Types of eukaryotic genes and their controlling regions

392

(1)

Type II eukaryotic gene promoters

392

(1)

Enhancers

393

(1)

Transcription factors (activators)

393

(1)

Most transcription factors themselves are regulated

394

(1)

How do transcription factors promote transcriptional initiation?

394

(1)

The role of chromatin in eukaryotic gene control

394

(1)

How do transcription factors open up gene promoters?

394

(2)

How is transcription initiated on the opened promoter?

396

(1)

Discovery of the mediator

397

(1)

The RNA polymerase II of eukaryotic cells

398

(1)

Termination of transcription in eukaryotic cells

399

(1)

Switching off the gene

399

(1)

mRNA stability and the control of gene expression

399

(1)

Determinants of mRNA stability and their role in gene expression control

399

(1)

Role of the polyA tail

399

(1)

Structural stability determinants of mRNAs

399

(1)

Gene transcription in mitochondria

400

(1)

Genes that do not code for proteins

401

(2)

The structure of DNA-binding proteins

401

(1)

Helix--turn--helix proteins

401

(1)

Leucine zipper proteins

402

(1)

Helix-loop-helix proteins

402

(1)

Zinc finger proteins

403

(1)

Summary

403

(1)

Further reading

404

(2)

Problems

406

(2)

Protein synthesis and controlled protein breakdown

408

(24)

Essential basis of the process of protein synthesis

409

(4)

The genetic code

409

(1)

How are the codons translated?

410

(1)

Transfer RNA

410

(1)

The wobble mechanism

411

(1)

How are amino acids attached to tRNA molecules?

411

(1)

Proofreading by aminoacyl-tRNA ligases

412

(1)

Ribosomes

413

(1)

Initiation of translation

414

(2)

Initiation of translation in C. coli

414

(2)

Once initiation is achieved, elongation is the next step

416

(2)

Cytoplasmic elongation factors in E. coli

416

(1)

Mechanism of elongation in E. coli

416

(1)

How is accuracy of translation achieved?

416

(2)

Mechanism of translocation on the E. coli ribosome

418

(1)

Effects of antibiotics and toxins on protein synthesis

418

(1)

Termination of protein synthesis in E. coli

419

(1)

Physical structure of the ribosome

419

(1)

What is a polysome?

420

(1)

Protein synthesis in eukaryotes

420

(1)

Protein synthesis in mitochondria

420

(1)

Folding up of the polypeptide chain

421

(3)

Chaperones (heat-shock proteins)

421

(1)

Mechanism of action of molecular chaperones

422

(1)

Enzymes involved in protein folding

423

(1)

Prion diseases and protein folding

424

(1)

Translational control mechanisms

424

(1)

Regulation of globin synthesis

424

(1)

Translational control of proteins involved in haem synthesis and iron metabolism

424

(1)

Programmed destruction of protein by proteasomes

425

(3)

The structure of proteasomes

426

(1)

Selection of proteins for destruction---the ubiquitination system

427

(1)

What determines which proteins are ubiquitinated?

427

(1)

The role of protea somes in the immune system

427

(1)

Summary

428

(1)

Further reading

429

(2)

Problems

431

(1)

Protein targeting---how proteins are delivered to their cellular destinations

432

(20)

A preliminary overview of the field

432

(3)

Structure and function of the ER and Golgi apparatus

433

(2)

The importance of the GTP/GDP switch mechanism in protein targeting

435

(1)

How are proteins translocated through the ER membrane?

435

(3)

Mechanism of cotranslational transport through the ER membrane

435

(2)

Folding of the polypeptides inside the ER

437

(1)

Glycosylation of proteins in the ER lumen and Golgi apparatus

437

(1)

Vesicles involved in protein translocation from the ER and Golgi

437

(1)

Lysosomes and the mechanism of their formation by receptor-mediated endocytosis

438

(1)

How are proteins sorted, packaged, and despatched by the Golgi apparatus?

439

(1)

Proteins to be returned to the ER

439

(1)

Proteins destined for lysosomes

439

(1)

Proteins to be secreted from the cell

439

(1)

Lysosomal storage disorders

439

(1)

Mechanism of COP-coated vesicle formation

440

(1)

How does a vesicle find its target membrane?

440

(1)

Synthesis of integral membrane proteins and their transport

441

(1)

How is the membrane protein given the correct orientation?

441

(1)

Posttranslational transport of proteins into organelles

442

(7)

Transport of proteins into mitochondria

442

(2)

Targeting peroxisomal proteins

444

(1)

Nuclear---cytoplasmic traffic

444

(1)

Why is there a nuclear membrane?

444

(1)

The nuclear pore complex

444

(2)

Nuclear localization signals

446

(1)

Mechanism of nuclear--cytoplasmic transport and the role of guanine nucleotide-binding proteins

446

(2)

Regulation of nuclear transport by cell signals and its role in gene control

448

(1)

Summary

449

(1)

Further reading

449

(2)

Problems

451

(1)

Signal transduction

452

(30)

Overview

452

(2)

Organization of this chapter

454

(1)

What are the signalling molecules?

454

(2)

Neurotransmitters

454

(1)

Hormones

454

(1)

Cytokines and growth factors

455

(1)

Growth factors/cytokines and the cell cycle

456

(1)

Vitamin D3 and retinoic acid

456

(1)

Intracellular receptor-mediated responses

456

(2)

The glucocorticoid receptor and anti-inflammatory drugs

457

(1)

Classification of types of membrane receptor signalling systems

458

(2)

Binding domains of signal transduction proteins

459

(1)

Terminating signals

460

(1)

Examples of signal transduction pathways

460

(1)

Signal transduction pathways from tyrosine kinase receptors

461

(14)

The Ras pathway

461

(1)

Mechanism of the Ras signalling pathway

461

(1)

Concept of the GTP/GDP switch mechanism, illustrated by the Ras pathway

461

(1)

The MAP kinase cascade in the Ras pathway

462

(1)

Nomenclature of the protein kinases of the Ras pathway

463

(1)

Concept of the role of protein phosphatases, illustrated by the Ras pathway

463

(1)

Some deadly toxins work by increasing or inhibiting dephosphorylation of proteins

464

(1)

Concept of signal sorting in Ras-type pathways

464

(1)

The phosphatidylinositide 3-kinase (PI 3-kinase) pathway and insulin signalling

465

(1)

The JAK/STAT pathways: another type of tyrosine kinase-associated signalling system

466

(1)

Negative control of JAK/STAT pathways

467

(1)

The G-protein-coupled receptors and associated signal transduction pathways

468

(1)

Overview

468

(1)

Structure of G-protein receptors

468

(1)

Epinephrine signalling---a G-protein pathway mediated by cAMP as second messenger

468

(1)

Control of cAMP levels in cells

469

(1)

GTPase-activating proteins (GAPs) regulate G-protein signalling

470

(1)

Different types of G-protein receptor

470

(1)

How does cAMP control gene activities?

470

(1)

Desensitization of the G-protein receptors

471

(1)

The phosphatidylinositol cascade: another example of a G-protein-coupled receptor which works via a different second messenger

471

(1)

Other control roles of calcium

472

(1)

Vision: a process dependent on a G-protein-coupled receptor

473

(1)

Transduction of the light signal

474

(1)

Signal transduction pathways using cGMP as second messenger

475

(2)

Activation of a guanylate cyclase by nitric oxide

477

(1)

Summary

477

(1)

Further reading

478

(2)

Problems

480

(2)

Manipulating DNA and genes

482

(27)

Basic methodologies

483

(2)

Some preliminary considerations

483

(1)

Cutting DNA with restriction endonucleases

483

(1)

Separating DNA pieces

484

(1)

Visualizing the separated pieces

484

(1)

Detection of specific DNA fragments by nucleic acid hybridization probes

484

(1)

Southern blotting

484

(1)

Sequencing DNA

485

(2)

Outline of the dideoxy DNA-sequencing technique

485

(1)

How is this interpreted as a base sequence?

486

(1)

Automated DNA sequencing

487

(1)

Amplification of DNA by the polymerase chain reaction (PCR)

487

(1)

Joining DNA to form recombinant molecules

488

(1)

Cloning DNA

489

(3)

Cloning in plasmids

489

(1)

Cloning using bacteriophage λ as vector

490

(1)

Cloning in cosmids

491

(1)

Applications of recombinant DNA technology

492

(9)

Production of human and other proteins

492

(1)

Preparation of a cDNA library

492

(1)

Expressing the cDNA in E. coli

493

(1)

Site-directed mutagenesis

494

(1)

PCR in forensic science

494

(1)

Locating disease-producing genes

495

(1)

`Knockout mice' or gene targeting

496

(1)

Method of obtaining a specific gene knockout

496

(1)

The embryonic stem (ES) cell system

496

(2)

Gene targeting

498

(1)

Gene silencing by RNA interference (RNAi)

499

(1)

Analysis of multiple gene expression in cells using DNA microarrays

499

(1)

Transgenic animals and plants

500

(1)

DNA databases and genomics

501

(1)

Summary

502

(1)

Further reading

503

(1)

Problems

504

(5)

Part 5 The immune system, cell cycle, apoptosis, and cancer

The immune system

509

(15)

Overview

509

(2)

The problem of autoimmune reactions

510

(1)

The cells involved in the immune system

510

(1)

There are two arms to the adaptive immune response

510

(1)

Where is the immune system located in the body?

511

(1)

Antibody-based or humoral immunity

511

(3)

Structure of antibodies

511

(1)

What are the functions of antibodies?

511

(1)

The different classes of antibodies

512

(1)

Generation of antibody diversity

512

(2)

Activation of B cells to produce antibodies

514

(3)

Deletion of potentially self-reacting B cells in the bone marrow

514

(1)

The theory of clonal selection

515

(1)

B cells must be activated before they can develop into antibody-secreting cells

515

(1)

Role of helper T cells

515

(1)

Activation of helper T cells

516

(1)

Activation of B cells by activated helper T cells

516

(1)

Role of the MHC proteins in presenting peptides on the outside of cells

517

(1)

Affinity maturation of antibodies

517

(1)

Memory cells

517

(1)

T cells and cell-mediated immunity

517

(2)

Mechanism of action of cytotoxic (killer T) cells

519

(1)

CD proteins reinforce the selectivity of T cell receptors for the two classes of MHC protein

519

(1)

Why does the human immune system reject transplanted human cells?

519

(1)

Monoclonal antibodies

520

(1)

Summary

521

(1)

Further reading

522

(1)

Problems

522

(2)

Cell-cycle control, apoptosis, and cancer

524

(14)

The eukaryotic cell cycle

524

(1)

Why the cell cycle must have controls

524

(1)

Cell-cycle controls

525

(2)

Cytokines and growth factor control in the cell cycle

525

(1)

Cell-cycle checkpoints

525

(1)

Cell-cycle controls depend on the synthesis and destruction of cyclins

525

(1)

Controls in G1 are complex

525

(1)

The G1 checkpoint

526

(1)

How is DNA damage detected?

526

(1)

Progression to S phase

526

(1)

Progression to M phase

526

(1)

Mitosis phase

526

(1)

Apoptosis

527

(1)

An overview of what initiates apoptosis

527

(1)

Mechanism of stress-damage-induced apoptosis

528

(1)

The role of caspases in apoptosis

528

(1)

Death receptor-mediated activation of apoptosis

528

(1)

Cancer

528

(6)

General concepts

528

(1)

Most normal cells can divide only a limited number of times

529

(1)

Cancer cells have no limitation on the number of cell divisions they can make

529

(1)

Types of abnormal cell multiplication

529

(1)

Malignant Darwinism: cancer development involves an evolutionary progression of mutations

530

(1)

Development of colorectal cancer

530

(1)

Mutations cause cancer

530

(1)

Tumour promoters

531

(1)

The types of genetic change involved in cancer

531

(1)

Oncogenes

531

(1)

How are oncogenes acquired?

532

(1)

A note on nomenclature of viral oncogenes

533

(1)

Tumour-suppression genes

533

(1)

Mechanism of protection by the p53 gene

533

(1)

Mechanism of protection by the retinoblastoma gene

534

(1)

Molecular biology advances have potential for development of new cancer therapies

534

(1)

Summary

534

(1)

Further reading

534

(3)

Problems

537

(1)

Figure acknowledgements

538

(2)

Answers to problems

540

(27)

Index of diseases and medically relevant topics

567

(2)

Index

569

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Biochemistry And Molecular Biology

Biochemistry And Molecular Biology

9780199271993

0199271992

Summary

Table of Contents

Supplemental Materials

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Amazon no longer offers textbook rentals. We do!

Biochemistry And Molecular Biology

Biochemistry And Molecular Biology

9780199271993

0199271992

Summary

Table of Contents

Supplemental Materials

Write a Review

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