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 Contents
7.8 Oxygen Transport from Lungs to Tissues: Protein
Conformational Change Enhances Function 200
7.9 The Oxygen Binding Sites in Myoglobin and
Hemoglobin 201
Analysis of Oxygen Binding by Myoglobin 202
7.10 The Role of Conformational Change in Oxygen
Transport 204
Cooperative Binding and Allostery 204
Models for the Allosteric Change in Hemoglobin 206
Changes in Hemoglobin Structure Accompanying Oxygen
Binding 207
A Closer Look at the Allosteric Change in
Hemoglobin 208
7.11 Allosteric Effectors of Hemoglobin Promote Efficient
Oxygen Delivery to Tissues 211
Response to pH Changes: The Bohr Effect 211
Carbon Dioxide Transport 212
Response to Chloride Ion at the a-Globin
N-Terminus 212
2,3-Bisphosphoglycerate 212
7.12 Myoglobin and Hemoglobin as Examples of the Evolution
of Protein Function 214
The Structure of Eukaryotic Genes: Exons
and Introns 214
7.13 Mechanisms of Protein Mutation 215
Substitution of DNA Nucleotides 215
Nucleotide Deletions or Insertions 215
Gene Duplications and Rearrangements 216
Evolution of the Myoglobin–Hemoglobin Family of
Proteins 216
7.14 Hemoglobin Variants and Their Inheritance: Genetic
Diseases 218
Pathological Effects of Variant Hemoglobins 219
7.15 Protein Function Requiring Large Conformational
Changes: Muscle Contraction 220
7.16 Actin and Myosin 220
Actin 220
Myosin 221
7.17 The Structure of Muscle 223
7.18 The Mechanism of Contraction 223
Regulation of Contraction: The Role of Calcium
Tools of Biochemistry 7A Immunological
Methods 230
| vii
Chapter 8
Enzymes: Biological Catalysts 232
8.1 Enzymes Are Biological Catalysts 234
8.2 The Diversity of Enzyme Function 234
8.3 Chemical Reaction Rates and the Effects of
Catalysts 235
Reaction Rates, Rate Constants, and Reaction
Order 235
First-Order Reactions 235
Second-Order Reactions 236
Transition States and Reaction Rates 237
Transition State Theory Applied to Enzymatic
Catalysis 238
8.4 How Enzymes Act as Catalysts: Principles and
Examples 240
Models for Substrate Binding and Catalysis 240
Mechanisms for Achieving Rate Acceleration 241
Case Study #1: Lysozyme 243
Case Study #2: Chymotrypsin, a Serine Protease 245
8.5 Coenzymes, Vitamins, and Essential Metals 247
Coenzyme Function in Catalysis 247
Metal Ions in Enzymes 249
8.6 The Kinetics of Enzymatic Catalysis 249
Reaction Rate for a Simple Enzyme-Catalyzed Reaction:
Michaelis–Menten Kinetics 250
Interpreting KM, kcat, and kcat/KM 251
Enzyme Mutants May Affect kcat and KM Differently 253
Analysis of Kinetic Data: Testing the Michaelis–Menten
Model 253
Multisubstrate Reactions 254
Random Substrate Binding 254
Ordered Substrate Binding 254
The Ping-Pong Mechanism 254
8.7 Enzyme Inhibition 254
Reversible Inhibition 255
Competitive Inhibition 255
Uncompetitive Inhibition 257
Mixed Inhibition 258
Irreversible Inhibition 259
226 8.8 The Regulation of Enzyme Activity 260
Substrate-Level Control 260
Feedback Control 260
viii | Contents

Allosteric Enzymes 261 9.4 Polysaccharides 288

Homoallostery 261 Storage Polysaccharides 289
Heteroallostery 261 Structural Polysaccharides 290
Aspartate Carbamoyltransferase: An Example of an Cellulose 290
Allosteric Enzyme 262 Chitin 291
8.9 Covalent Modifications Used to Regulate Enzyme Glycosaminoglycans 292
Activity 264 The Proteoglycan Complex 292
Pancreatic Proteases: Activation by Irreversible Protein Nonstructural Roles of Glycosaminoglycans 292
Backbone Cleavage 264 Bacterial Cell Wall Polysaccharides; Peptidoglycan 293
8.10 Nonprotein Biocatalysts: Catalytic Nucleic Acids 265 9.5 Glycoproteins 294
Tools Of Biochemistry 8A How to Measure the N-Linked and O-Linked Glycoproteins 294
Rates of Enzyme-Catalyzed Reactions 269 N-Linked Glycans 294
Foundation figure Regulation of Enzyme O-Linked Glycans 294
Activity 272 Blood Group Antigens 295
Erythropoetin: A Glycoprotein with Both O- and N-Linked
Oligosaccharides 296
Chapter 9 Influenza Neuraminidase, a Target for Antiviral
Drugs 296
Carbohydrates: Sugars, Saccharides, Tools Of Biochemistry 9A The Emerging Field
Glycans 274 of Glycomics 299
9.1 Monosaccharides 276
Aldoses and Ketoses 276
Enantiomers 277
Chapter 10
Alternative Designations for Enantiomers: d–l Lipids, Membranes, and Cellular
and R–S 278 Transport 300
Monosaccharide Enantiomers in Nature 278 10.1 The Molecular Structure and Behavior of Lipids 302
Diastereomers 278 Fatty Acids 302
Tetrose Diastereomers 278 Triacylglycerols: Fats 304
Pentose Diastereomers 279 Soaps and Detergents 305
Hexose Diastereomers 279 Waxes 305
Aldose Ring Structures 279
10.2 The Lipid Constituents of Biological Membranes 305
Pentose Rings 279
Glycerophospholipids 306
Hexose Rings 282
Sphingolipids and Glycosphingolipids 307
Sugars with More Than Six Carbons 283
Glycoglycerolipids 308
9.2 Derivatives of the Monosaccharides 283 Cholesterol 308
Phosphate Esters 283
10.3 The Structure and Properties of Membranes and
Lactones and Acids 284
Membrane Proteins 309
Alditols 284
Motion in Membranes 310
Amino Sugars 284
Motion in Synthetic Membranes 310
Glycosides 284
Motion in Biological Membranes 311
9.3 Oligosaccharides 285 The Asymmetry of Membranes 311
Oligosaccharide Structures 285 Characteristics of Membrane Proteins 312
Distinguishing Features of Different Disaccharides 285 Insertion of Proteins into Membranes 313
Writing the Structure of Disaccharides 286 Evolution of the Fluid Mosaic Model of Membrane
Stability and Formation of the Glycosidic Bond 287 Structure 315
 Contents | ix

10.4 Transport Across Membranes 317 Thermodynamic Properties of ATP 349

The Thermodynamics of Transport 317 The Important Differences Between ∆G and ∆G °′ 350
Nonmediated Transport: Diffusion 318 Kinetic Control of Substrate Cycles 350
Facilitated Transport: Accelerated Diffusion 319 Other High-Energy Phosphate Compounds 351
Carriers 319 Other High-Energy Nucleotides 352
Permeases 320 Adenylate Energy Charge 352
Pore-Facilitated Transport 321 11.5 Major Metabolic Control Mechanisms 352
Ion Selectivity and Gating 322 Control of Enzyme Levels 352
Active Transport: Transport Against a Concentration Control of Enzyme Activity 353
Gradient 324
Compartmentation 353
10.5 Ion Pumps: Direct Coupling of ATP Hydrolysis to Hormonal Regulation 355
Transport 324 Distributive Control of Metabolism 355
10.6 Ion Transporters and Disease 326 11.6 Experimental Analysis of Metabolism 356
10.7 Cotransport Systems 327 Goals of the Study of Metabolism 356
Levels of Organization at Which Metabolism is
10.8 Excitable Membranes, Action Potentials,
Studied 356
and Neurotransmission 328
Whole Organisms 356
The Resting Potential 328
Isolated or Perfused Organs 356
The Action Potential 329
Whole Cells 356
Toxins and Neurotransmission 330
Cell-Free Systems 357
Chapter 11 Purified Components 357
Systems Level 357
Chemical Logic of Metabolism 334 Metabolic Probes 357
11.1 A First Look at Metabolism 336 Tools Of Biochemistry 11A Metabolomics 361

11.2 Freeways on the Metabolic Tools Of Biochemistry 11B Radioactive and

Road Map 337 Stable Isotopes 364
Central Pathways of Energy Foundation Figure Enzyme Kinetics and Drug
Metabolism 337 Action 366
Distinct Pathways for

11.3
Biosynthesis and Degradation
Biochemical Reaction Types 341
340 Chapter 12
Nucleophilic Substitutions 341
Carbohydrate Metabolism:
Nucleophilic Additions 342
Glycolysis,
Gluconeogenesis,
Carbonyl Condensations 342
Glycogen Metabolism,
Eliminations 344
and the Pentose
Oxidations and Reductions 344
Phosphate Pathway 368
11.4 Bioenergetics of Metabolic Pathways 344
12.1 An Overview of Glycolysis 371
Oxidation as a Metabolic Energy Source 345
Relation of Glycolysis to Other Pathways 371
Biological Oxidations: Energy Release in Small
Anaerobic and Aerobic Glycolysis 371
Increments 345
Chemical Strategy of Glycolysis 373
Energy Yields, Respiratory Quotients, and Reducing
Equivalents 345 12.2 Reactions of Glycolysis 373
ATP as a Free Energy Currency 346 Reactions 1–5: The Energy Investment Phase 373
Metabolite Concentrations and Solvent Capacity 348 Reaction 1: The First ATP Investment 373
x | Contents

Reaction 2: Isomerization of Glucose-6-Phosphate 375 Fructose-2,6-bisphosphate and the Control of Glycolysis and
Reaction 3: The Second Investment of ATP 375 Gluconeogenesis 390
Reaction 4: Cleavage to Two Triose Phosphates 375 Regulation at the Pyruvate Kinase/Pyruvate Carboxylase
Reaction 5: Isomerization of Dihydroxyacetone + PEPCK Substrate Cycle 393
Phosphate 376 Regulation at the Hexokinase/Glucose-6-Phosphatase
Reactions 6–10: The Energy Generation Phase 377 Substrate Cycle 393
Reaction 6: Generation of the First Energy-Rich 12.7 Entry of Other Sugars into the Glycolytic Pathway 394
Compound 377 Monosaccharide Metabolism 394
Reaction 7: The First Substrate-Level Phosphorylation 378 Galactose Utilization 394
Reaction 8: Preparing for Synthesis of the Next High-Energy Fructose Utilization 394
Compound 378 Disaccharide Metabolism 394
Reaction 9: Synthesis of the Second High-Energy Glycerol Metabolism 395
Compound 379
Polysaccharide Metabolism 395
Reaction 10: The Second Substrate-Level
Hydrolytic and Phosphorolytic Cleavages 395
Phosphorylation 379
Starch and Glycogen Digestion 396
12.3 Metabolic Fates of Pyruvate 380
12.8 Glycogen Metabolism in Muscle and
Lactate Metabolism 380
Liver 396
Isozymes of Lactate Dehydrogenase 382
Glycogen Breakdown 396
Ethanol Metabolism 382
Glycogen Biosynthesis 397
12.4 Energy and Electron Balance Sheets 383 Biosynthesis of UDP-Glucose 397
12.5 Gluconeogenesis 384 The Glycogen Synthase Reaction 398
Physiological Need for Glucose Synthesis in Formation of Branches 399
Animals 384 12.9 Coordinated Regulation of Glycogen Metabolism 399
Enzymatic Relationship of Gluconeogenesis to Structure of Glycogen Phosphorylase 399
Glycolysis 385 Control of Phosphorylase Activity 400
Bypass 1: Conversion of Pyruvate to Proteins in the Glycogenolytic Cascade 400
Phosphoenolpyruvate 385
Cyclic AMP–Dependent Protein Kinase 400
Bypass 2: Conversion of Fructose-1,6-bisphosphate to
Phosphorylase b Kinase 401
Fructose-6-phosphate 386
Calmodulin 401
Bypass 3: Conversion of Glucose-6-phosphate to
Nonhormonal Control of Glycogenolysis 402
Glucose 386
Control of Glycogen Synthase Activity 402
Stoichiometry and Energy Balance of
Gluconeogenesis 387 Congenital Defects of Glycogen Metabolism in
Humans 403
Gluconeogenesis 387
Reversal of Glycolysis 387 12.10 A Biosynthetic Pathway That Oxidizes Glucose: The
Substrates for Gluconeogenesis 387 Pentose Phosphate Pathway 404
Lactate 387 The Oxidative Phase: Generating Reducing Power as
Amino Acids 388 NADPH 405
Ethanol Consumption and Gluconeogenesis 388 The Nonoxidative Phase: Alternative Fates of Pentose
Phosphates 405
12.6 Coordinated Regulation of Glycolysis and Production of Six-Carbon and Three-Carbon Sugar
Gluconeogenesis 388 Phosphates 405
The Pasteur Effect 388 Tailoring the Pentose Phosphate Pathway to Specific
Reciprocal Regulation of Glycolysis and Needs 407
Gluconeogenesis 389 Regulation of the Pentose Phosphate Pathway 408
Regulation at the Phosphofructokinase/Fructose-1,6- Human Genetic Disorders Involving Pentose Phosphate
Bisphosphatase Substrate Cycle 390 Pathway Enzymes 409
 Contents
Chapter 13
The Citric Acid Cycle 414
13.1 Overview of Pyruvate Oxidation and the
Citric Acid Cycle 417
The Three Stages of Respiration 417
Chemical Strategy of the Citric Acid Cycle 418
Discovery of the Citric Acid Cycle 420
13.2 Pyruvate Oxidation: A Major Entry Route for Carbon into
the Citric Acid Cycle 420
Overview of Pyruvate Oxidation and the Pyruvate
Dehydrogenase Complex 420
Coenzymes Involved in Pyruvate Oxidation
and the Citric Acid Cycle 421
Thiamine Pyrophosphate (TPP) 422
Lipoic Acid (Lipoamide) 422
Nicotinamide Adenine Dinucleotide (NAD+) 422
Flavin Adenine Dinucleotide (FAD) 423
Coenzyme A: Activation of Acyl Groups 423
Action of the Pyruvate Dehydrogenase Complex 424
13.3 The Citric Acid Cycle 427
Step 1: Introduction of Two Carbon Atoms as
Acetyl-CoA 427
Step 2: Isomerization of Citrate 428
Step 3: Conservation of the Energy Released by an
Oxidative Decarboxylation in the Reduced Electron
Carrier NADH 429
Step 4: Conservation of Energy in NADH by a Second
Oxidative Decarboxylation 429
Step 5: A Substrate-Level Phosphorylation 430
Step 6: A Flavin-Dependent Dehydrogenation 430
Step 7: Hydration of a Carbon–Carbon Double Bond 431
Step 8: An Oxidation that Regenerates Oxaloacetate 431
13.4 Stoichiometry and Energetics of the Citric Acid
Cycle 431
13.5 Regulation of Pyruvate Dehydrogenase and the Citric
Acid Cycle 432
Control of Pyruvate Oxidation 432
Control of the Citric Acid Cycle 434
13.6 Organization and Evolution of the Citric
Acid Cycle 434
13.7 Citric Acid Cycle Malfunction as a Cause of Human
Disease 435
13.8 Anaplerotic Sequences: The Need to Replace Cycle
Intermediates 435
| xi
Reactions that Replenish Oxaloacetate 436
The Malic Enzyme 436
Reactions Involving Amino Acids 436
13.9 The Glyoxylate Cycle: An Anabolic Variant of the Citric
Acid Cycle 437
Tools Of Biochemistry 13A Detecting and
Analyzing Protein–Protein Interactions 442
Chapter 14
Electron Transport, Oxidative
Phosphorylation, and
Oxygen Metabolism 444
14.1 The Mitochondrion: Scene of the
Action 447
14.2 Free Energy Changes in Biological Oxidations 447
14.3 Electron Transport 450
Electron Carriers in the Respiratory Chain 450
Flavoproteins 450
Iron–Sulfur Proteins 450
Coenzyme Q 451
Cytochromes 451
Respiratory Complexes 452
NADH–Coenzyme Q Reductase (Complex I) 453
Succinate–Coenzyme Q Reductase (Complex II) 454
Coenzyme Q:Cytochrome c Oxidoreductase
(Complex III) 455
Cytochrome c Oxidase (Complex IV) 457
14.4 Oxidative Phosphorylation 457
The P/O Ratio: Energetics of Oxidative
Phosphorylation 457
Oxidative Reactions That Drive ATP Synthesis 458
Mechanism of Oxidative Phosphorylation: Chemiosmotic
Coupling 459
A Closer Look at Chemiosmotic Coupling: The
Experimental Evidence 460
Membranes Can Establish Proton Gradients 460
An Intact Inner Membrane Is Required for Oxidative
Phosphorylation 461
Key Electron Transport Proteins Span the Inner
Membrane 461
Uncouplers Act by Dissipating the Proton Gradient 461
Generation of a Proton Gradient Permits ATP Synthesis
Without Electron Transport 461
Complex V: The Enzyme System for ATP Synthesis 461
xii | Contents

Discovery and Reconstitution of ATP Synthase 461 Reaction Center Complexes in Photosynthetic
Structure of the Mitochondrial F1 ATP Synthase Bacteria 496
Complex 463 Evolution of Photosynthesis 496
Mechanism of ATP Synthesis 463 15.4 The Dark Reactions: The Calvin Cycle 497
14.5 Respiratory States and Respiratory Control 466 Stage I: Carbon Dioxide Fixation and Sugar
Production 498
14.6 Mitochondrial Transport Systems 469
Incorporation of CO2 into a Three-Carbon Sugar 498
Transport of Substrates and Products into and out of
Mitochondria 469 Formation of Hexose Sugars 499
Shuttling Cytoplasmic Reducing Equivalents into Stage II: Regeneration of the Acceptor 499
Mitochondria 470 15.5 A Summary of the Light and Dark Reactions in Two-
14.7 Energy Yields from Oxidative Metabolism 471 System Photosynthesis 500
The Overall Reaction and the Efficiency of
14.8 The Mitochondrial Genome, Evolution, and Disease 471 Photosynthesis 500
14.9 Oxygen as a Substrate for Other Metabolic Regulation of Photosynthesis 500
Reactions 473
15.6 Photorespiration and the C4 Cycle 501
Oxidases and Oxygenases 473
Cytochrome P450 Monooxygenase 473
Reactive Oxygen Species, Antioxidant Defenses, and
Human Disease 473
Chapter 16
Lipid Metabolism 506
Formation of Reactive Oxygen Species 473
Dealing with Oxidative Stress 474 Part I: Bioenergetic Aspects of
Lipid Metabolism 509
Foundation figure Intermediary Metabolism 478
16.1 Utilization and Transport of
Fat and Cholesterol 509
Chapter 15 Fats as Energy Reserves 509
Fat Digestion and Absorption 509
Photosynthesis 480
Transport of Fat to Tissues: Lipoproteins 511
15.1 The Basic Processes of Classification and Functions of Lipoproteins 511
Photosynthesis 484
Transport and Utilization of Lipoproteins 512
15.2 The Chloroplast 485 Cholesterol Transport and Utilization in Animals 513
15.3 The Light Reactions 486 The LDL Receptor and Cholesterol Homeostasis 514
Absorption of Light: The Cholesterol, LDL, and Atherosclerosis 516
Light-Harvesting System 486 Mobilization of Stored Fat for Energy Generation 517
The Energy of Light 486 16.2 Fatty Acid Oxidation 517
The Light-Absorbing Pigments 486 Early Experiments 517
The Light-Gathering Structures 487 Fatty Acid Activation and Transport into
Photochemistry in Plants and Algae: Two Photosystems Mitochondria 519
in Series 489 The B-Oxidation Pathway 520
Photosystem II: The Splitting of Water 491 Reaction 1: The Initial Dehydrogenation 521
Photosystem I: Production of NADPH 493 Reactions 2 and 3: Hydration and Dehydrogenation 521
Summation of the Two Systems: The Overall Reaction and ATP Reaction 4: Thiolytic Cleavage 521
Generation 494 Mitochondrial B-Oxidation Involves Multiple
An Alternative Light Reaction Mechanism: Cyclic Electron Isozymes 522
Flow 496 Energy Yield from Fatty Acid Oxidation 522
 Contents | xiii

Oxidation of Unsaturated Fatty Acids 522

Oxidation of Fatty Acids with Odd-Numbered Carbon
Chapter 17
Chains 523 Interorgan and Intracellular Coordination
Control of Fatty Acid Oxidation 524 of Energy Metabolism in Vertebrates 548
Ketogenesis 524 17.1 Interdependence of the Major Organs in Vertebrate Fuel
16.3 Fatty Acid Biosynthesis 525 Metabolism 550
Relationship of Fatty Acid Synthesis to Carbohydrate Fuel Inputs and Outputs 550
Metabolism 525 Metabolic Division of Labor
Early Studies of Fatty Acid Synthesis 526 Among the Major Organs 550
Biosynthesis of Palmitate from Acetyl-CoA 526 Brain 550
Synthesis of Malonyl-CoA 526 Muscle 552
Malonyl-CoA to Palmitate 527 Heart 552
Multifunctional Proteins in Fatty Acid Synthesis 529 Adipose Tissue 552
Transport of Acetyl Units and Reducing Equivalents into the Liver 552
Cytosol 530 Blood 552
Elongation of Fatty Acid Chains 530 17.2 Hormonal Regulation of Fuel Metabolism 553
Fatty Acid Desaturation 530 Actions of the Major Hormones 553
Control of Fatty Acid Synthesis 532 Insulin 554
16.4 Biosynthesis of Triacylglycerols 533 Glucagon 554
Epinephrine 555
Part II: Metabolism of Membrane Lipids, Steroids, and
Other Complex Lipids 534 Coordination of Energy Homeostasis 555
AMP-Activated Protein Kinase (AMPK) 555
16.5 Glycerophospholipids 534
Mammalian Target of Rapamycin (mTOR) 556
16.6 Sphingolipids 535 Sirtuins 557
16.7 Steroid Metabolism 536 Endocrine Regulation of Energy Homeostasis 558
Steroids: Some Structural Considerations 536 17.3 Responses to Metabolic Stress: Starvation,
Biosynthesis of Cholesterol 537 Diabetes 559
Early Studies of Cholesterol Biosynthesis 537 Starvation 560
Stage 1: Formation of Mevalonate 537 Diabetes 561
Stage 2: Synthesis of Squalene from Mevalonate 538
Stage 3: Cyclization of Squalene to Lanosterol and Its
Conversion to Cholesterol 539
Chapter 18 H2N
N
O

N
H
N

N
H
Sepiapterin
O

OH

N
Pteridine
N

Amino Acid and Nitrogen

O
H

Control of Cholesterol Biosynthesis 539

N O
N

H2N N N O
H H OH
O

Metabolism 564
Leukopterin N
N

H2 N N N OH
H

Cholesterol Derivatives: Bile Acids, Steroid Hormones,

Biopterin

O
H
N O
N

H 2N N N

and Vitamin D 541

O H H

18.1 Utilization of Inorganic

O
N O
HN OH
Erythropterin
H2N N N O
H
Isoxanthopterin

Bile Acids 541 Nitrogen: The Nitrogen

Steroid Hormones 541 Cycle 567
Vitamin D 541 Biological Nitrogen Fixation 567
Lipid-Soluble Vitamins 542 Nitrate Utilization 569
Vitamin A 542 18.2 Utilization of Ammonia: Biogenesis of Organic
Vitamin E 543 Nitrogen 569
Vitamin K 543 Glutamate Dehydrogenase: Reductive Amination of
16.8 Eicosanoids: Prostaglandins, Thromboxanes, and a-Ketoglutarate 569
Leukotrienes 544 Glutamine Synthetase: Generation of Biologically Active
Amide Nitrogen 569
xiv | Contents
Carbamoyl Phosphate Synthetase: Generation of an
Intermediate for Arginine and Pyrimidine Synthesis 570
18.3 The Nitrogen Economy and Protein Turnover 570
Metabolic Consequences of the Absence of Nitrogen
Storage Compounds 570
Protein Turnover 570
Intracellular Proteases and Sites of Turnover 571
Chemical Signals for Turnover—Ubiquitination 571
18.4 Coenzymes Involved in Nitrogen Metabolism 572
Pyridoxal Phosphate 572
Folic Acid Coenzymes and One-Carbon Metabolism 573
Discovery and Chemistry of Folic Acid 573
Conversion of Folic Acid to Tetrahydrofolate 574
Tetrahydrofolate in the Metabolism of One-Carbon
Units 575
Folic Acid in the Prevention of Heart Disease and Birth
Defects 577
B12 Coenzymes 577
B12 Coenzymes and Pernicious Anemia 577
18.5 Amino Acid Degradation and Metabolism of Nitrogenous
End Products 578
Transamination Reactions 578
Detoxification and Excretion of Ammonia 578
Transport of Ammonia to the Liver 579
The Krebs–Henseleit Urea Cycle 579
18.6 Pathways of Amino Acid Degradation 581
Pyruvate Family of Glucogenic Amino Acids 581
Oxaloacetate Family of Glucogenic Amino Acids 583
a-Ketoglutarate Family of Glucogenic Amino Acids 583
Succinyl-CoA Family of Glucogenic Amino Acids 583
Acetoacetate/Acetyl-CoA Family of Ketogenic Amino
Acids 585
Phenylalanine and Tyrosine Degradation 585
18.7 Amino Acid Biosynthesis 587
Biosynthetic Capacities of Organisms 587
Amino Acid Biosynthetic Pathways 587
Synthesis of Glutamate, Aspartate, Alanine, Glutamine,
and Asparagine 588
Synthesis of Serine and Glycine from
3-Phosphoglycerate 588
Synthesis of Valine, Leucine, and Isoleucine from
Pyruvate 588
18.8 Amino Acids as Biosynthetic Precursors 589
S-Adenosylmethionine and Biological Methylation
Precursor Functions of Glutamate 591
Arginine Is the Precursor for Nitric Oxide and Creatine
Phosphate 592
Tryptophan and Tyrosine Are Precursors of
Neurotransmitters and Biological Regulators 592
Chapter 19
Nucleotide Metabolism 598
19.1 Outlines of Pathways in
Nucleotide Metabolism 600
Biosynthetic Routes: De Novo
and Salvage Pathways 600
Nucleic Acid Degradation and
the Importance of Nucleotide
Salvage 601
PRPP, a Central Metabolite in
De Novo and Salvage Pathways 601
19.2 De Novo Biosynthesis of Purine Ribonucleotides 602
Synthesis of the Purine Ring 602
Enzyme Organization in the Purine Biosynthetic
Pathway 604
Synthesis of ATP and GTP from Inosine
Monophosphate 604
19.3 Purine Catabolism and Its Medical Significance 605
Uric Acid, a Primary End Product 605
Medical Abnormalities of Purine Catabolism 606
Gout 606
Lesch-Nyhan Syndrome 607
Severe Combined Immunodeficiency Disease 607
19.4 Pyrimidine Ribonucleotide Metabolism 608
De Novo Biosynthesis of UTP and CTP 608
Glutamine-dependent Amidotransferases 608
Multifunctional Enzymes in Eukaryotic Pyrimidine
Metabolism 610
19.5 Deoxyribonucleotide Metabolism 610
Reduction of Ribonucleotides to
Deoxyribonucleotides 611
RNR Structure and Mechanism 611
Source of Electrons for Ribonucleotide Reduction 613
Regulation of Ribonucleotide Reductase
Activity 613
Regulation of dNTP Pools by Selective dNTP
Degradation 614
589 Biosynthesis of Thymine Deoxyribonucleotides 615
Salvage Routes to Deoxyribonucleotides 616
 Contents
Thymidylate Synthase: A Target Enzyme for
Chemotherapy 617
19.6 Virus-Directed Alterations of Nucleotide
Metabolism 619
19.7 Other Medically Useful Analogs 621
Chapter 20
Mechanisms of Signal
Transduction 624
20.1 An Overview of Hormone
Action 626
Chemical Nature of Hormones and Other Signaling
Agents 627
Hierarchical Nature of Hormonal Control 627
Hormone Biosynthesis 628
20.2 Modular Nature of Signal Transduction Systems:
G Protein-Coupled Signaling 628
Receptors 628
Receptors as Defined by Interactions with Drugs 628
Receptors and Adenylate Cyclase as Distinct Components of
Signal Transduction Systems 628
Structural Analysis of G Protein-coupled Receptors 629
Transducers: G Proteins 630
Actions of G Proteins 630
Structure of G Proteins 631
Consequences of Blocking GTPase 631
The Versatility of G Proteins 631
Interaction of GPCRs with G Proteins 632
G Proteins in the Visual Process 632
Effectors 632
Second Messengers 633
Cyclic AMP 633
Cyclic GMP and Nitric Oxide 633
Phosphoinositides 634
20.3 Receptor Tyrosine Kinases and Insulin
Signaling 636
20.4 Hormones and Gene Expression: Nuclear
Receptors 639
20.5 Signal Transduction, Growth Control, and Cancer
Viral and Cellular Oncogenes 641
Oncogenes in Human Tumors 641
The Cancer Genome Mutational Landscape 643
20.6 Neurotransmission 644
The Cholinergic Synapse 644
| xv
Fast and Slow Synaptic Transmission 645
Actions of Specific Neurotransmitters 646
Drugs That Act in the Synaptic Cleft 647
Peptide Neurotransmitters and Neurohormones 647
Foundation Figure Cell Signaling and Protein
Regulation 650
Chapter 21
Genes, Genomes, and
Chromosomes 652
21.1 Bacterial and Viral Genomes 654
Viral Genomes 654
Bacterial Genomes—The Nucleoid 654
21.2 Eukaryotic Genomes 655
Genome Sizes 655
Repetitive Sequences 656
Satellite DNA 657
Duplications of Functional Genes 657
Alu Elements 658
Introns 658
Gene Families 658
Multiple Variants of a Gene 658
Pseudogenes 659
The ENCODE Project and the Concept of “Junk DNA” 659
21.3 Physical Organization of Eukaryotic Genes:
Chromosomes and Chromatin 659
The Nucleus 659
Chromatin 660
Histones and Nonhistone Chromosomal Proteins 660
The Nucleosome 661
Higher-order Chromatin Structure in the Nucleus 663
21.4 Nucleotide Sequence Analysis of Genomes 663
Restriction and Modification 663
Properties of Restriction and Modification Enzymes 664
Determining Genome Nucleotide Sequences 666
Mapping Large Genomes 666
Generating Physical Maps 667
The Principle of Southern Analysis 668
641
Southern Transfer and DNA Fingerprinting 668
Locating Genes on the Human Genome 669
Sequence Analysis Using Artificial Chromosomes 670
Size of the Human Genome 670
Tools Of Biochemistry 21A Polymerase Chain
Reaction 674
xvi | Contents
Chapter 22
DNA Replication 676
22.1 Early Insights into DNA Replication 678
22.2 DNA Polymerases: Enzymes Catalyzing Polynucleotide
Chain Elongation 679
Structure and Activities of DNA Polymerase I 679
DNA Substrates for the Polymerase Reaction 680
Multiple Activities in a Single Polypeptide Chain 680
Structure of DNA Polymerase I 681
Discovery of Additional DNA Polymerases 681
Structure and Mechanism of DNA Polymerases 682
22.3 Other Proteins at the Replication Fork 683
Genetic Maps of E. coli and Bacteriophage T4 683
Replication Proteins in Addition to DNA
Polymerase 683
Discontinuous DNA Synthesis 684
RNA Primers 686
Proteins at the Replication Fork 686
The DNA Polymerase III Holoenzyme 686
Sliding Clamp 687
Clamp Loading Complex 687
Single-stranded DNA-binding Proteins: Maintaining Optimal
Template Conformation 688
Helicases: Unwinding DNA Ahead of the Fork 688
Topoisomerases: Relieving Torsional Stress 689
Actions of Type I and Type II Topoisomerases 689
The Four Topoisomerases of E. coli 691
A Model of the Replisome 692
22.4 Eukaryotic DNA Replication 692
DNA Polymerases 692
Other Eukaryotic Replication Proteins 693
Replication of Chromatin 694
22.5 Initiation of DNA Replication 694
Initiation of E. coli DNA Replication at ori c
Initiation of Eukaryotic Replication 695
22.6 Replication of Linear Genomes 696
Linear Virus Genome Replication 696
Telomerase 697
22.7 Fidelity of DNA Replication 698
3′ Exonucleolytic Proofreading 698
Polymerase Insertion Specificity 698
DNA Precursor Metabolism and Genomic Stability 700
Ribonucleotide Incorporation and Genomic
Stability 700
22.8 RNA Viruses: The Replication of RNA Genomes 700
RNA-dependent RNA Replicases 700
Replication of Retroviral Genomes 701
Chapter 23
DNA Repair,
Recombination, and
Rearrangement 704
23.1 DNA Repair 706
Types and Consequences of
DNA Damage 706
Direct Repair of Damaged DNA Bases:
Photoreactivation and Alkyltransferases 708
Photoreactivation 708
O6-Alkylguanine Alkyltransferase 708
Nucleotide Excision Repair: Excinucleases 709
Base Excision Repair: DNA N-Glycosylases 710
Replacement of Uracil in DNA by BER 710
Repair of Oxidative Damage to DNA 711
Mismatch Repair 712
Double-strand Break Repair 714
Daughter-strand Gap Repair 714
Translesion Synthesis and the DNA Damage
Response 716
23.2 Recombination 716
Site-specific Recombination 716
Homologous Recombination 717
Breaking and Joining of Chromosomes 717
Models for Recombination 717
Proteins Involved in Homologous Recombination 718
694 23.3 Gene Rearrangements 720
Immunoglobulin Synthesis: Generating Antibody
Diversity 720
Transposable Genetic Elements 722
Retroviruses 723
Gene Amplification 723
Foundation figure Antibody Diversity and Use as
Therapeutics 728
 Contents | xvii

Chapter 24 Chapter 25
Transcription and Post-transcriptional Information Decoding:
Processing 730 Translation and Post-
24.1 DNA as the Template for RNA Synthesis 732 translational Protein
The Predicted Existence of Messenger RNA 732
Processing 756
T2 Bacteriophage and the Demonstration of Messenger 25.1 An Overview of
RNA 733 Translation 758
RNA Dynamics in Uninfected Cells 734
25.2 The Genetic Code 759
24.2 Enzymology of RNA Synthesis: RNA Polymerase 735 How the Code Was Deciphered 759
Biological Role of RNA Polymerase 735 Features of the Code 760
Structure of RNA Polymerase 736 Deviations from the Genetic Code 761
24.3 Mechanism of Transcription in Bacteria 737 The Wobble Hypothesis 761
Initiation of Transcription: Interactions with tRNA Abundance and Codon Bias 762
Promoters 737 Punctuation: Stopping and Starting 762
Initiation and Elongation: Incorporation of 25.3 The Major Participants in Translation: mRNA, tRNA,
Ribonucleotides 739 and Ribosomes 762
Punctuation of Transcription: Termination 740 Messenger RNA 762
Factor-Independent Termination 740 Transfer RNA 763
Factor-Dependent Termination 741 Aminoacyl-tRNA Synthetases: The First Step in Protein
24.4 Transcription in Eukaryotic Cells 741 Synthesis 765
RNA Polymerase I: Transcription of the Major Ribosomal The Ribosome and Its Associated Factors 767
RNA Genes 742 Soluble Protein Factors in Translation 767
RNA Polymerase III: Transcription of Small RNA Components of Ribosomes 767
Genes 742 Ribosomal RNA Structure 769
RNA Polymerase II: Transcription of Structural Internal Structure of the Ribosome 770
Genes 742
25.4 Mechanism of Translation 771
Chromatin Structure and Transcription 745
Initiation 771
Transcriptional Elongation 745
Elongation 772
Termination of Transcription 746
Termination 774
24.5 Post-transcriptional Processing 746 Suppression of Nonsense Mutations 775
Bacterial mRNA Turnover 746
25.5 Inhibition of Translation by Antibiotics 776
Post-transcriptional Processing in the Synthesis of
Bacterial rRNAs and tRNAs 747 25.6 Translation in Eukaryotes 777
rRNA Processing 747
25.7 Rate of Translation; Polyribosomes 778
tRNA Processing 747
Processing of Eukaryotic 25.8 The Final Stages in Protein Synthesis: Folding and
mRNA 748 Covalent Modification 778
Capping 748 Chain Folding 779
Splicing 748 Covalent Modification 779
Alternative Splicing 750 25.9 Protein Targeting in Eukaryotes 780
Tools Of Biochemistry 24A DNA Proteins Synthesized in the Cytoplasm 780
Microarrays 753 Proteins Synthesized on the Rough Endoplasmic
Tools Of Biochemistry 24B Chromatin Reticulum 782
Immunoprecipitation 754 Role of the Golgi Complex 782
xviii | Contents

Chapter 26 26.3 DNA Methylation, Gene Silencing, and Epigenetics 802

DNA Methylation in Eukaryotes 802
Regulation of Gene DNA Methylation and Gene Silencing 803
Expression 786 Genomic Distribution of Methylated Cytosines 804
26.1 Regulation of Transcription in Other Proposed Epigenetic Phenomena 804
Bacteria 788 5-Hydroxymethylcytosine 804
The Lactose Operon—Earliest Chromatin Histone Modifications 804
Insights into Transcriptional Regulation 788 26.4 Regulation of Translation 804
Isolation and Properties of the Lactose Repressor 790 Regulation of Bacterial Translation 805
The Repressor Binding Site 790 Regulation of Eukaryotic Translation 805
Regulation of the lac Operon by Glucose: A Positive Control Phosphorylation of Eukaryotic Initiation Factors 806
System 792 Long Noncoding RNAs 806
The CRP–DNA Complex 792
Some Other Bacterial Transcriptional Regulatory 26.5 RNA Interference 806
Systems: Variations on a Theme 793 Micro RNAs 807
Bacteriophage l: Multiple Operators, Dual Repressors, Small Interfering RNAs 807
Interspersed Promoters and Operators 793 26.6 Riboswitches 808
The SOS Regulon: Activation of Multiple Operons by a
26.7 RNA Editing 808
Common Set of Environmental Signals 795
Biosynthetic Operons: Ligand-Activated Repressors and Foundation Figure Information Flow in Biological
Attenuation 796 Systems 812
Applicability of the Operon Model—Variations on a
A n s w e r s t o S e l e c t e d P r o b l e m s  A - 1
Theme 798
G l o s s a ry  G - 1
26.2 Transcriptional Regulation in Eukaryotes 798 C r e d i t s  C - 1
Chromatin and Transcription 798
I n d e x  I - 1
Transcriptional Control Sites and Genes 799
Nucleosome Remodeling Complexes 800
Transcription Initiation 801
Regulation of the Elongation Cycle by RNA Polymerase
Phosphorylation 802
 Preface
Biochemistry: Concepts and Connections
As genomics and informatics revolutionize biomedical ­science and
health care, we must prepare students for the challenges of the twenty-
first century and ensure their ability to apply quantitative r­ easoning
skills to the science most fundamental to medicine: biochemistry.
We have written Biochemistry: Concepts and Connections to provide
students with a clear understanding of the chemical logic underlying
the mechanisms, pathways, and processes in living cells. The title re-
inforces our vision for this book—twin emphases upon fundamental
concepts at the expense of lengthy descriptive information, and upon
connections, showing how biochemistry relates to all other life sci-
ences and to practical applications in medicine, agricultural sciences,
environmental sciences, and forensics.
Inspired by our experience as authors of the biochemistry ­majors’
text, Biochemistry, Fourth Edition, and as teachers of biochemistry
­majors’ and mixed-science-majors’ courses, we believe there are s­ everal
requirements that a textbook for the mixed-majors’ course must address:
• The need for students to understand the structure and function of
biological molecules before moving into metabolism and dynamic
aspects of biochemistry.
• The need for students to understand that biochemical concepts
derive from experimental evidence, meaning that the principles
of biochemical techniques must be presented to the greatest ex-
tent possible.
• The need for students to encounter many and diverse real-world
applications of biochemical concepts.
• The need for students to understand the quantitative basis for
biochemical concepts. The Henderson–Hasselbalch equation,
the quantitative expressions of thermodynamic laws, and the
­Michaelis–Menten equation, for example, are not equations to be
memorized and forgotten when the course moves on. The basis
for these and other quantitative statements must be understood
and constantly repeated as biochemical concepts, such as mecha-
nisms of enzyme action, are developed. They are essential to help
students grasp the concepts.
In designing Biochemistry: Concepts and Connections, we have
stayed with the organization that serves us well in our own classroom
experience. The first 10 chapters cover structure and function of bio-
logical molecules, the next 10 deal with intermediary metabolism, and
the final 6 with genetic biochemistry. Our emphasis on biochemistry
as a quantitative science can be seen in Chapters 2 and 3, where we
focus on water, the matrix of life, and bioenergetics. Chapter 4 intro-
duces nucleic acid structure, with a brief introduction to nucleic acid
and protein synthesis—topics covered in much more detail at the end
of the book.
Chapters 11 through 20 deal primarily with intermediary metab-
olism. We cover the major topics in carbohydrate metabolism, lipid
metabolism, and amino acid metabolism in one chapter each (12, 16,
and 18, respectively). Our treatment of cell signaling is a bit uncon-
ventional, since it appears in Chapter 20, well after we present hor-
monal control of carbohydrate and lipid metabolism. However, this
treatment allows more extended presentation of receptors, G proteins,
oncogenes, and neurotransmission. In addition, because cancer often
results from aberrant signaling processes, our placement of the sig-
naling chapter leads fairly naturally into genetic biochemistry, which
follows, beginning in Chapter 21.
With assistance from talented artists, we have built a compelling
visual narrative from the ground up, composed of a wide range of
graphic representations, from macromolecules to cellular structures as
well as reaction mechanisms and metabolic pathways that highlights
and reinforces overarching themes (chemical logic, regulation, inter-
face between chemistry and biology). In addition, novel ­Foundation
Figures integrate core chemical and biological ­connections visually,
providing a way to organize the complex and detailed material intel-
lectually, thus making relationships among key concepts clear and
easier to study. “Concept” and “Connection” statements within the
narrative highlight fundamental concepts and real-world applications
of biochemistry.
In Biochemistry: Concepts and Connections, we emphasize our field
as an experimental science by including 15 separate sections, called
Tools of Biochemistry, that highlight the most important research
techniques. We also provide students with end-of-chapter references
(about 12 per chapter), choosing those that would be most appropriate
for our target audience, such as links to Nobel Prize lectures.
We consider end-of-chapter problems to be an indispensable
learning tool and have provided 15 to 25 problems for each chapter.
About half of the problems have brief answers at the end of the book,
with complete answers provided in a separate solutions manual. Addi-
tional tutorials in MasteringChemistry® will help students with some
of the most basic concepts and operations.
Producing a book of this magnitude involves the efforts of dedi-
cated editorial and production teams. We have not had the pleasure of
meeting all of these talented individuals, but we consider them close
friends nonetheless. First, of course, is Jeanne Zalesky, our sponsoring
editor, now Editor-in-Chief, Physical Sciences, who always found a
way to keep us focused on our goal. Coleen Morrison, Program Man-
ager, kept us organized and on schedule, juggling disparate elements
in this complex project. Jay McElroy, Art Development Editor, was
our intermediary with the talented artists at Imagineering, Inc., and
displayed considerable artistic and editorial gifts in his own right.
Over the course of the project, we worked with three experienced de-
velopment editors—Dan Schiller, John Murdzek, and Erica Pantages
xix
xx | Preface
Frost. Their edits, insights, and attention to detail were invaluable.
Beth Sweeten, Senior Project Manager, coordinated the production
of the main text and preparation of the Solutions Manual for the end-
of-chapter problems. Gary Carlton provided great assistance with
many of the illustrations. Chris Hess provided the inspiration for our
cover illustration, and Stephen Merland helped us locate much excel-
lent illustrative material. Once the book was in production, Francesca
­Monaco skillfully kept us all on a complex schedule.
The three of us give special thanks to friends and colleagues who
provided unpublished material for us to use as illustrations. These con-
tributors include John S. Olson (Rice University), Jack Benner (New
England BioLabs), Andrew Karplus (Oregon State University), Scott
Delbecq and Rachel Klevit (University of Washington), William Hor-
ton (Oregon Health and Science University), Cory Hamada (Western
Washington University), Nadrian C. Seaman (New York University),
P. Shing Ho (Colorado State University), Catherine Drennan and
­Edward Brignole (MIT), John G. Tesmer (University of Michigan),
Katsuhiko Murakami (Penn State University), Alan Cheung (Uni-
versity College London), Joyce Hamlin (University of Virginia), Erik
­Johansson (Umeå University), Stefano Tiziani, Edward Marcotte, Da-
vid Hoffman, and Robin Gutell (University of Texas at Austin), An-
dreas Martin and Gabriel Lander (University of California, Berkeley),
Dean Sherry and Craig Malloy (University of Texas-Southwestern
Medical Center), and Stephen C. Kowalczykowski (University of Cali-
fornia, Davis).
We are also grateful to the numerous talented biochemists re-
tained by our editors to review our outline, prospectus, chapter drafts,
and solutions to our end-of-chapter problems. Their names and affili-
ations are listed separately.
Our team—authors and editors—put forth great effort to detect
and root out errors and ambiguities. We undertook an arduous process
of editing and revising several drafts of each chapter in manuscript
stage, as well as copyediting, proofreading, and accuracy reviewing
multiple rounds of page proofs in an effort to ensure the highest level
of quality control.
Throughout this process, as in our previous writing, we have been
most grateful for the patience, good judgment, and emotional support
provided by our wives—Maureen Appling, Yvonne Anthony-Cahill,
and Kate Mathews. We expect them to be as relieved as we are to see
this project draw to a close, and hope that they can share our pleasure
at the completed product.
Dean R. Appling
Spencer J. Anthony-Cahill
Christopher K. Mathews
Reviewers
The following reviewers provided valuable feedback on the manu-
script at various stages throughout the wiring process:
Paul D. Adams, University of Arkansas
Harry Ako, University of Hawaii–Manoa
Eric J. Allaine, Appalachian State University
Mark Alper, University of Califonia—Berkeley
John Amaral, Vancouver Island University
Trevor R. Anderson, Purdue University
Steve Asmus, Centre College
Kenneth Balazovich, University of Michigan
Karen Bame, University of Missouri—Kansas City
Jim Bann, Wichita State University
Daniel Barr, Utica College
Moriah Beck, Wichita State University
Marilee Benore, University of Michigan
Wayne Bensley, State University of New York—Alfred State College
Werner Bergen, Auburn University
Edward Bernstine, Bay Path College
Steven Berry, University of Minnesota—Duluth
Jon-Paul Bingham, University of Hawaii—Honolulu
Franklyn Bolander, University of South Carolina—Columbia
Dulal Borthakur, University of Hawaii–Manoa
David W. Brown, Florida Gulf Coast University
Donald Burden, Middle Tennessee State University
Jean A. Cardinale, Alfred University
R. Holland Cheng, University of California—Davis
Jared Clinton Cochran, Indiana University
Sulekha (Sue) Rao Coticone, Florida Gulf Coast University
Scott Covey, University of British Columbia
Martin Di Grandi, Fordham University
Stephanie Dillon, Florida State University
Brian Doyle, Alma College
Lawrence Duffy, University of Alaska
David Eldridge, Baylor University
Matt Fisher, Saint Vincent College
Kathleen Foley, Michigan State University
Scott Gabriel, Viterbo University
Matthew Gage, Northern Arizona University
Peter Gegenheimer, University of Kansas
Philip Gibson, Gwinnett Technical College
James Gober, University of California—Los Angeles
Christina Goode, California State University at Fullerton
Anne A. Grippo, Arkansas State University
Sandra Grunwald, University of Wisconsin—LaCrosse
January Haile, Centre College
Marc W. Harrold, Duqsuene University
Eric Helms, State University of New York—Geneseo
Marc Hemric, Liberty University
Deborah Heyl-Clegg, Eastern Michigan University
Jane Hobson, Kwantlen Polytechnic University
Charles Hoogstraten, Michigan State University
Roderick Hori, University of Tennessee
Andrew Howard, Illinois Institute of Technology
Swapan S. Jain, Bard College
Henry Jakubowski, Saint John’s University—College of Saint Benedict
Joseph Jarrett, University of Hawaii at Manoa
Constance Jeffery, University of Illinois at Chicago
Philip David Josephy, University of Guelph
Jason Kahn, University of Maryland
Michael Klemba, Virginia Polytechnic Institute
Michael W. Klymkowsky, University of Colorado—Boulder
Greg Kothe, Penn State University
Joseph Kremer, Alvernia University
Ramaswamy Krishnamoorthi, Kansas State University

Brian Kyte, Humboldt State University
Kelly Leach, University of South Florida
Scott Lefler, Arizona State University
Brian Lemon, Brigham Young University—Idaho
Arthur Lesk, Penn State University
Robert Lettan, Chatham University
Harpreet Malhotra, Florida State University
Neil Marsh, University of Michigan
Michael Massiah, George Washington University
Glen Meades, Kennesaw State University
Eddie J. Merino, University of Cincinnati
Stephen Miller, Swarthmore College
Kristy Miller, University of Evansville
David Mitchell, Saint John’s University—College of Saint Benedict
Rakesh Mogul, California State Polytechnic University—­Pomona
Tami Mysliwiec, Penn State University, Berks College
Pratibha Nerurkar, University of Hawaii
Jeff Newman, Lycoming College
Kathleen Nolta, University of Michigan
Sandra L. Olmsted, Augsburg College
Beng Ooi, Middle Tennessee State University
Edith Osborne, Angelo State University
Wendy Pogozelski, State University of New York at Geneseo
Sarah Prescott, University of New Hampshire
Gerry A. Prody, Western Washington University
Mohammad Qasim, Indiana University
Madeline E. Rasche, California State University at Fullerton
Reza Razeghifard, Nova Southeastern University
Robin Reed, Austin Peay State University
Susan A. Rotenberg, Queens College—City University of New York
Shane Ruebush, Brigham Young University—Idaho
Lisa Ryno, Oberlin College
Matthew Saderholm, Berea College
Wilma Saffran, QC Queens College
Preface | xxi
Theresa Salerno, Minnesota State University—Mankato
Jeremy Sanford, University of California—Santa Cruz
Seetharama Satyanarayana-Jois, University of Louisiana—Monroe
Jamie Scaglione, Eastern Michigan University
Jeffrey B. Schineller, Humboldt State University
Allan Scruggs, Arizona State University
Robert Seiser, Roosevelt University
Michael Sierk, Saint Vincent College
John Sinkey, University of Cincinnati—Clermont College
Jennifer Sniegowski, Arizona State University
Blair Szymczyna, Western Michigan University
Jeremy Thorner, University of California—Berkeley
Dean Tolan, Boston University
Michael Trakselis, University of Pittsburgh
Toni Trumbo-Bell, Bloomsburg University
Pearl Tsang, University of Cincinnati
David Tu, Pennsylvania State University
Harry Van Keulen, University of Ohio
Francisco Villa, Northern Arizona University
Yufeng Wei, Seton Hall University
Lisa Wen, Western Illinois University
Rosemary Whelan, University of New Haven
Vladi Heredia Wilent, Temple University
Foundation Figure Advisory Board
David W. Brown, Florida Gulf Coast University
Paul Craig, Rochester Institute of Technology
Peter Gegenheimer, University of Kansas
Jayant Ghiara, University of California—San Diego
Pavan Kadandale, University of California—Irvine
Walter Novak, Wabash College
Heather Tienson, University of California—Los Angeles
Brian G. Trewyn, Colorado School of Mines
 About the Authors
Dean R. Appling is the Lester J.
Reed Professor of Biochemistry and
the Associate Dean for Research and
Facilities for the College of Natural
Sciences at the University of Texas
at Austin, where he has taught and
done research for the past 29 years.
Dean earned his B.S. in Biology
from Texas A&M University (1977)
and his Ph.D. in Biochemistry from
Vanderbilt University (1981). The Appling laboratory studies the or-
ganization and regulation of metabolic pathways in eukaryotes, focus-
ing on folate-mediated one-carbon metabolism. The lab is particularly
interested in understanding how one-carbon metabolism is organized
in mitochondria, as these organelles are central players in many hu-
man diseases. In addition to coauthoring Biochemistry, Fourth Edi-
tion, a textbook for majors and graduate students, Dean has published
over 60 scientific papers and book chapters.
As much fun as writing a textbook might be, Dean would rather
be outdoors. He is an avid fisherman and hiker. Recently, Dean and his
wife, Maureen, have become entranced by the birds on the ­Texas coast.
They were introduced to bird-watching by coauthor Chris Mathews
and his wife Kate—an unintended consequence of writing textbooks!
Spencer J. Anthony-Cahill is a Profes-
sor in the Department of ­ Chemistry
at Western Washington University
(WWU), Bellingham, WA. Spencer
earned his B.A. in chemistry from
­Whitman College, and his Ph.D. in bio-
organic chemistry from the University
of ­
California, Berkeley. His graduate
work, in the laboratory of Peter Schultz,
focused on the biosynthetic incorpo-
ration of unnatural amino acids into proteins. Spencer was an NIH
postdoctoral fellow in the laboratory of Bill DeGrado (then at DuPont
Central Research), where he worked on de novo peptide design and the
prediction of the tertiary structure of the HLH DNA-binding motif.
He then worked for five years as a research scientist in the biotechnol-
ogy industry, developing recombinant hemoglobin as a treatment for
acute blood loss. In 1997, Spencer decided to pursue his long-standing
interest in teaching and moved to WWU, where he is today. In 2012
Spencer was recognized by WWU with the Peter J. Elich Award for
Excellence in Teaching.
xxii
Research in the Anthony-Cahill laboratory is directed at the pro-
tein engineering and structural biology of oxygen-binding proteins.
The primary focus is on circular permutation of human b-globin as a
means of developing a single-chain hemoglobin with desirable thera-
peutic properties as a blood replacement.
Outside the classroom and laboratory, Spencer is a great fan of
the outdoors—especially the North Cascades and southeastern Utah,
where he has often backpacked, camped, climbed, and mountain
biked. He also plays electric bass (poorly) in a local blues–rock band
and teaches Aikido in Bellingham.
Christopher K. Mathews is Distin-
guished Professor Emeritus of Biochem-
istry at Oregon State University. He
earned his B.A. in chemistry from Reed
College (1958) and Ph.D. in biochemis-
try from the University of Washington
(1962). He served on the faculties of Yale
University and the University of Arizona
from 1963 until 1978, when he moved to
Oregon State University as Chair of the
Department of Biochemistry and Biophysics, a position he held until
2002. His major research interest is the enzymology and regulation
of DNA precursor metabolism and the intracellular coordination be-
tween deoxyribonucleotide synthesis and DNA replication. From 1984
to 1985, Dr. Mathews was an Eleanor Roosevelt International Cancer
Fellow at the Karolinska Institute in Stockholm, and in 1994–1995 he
held the Tage Erlander Guest Professorship at Stockholm University.
Dr. Mathews has published about 185 research papers, book chapters,
and reviews dealing with molecular virology, metabolic regulation, nu-
cleotide enzymology, and biochemical genetics. From 1964 until 2012
he was principal investigator on grants from the National Institutes of
Health, National Science Foundation, and the Army Research Office.
He is the author of Bacteriophage Biochemistry (1971) and coeditor
of Bacteriophage T4 (1983) and Structural and Organizational Aspects
of Metabolic Regulation (1990). He was lead author of four editions of
Biochemistry, a textbook for majors and graduate students. His teach-
ing experience includes undergraduate, graduate, and medical school
biochemistry courses.
He has backpacked and floated the mountains and rivers,
­respectively, of Oregon and the Northwest. As an enthusiastic birder
he has served as President of the Audubon Society of Corvallis and is
President of the Great Basin Society, which operates the Malheur Field
­Station in eastern Oregon.
 Tools of Biochemistry
TOOLS OF
364 | CHAPTER 11 Chemical Logic of Metabolism 11.6 Experimental Analysis of Metabolism | 365
11B Radioactive and Stable Isotopes
BIOCHEMISTRY Creatine phosphate 2

Radioisotopes revolutionized biochemistry when they became avail-
able to investigators shortly after World War II. Radioisotopes ex-
tend—by orders of magnitude—the sensitivity with which chemical
species can be detected. Traditional chemical analysis can detect and
quantify molecules in the micromole (10-6 mole) or nanomole (10-9
mole) range. A compound that is “labeled,” containing one or more
atoms of a radioisotope, can be detected in picomole (10-12 mole) or
even femtomole (10-15 mole) amounts. Radiolabeled compounds are
called tracers because they allow an investigator to follow specific
chemical or biochemical transformations in the presence of a huge
excess of nonradioactive material.
Isotopes are different forms of the same element, so they have dif-
compounds physically, as in the Meselson–Stahl experiment on
DNA replication (see Chapter 4).
Second, compounds labeled with stable isotopes, particularly 13C,
are widely used in nuclear magnetic resonance studies of molecu-
lar structure and dynamics (see Tools of Biochemistry 6A).
Third, stable isotopes are used to study reaction mechanisms.
The “isotope rate effect” refers to the effect on reaction rate of
replacing an atom by a heavy isotope. As discussed in Chapter
8, this effect helps to identify rate-limiting steps in enzyme-
catalyzed reactions. TABLE 11B.1 lists information about the
isotopes, both stable and radioactive, that have found the great-
est use in biochemistry.
where N0 is the number of radioactive atoms at time zero, N is the
number remaining at time t, and l is a radioactive decay constant for
a particular isotope, related to the intrinsic instability of that isotope.
According to this equation, the fraction of nuclei in a population that
decays within a given time interval is constant. For this reason, a
more convenient parameter than the decay constant l is the half-life,
t1/2, the time required for half of the nuclei in a sample to decay. The ATP γ-phosphate
half-life is equal to -ln 0.5/l or +0.693/l. The half-life, like l, is an ATP α-phosphate
intrinsic property of a given radioisotope (see Table 11B.1).
The basic unit of radioactive decay is the curie (Ci). This unit is
4 ATP β-phosphate
defined as an amount of radioactivity equivalent to that in 1 g of Pi 3
1
radium—specifically, 2.22 * 1012 disintegrations per minute (dpm). 5

ferent atomic weights but the same atomic number. Thus, the chemical
properties of the different isotopes of a particular element are virtually
identical. Isotopic forms of an element exist naturally, and substances
enriched in rare isotopes can be isolated and purified from natural
sources. Most of the isotopes used in biochemistry, however, are
produced in nuclear reactors. Simple chemical compounds produced
in such reactors are then converted to radiolabeled biochemicals by
chemical and enzymatic synthesis.
Although radioisotopes are still commonly used in biochemis-
try, stable isotopes are also used as tracers. For example, the two rare
isotopes of hydrogen include a stable isotope (deuterium, 2H) and a
radioactive isotope (tritium, 3H). Of the many uses of stable isotopes
The Nature of Radioactive Decay
The atomic nucleus of an unstable element can decay, giving rise to
one or more of the three types of ionizing radiation: a-, b-, and g-
rays. Only b- and g-emitting radioisotopes are used in biochemical
research; the most useful are listed in TABLE 11B.1. A b-ray is an emit-
ted electron, and a g-ray is a high-energy photon. Most biochemical
uses of radioisotopes involve b emitters.
Radioactive decay is a first-order kinetic process. The probability
that a given atomic nucleus will decay is affected neither by the num-
ber of preceding decay events that have occurred nor by interaction
with other radioactive nuclei. Rather, it is an intrinsic property of that
The most widely used method for measuring b-emissions is liquid
scintillation counting. The sample is dissolved or suspended in an (a) Before exercise.
organic solvent containing one or two fluorescent organic compounds,
2
or fluors. A b-particle emitted from the sample has a high probability of
hitting a molecule of the solvent. This contact excites the solvent mol-
ecule, boosting an electron to a higher energy level. When that electron
1 4
returns to the ground state, a photon of light is emitted. The photon is 3
5
absorbed by a molecule of the fluor, which in turn becomes excited. A
photomultiplier detects the fluorescence and for each disintegration
converts it to an electrical signal, which is recorded and counted. (b) 30 seconds into a 2 minute exercise period.
Nuclear Magnetic Resonance 1

in biochemical research, we mention three applications here.

First, incorporation of a stable isotope often increases the den-
sity of a material because the rare isotopes usually have higher
atomic weights than their more abundant counterparts. This
nucleus. Thus, the number of decay events occurring in a given time In recent years, nuclear magnetic resonance (NMR) spectroscopy
2
interval is related only to the number of radioactive atoms present. has become widely available for noninvasive monitoring of intact
cells and organs. As explained in Tools of Biochemistry 6A, Phospho-
This phenomenon gives rise to the law of radioactive decay: monoesters
compounds containing certain atomic nuclei can be identified 4

difference presents a way to separate labeled from nonlabeled N = N0e - lt from an NMR spectrum, which measures shifts in the frequency of 6
3
5
absorbed electromagnetic radiation. A researcher can determine an
NMR spectrum of whole cells, or of organs or tissues in an intact (c) At the end of exercise.
TABLE 11B.1 Some Useful Isotopes in Biochemistry plant or animal. NMR has even become a powerful noninvasive
diagnostic tool, referred to as magnetic resonance imaging (MRI) 2 FIGURE 11B.1
Isotope Stable or Radioactive Emission Half-Life Maximum Energy (MeV*) in the medical arena.
The effect of anaerobic exercise
2 For the most part, macromolecular components do not contrib- on 31P NMR spectra of human forearm
H Stable b
ute to the spectrum, nor do compounds that are present at less than muscle. Peak areas are proportional to
3
H Radioactive b 12.3 years 0.018 about 0.5 mM. The nuclei most commonly used in this in vivo tech- intracellular concentrations. See Tools of
13
C Stable nique are 1H, 31P, and 13C (Table 11B.1). FIGURE 11B.1 shows 31P NMR Biochemistry 6A for the interpretation of
14
C Radioactive b 5730 years 0.155 spectra that represent components in the human forearm muscle. The NMR spectra. Courtesy of Dean Sherry, Craig
Malloy and Jimin Ren of University of Texas-
15
N Stable five major peaks correspond to the phosphorus nuclei in orthophos- Southwestern Medical Center.
18
O Stable
phate (Pi), creatine phosphate, and the three phosphates of ATP.
24
Because peak area is proportional to concentration, the energy status
Na Radioactive b (and g) 15 hours 1.39
of intact cells can be determined. For example, an energy-rich muscle
31
P Stable has lots of creatine phosphate, whereas a fatigued muscle uses up
32
P Radioactive b 14.3 days 1.71 most of its creatine phosphate in order to maintain ATP levels (note 4
35
S Radioactive b 87 days 0.167 also the accumulation of AMP—peak 6—in the third scan). NMR is 3
1 5
45
Ca Radioactive b 163 days 0.254 finding wide applicability in monitoring recovery from heart attacks,
59 in which cellular ischemia (insufficient oxygenation) damages cells
Fe Radioactive b (and g) 45 days 0.46, 0.27
131
by reducing ATP content. NMR can also be used to study metabolite 5 0 −5 −10 −15
I Radioactive b (and g) 8 days 0.335, 0.608 ppm
compartmentation, flux rates through major metabolic pathways, and
*MeV = million electron volts intracellular pH. (d) Ten minutes after exercise.

Tools of Biochemistry emphasize our field as an experimental science and highlight the

most important research techniques relevant to students today.

2A Electrophoresis and Isoelectric Focusing 44 8A How to Measure the Rates of Enzyme-Catalyzed

Reactions 269
4A Manipulating DNA 99
9A The Emerging Field of Glycomics 299
4B An Introduction to X-Ray Diffraction 104
11A Metabolomics 361
5A Protein Expression and Purification 131
11B Radioactive and Stable Isotopes 364
5B Mass, Sequence, and Amino Acid Analyses of
Purified Proteins 138 13A Detecting and Analyzing Protein–Protein
Interactions 442
6A Spectroscopic Methods for Studying
Macromolecular Conformation in Solution 178 21A Polymerase Chain Reaction 674
6B Determining Molecular Masses and the Number of 24A DNA Microarrays 753
Subunits in a Protein Molecule 185
24B Chromatin Immunoprecipitation 754
7A Immunological Methods 230

xxiii
 Foundation Figures
FOUNDATION FIGURE |
Triacylglycerol
for Biochemistry
Biomolecules: Structure and Function MasteringChemistry® for Biochemistry provides select end-of-chapter problems
and feedback-enriched tutorial problems, animations, and interactive figures to
deepen your understanding of complex topics while practicing problem solving.
PROTEINS Chapters 5 and 6-Introduction to Proteins
Phospholipid Glycerophospholipid monomer Proteins perform a wide range of cellular functions
LIPIDS Chapter 10-Lipids, Membranes, and Cellular Transport and are macromolecules containing one or more
polypeptide chains. These polypeptides are polymerss of
+
CH2 N (CH3)3
choline Lipids are water-insoluble biomolecules that include
CH2

a-amino acids linked together via Polypeptide chain Amino acid monomers
O

phosphate
phospholipids, steroids, and fatty acids. Cell
Hydrophilic O P

O
O–
membranes are largely composed of bilayers of amide, or peptide, O
head CH2 CH CH2
glycerol glycerophospholipids. A glycerophospholipid bonds. Three of the 20
common a-amino acids C
O O
monomer contains two long aliphatic chains linked to CH3CH CH O2
are shown at right; each amino
C OC O

CH2 CH2 a glycerol-3-phosphate backbone via an ester Ala

CH2 CH2
linkage, and a polar group such as choline acid contains an amine group and CH3 NH3
1

a carboxylic acid functional group. Gly

connected to the phosphoryl group. The aliphatic
CH2 CH2

CH2 CH2 Val Valine (Val)

CH2 CH2
tails interact with each other to form the hydrophobic The order of amino acid residues
CH2 CH2
bilayer, while the polar head groups interact with the in a polypeptide dictates its folding
into a specific and highly complex
CH2 CH2

CH2 CH
fatty acids
aqueous environments on either side of the cell
CH2 CH
membrane. structure, such as the protein O O
Hydrophobic CH2
CH2
ubiquitin shown to the right. Carboxylic acid
CH2
tail CH2
CH2 C C group (–)
O2
CH2
CH2 H CH CH3 CH O2
CH2 CH2
CH2 CH2 Protein (ubiquitin) 1NH 1NH
Amine group (+)
CH2 CH2 3 3
CH2 CH3

CH3
Glycine (Gly) Alanine (Ala)

Carbohydrate covalently
attached to side chains of CARBOHYDRATES Chapter 9-Carbohydrates and Glycans
glycoproteins Also called saccharides, they have the simple empirical formula (CH2O)n. Carbohydrates are used diversely in cells, from energy storage
to structure to cell recognition. The ring forms of monosaccharides are polyalcohols with hemiacetal or hemiketal functional groups. Cyclic
Glycoprotein monosaccharides can be modified in a variety of ways and covalently linked via glycosidic bonds to form highly complex structures. Here
an N-linked polysaccharide is shown attached to an integral membrane protein.
Phospholipid
bilayer Asparagine-linked (N-linked) oligosaccharide GlcNAc-disaccharide complex Cyclic monosaccharide monomers
H
CH2OH O
H
Mannose HO
H H
HO HO
Integral OH
H Hemiacetal group
Peripheral membrane Alcohols H OH
membrane Mannose (Man) O
protein
protein HO
Structural
OH
protein N-acetylglucosamine HO NH
O
(GlcNAc)
CH3 Amide group
N-acetylglucosamine (GlcNAc),
Nucleus a modified monosaccharide

Chromatin
Nucleosome
NUCLEIC ACIDS Chapter 4-Nucleic Acids DNA double helix DNA single strand Nucleotide monomers
NH2 Aromatic
Nucleic acids are polymers of nucleotides –
O N base ring
linked via phosphodiester bonds. Nucleotides N
H
are made up of a ribose or deoxyribose sugar –
O P O
CH2 N N H
with an aromatic nitrogenous base attached. A O
O
These bases display hydrogen bond donors
and acceptors which interact in a
H H Deoxyribose
H H
complementary fashion between the two
CELLS ARE COMPOSED OF ORGANIC MOLECULES. strands of the double helix. This base-pairing T OH H
complementarity establishes the mechanism to Deoxyadenosine 5′-monophosphate (dAMP)
Cells constitute the fundamental unit of life. They carry genetic information in the form of maintain the fidelity of genetic information.
DNA, respond to external stimuli, and reproduce through cell division. Although extremely Individual nucleotides, such as ATP, can also NH2
complex systems, cellular components are assembled from four major categories of function as energy –
O H N
molecules: lipids, proteins, carbohydrates, and nucleic acids. These molecules are transfer C
DNA –
molecules. O P O H O
organic molecules; they primarily contain the elements C, H, O, N, P and S, and contain Hydrogen bond
CH2
O
N
O
common organic functional groups such as esters, amides, alcohols, disulfides and between bases H H
aromatic rings. A central theme of biochemistry is that function is determined by H H
Phosphodiester linkage
structure. The cellular functions of these various classes of molecules are dictated by OH H
their structures and the organic functional groups they contain. Deoxycytidine 5′-monophosphate (dCMP)

Foundation Figures integrate core chemical and biological connections visually and provide a way to
organize the complex and detailed material intellectually, thus making relationships among key concepts
clear and easier to study.

1 Biomolecules: Structure and Function 46

2 Protein Structure and Function 188
3 Regulation of Enzyme Activity 272
4 Enzyme Kinetics and Drug Action 366
5 Intermediary Metabolism 478
6 Cell Signaling and Protein Regulation 650
7 Antibody Diversity and Use as Therapeutics 728
8 Information Flow in Biological Systems 812

xxiv
Another random document with
no related content on Scribd:
nationality, deemed it an honour to be allowed to worship. Though
faithful to the cult of his Hebrew fathers, Mendelssohn was deeply
imbued with Hellenic thought and sense of beauty. His famous
dialogue, Phaedo, or the Immortality of the Soul, might have been
written by Plato, had Plato lived in the eighteenth century; so much
so that an enthusiastic pastor and physiognomist of Zurich,
enchanted by Mendelssohn’s masterpiece, declared that he saw the
spirit of Socrates not only in every line of the book, but in every line
of the author’s face. Like a present-day phrenologist, Lavater was
anxious to obtain a model of Mendelssohn’s head as an
advertisement for his science; but, being in addition a pious
evangelical minister, he also nourished hopes of winning
Mendelssohn over to the Christian faith. In both these objects of his
ambition the well-meaning physiognomist was sadly disappointed.
The great work of Mendelssohn’s life is the partial reconciliation
which by his writings he assisted in effecting between the two worlds
that had so long misjudged and mistrusted each other. His
translation of the Pentateuch into pure German inaugurated for the
Jews of Germany a new era of literary activity. By substituting
modern German for the barbarous Yiddish in their education the
book established an intellectual bond between them and their
Christian fellow-countrymen. Lessing made the Jew known to the
Gentile; Mendelssohn made the Gentile known to the Jew. And even
the hostility of Frederick, the master of legions, the sneers of
Voltaire, the master of laughter, and the bigotry of the Protestant
public and of the Synagogue prevailed not against the united
endeavours of the two apostles. In 1763 Mendelssohn carried off the
prize offered by the Academy of Berlin for an essay on a
philosophical subject, beating no less a competitor than Kant. In the
same year Frederick, who three years before, enraged at some
thinly-veiled disparagement of his verses by the Jewish critic, had
been prevented from punishing him only by the fear of French
ridicule, was induced to honour Mendelssohn by granting him the
status of a Protected Jew.
Among Mendelssohn’s young contemporaries three are pre-
eminent as representatives of the new Hebrew culture: Herz, Ben
David, and Maimon. Herz was Kant’s favourite pupil and
distinguished himself as a popular exponent of his master’s
philosophy. Ben David was a mathematician and a student of Kant’s
philosophy. On the latter subject he lectured at the University of
Vienna and afterwards in Berlin. Maimon was a Polish Jew who had
inherited restlessness of body from his fathers and restlessness of
mind from the writings of his great namesake Maimonides. He
wandered over the limitless and cheerless desert of Negation,
sought to slake his thirst at the mirage of the Cabbala, or to forget it
in the mysticism of the “Pious,” and finally, at the age of five-and-
twenty, quitting home and family with the readiness characteristic of
the born vagrant, he arrived in Berlin, unwashed, unkempt, and
untaught in any tongue but his native jargon of Germano-Polish
Hebrew. Some time afterwards, however, he became famous by the
publication of an Autobiography—a work worthy to stand beside
Rousseau’s Confessions in one respect at least: its unsparing and
almost savage unreserve. Its sincerity was doubted by George Eliot
and by other critics also. But Schiller and Goethe were both
impressed by this work, and Maimon was honoured with the latter
poet’s acquaintance.
Gradually there was formed in the capital of Prussia a wide circle
of intellectual Jews and Jewesses, which stood in strong contrast to
the proud and stupid nobility on the one hand and to the homely and
stupid bourgeoisie on the other. Between these two frigid zones
spread the Jewish class of men and women rich in money and
brains, cultivating French literature, wit, and infidelity. Mendelssohn’s
house was at first the centre of this circle, and after his death it was
succeeded by that of Herz, whose own brilliancy was eclipsed by
that of his wife. In her salon were to be met more celebrities than at
Court. Mirabeau was captivated by the gifted Jewess’s charm, and
little by little even the wives of distinguished men began to
acknowledge the beautiful Henrietta’s attraction. Another literary
salon was at the same time opened by a Jewish lady in Vienna, and
it attained an equal degree of social success. These are only a few
examples of that spiritual emancipation which accelerated the
political emancipation of Israel in Europe. It is true that the
intoxication of freedom produced a certain amount of frivolity,
immorality, and blind imitation of Gentile vice; for many Jews and
Jewesses, having once broken loose of the Synagogue, drifted into
profligacy. But where there is much ripe fruit there must always be
some that is rotten.
The campaign for the removal of Jewish disabilities, begun by
the two friends, was continued by others. In 1781 Christian William
Dohm, a distinguished German author and disciple of
Mendelssohn’s, advocated the cause in an eloquent treatise in which
he not only reviewed the pathetic history of the Jews in Europe, and
defended them against the venerable slanders of seventeen hundred
years, but also discussed practical measures for the amelioration of
their lot. The plea was read by thousands, and, though refuted by
many, it was approved by more. Its earliest tangible effect, however,
was produced, not in Berlin, but in Vienna. The new spirit had
penetrated into the remotest corners of the German world. Austria,
long a by-word among the Jews as a house of bondage, established
an era of toleration under the philosophical monarch Joseph II., who,
soon after the appearance of Dohm’s work, abolished many of the
imposts paid by the children of Israel, granted them permission to
pursue all arts and sciences, trades and handicrafts, admitted them
to the universities and academies, founded and endowed Jewish
schools, and, in pursuance of his futile plan to secure internal
harmony by the Germanisation of the various races of his Empire, he
made the study of German compulsory on all Jewish adults. The
reign of toleration, it is true, ended with the good
1782
monarch’s life; but nevertheless it forms a landmark on
the road to civilisation.
Meanwhile, in Germany also, the new gospel was fighting its
way laboriously to the front. The death of Frederick the Great
removed a great obstacle from the path of the advocates of the
Jewish cause. Under his successor, Frederick William II., a
commission was appointed to investigate the complaints of the
Prussian Jews and to suggest remedies; and the Jews were asked
to choose “honest men” from amongst themselves, with whom the
matter might be discussed. The Jewish deputies laid
1787
before the commission all their grievances; and the
poll-tax, levied upon every Jew who crossed or re-crossed the
frontiers of a city or province, was abolished in Prussia. But the Jews
justly pronounced this concession as falling far below their hopes
and their needs. German public opinion was still averse to Jewish
emancipation, and its prejudices were shared even by such men as
Goethe and Fichte, both of whom, though representing opposite
political ideals and though despising Christianity, yet agreed in the
orthodox estimate of the Jew—and that in spite of the admiration
which the former entertained for “the divine lessons” of Nathan der
Weise. Thus, though the good seed had been sown in German soil,
it was not in Germany that the flower saw the light of the sun.
Notwithstanding Voltaire’s unfriendly utterances regarding the
Jews, the general tenour of his teaching was, of course, in favour of
toleration, and it was on the French side of the Rhine that Lessing’s
intellectual dream was to find its first realisation in practical politics.
Montesquieu, moved to righteous indignation by the
1748
sight of the suffering Marranos in Portugal, had already
protested against the barbarous treatment of the Jews in his Esprit
des Lois, stigmatising its injustice, and demonstrating the injury
which it had caused to various countries. Nor did he argue in vain.
Since the middle of the sixteenth century there had been Jewish
communities in France, consisting of refugees from Spain and
Portugal. But they were only tolerated as pseudo-Christians.
Dissimulation was absolutely necessary for self-preservation, and
these hypocrites in spite of themselves were obliged to have their
marriages solemnised at church, and otherwise to conform to rites
which they detested. To these immigrants were gradually added
new-comers from Germany and Poland, whom the Portuguese Jews
despised and persecuted in a most revolting manner. An internecine
feud between these two classes of refugees at Bordeaux gave King
Louis XV. an opportunity of interfering in the affairs of the community.
The Portuguese section passed a resolution
1760
calumniating their poor co-religionists, and trying to
procure their exclusion as sturdy beggars and vagabonds. The
communal resolution was submitted to the king, and every stone was
turned to obtain his ratification of the iniquitous statute. Truly, there is
no tyrant like a slave. Soon after Louis XV. issued an order expelling
all the stigmatised Jews from Bordeaux within a fortnight; but in the
chaos which pervaded French administration at that time there was a
gulf between the issue and the execution of royal edicts, which,
happily for the wretched outcasts, was never bridged over.
Meanwhile the protest against the servile position to
1776
which Israel had been doomed for ages gained in
strength, and, as its first result, the Jews of Paris obtained a legal
confirmation of the right of abode in the capital of France.
Far worse was the condition of the Jew in Alsace—a district
German in everything save political allegiance. In that province
oppression was of that dull, chronic kind which begets degradation
without driving its victims to violent despair. The Jews in Alsace were
simply regarded and treated as inferior animals. They lived in
jealously guarded ghettos, egress from which had to be purchased
from the local officials. The right of abode was vested in the hands of
the feudal nobility; the same limitations as to the number of residents
and marriages prevailed, and the same extortions were practised
there as in Germany. The Jews had to pay tribute to king, bishop,
and lord paramount for protection, besides the taxes levied by the
barons on whose domains they dwelt, and the irregular gifts wrung
out of them by the barons’ satellites. And, while money was
demanded at every turn, most of the avenues through which money
comes were closed to the Jews, cattle-dealing and jewellery being
the only trades which they were permitted to pursue openly. The
profits derived from these pursuits were, of course, supplemented by
surreptitious and, consequently, excessive usury. This last
occupation exposed the Jew to the hatred of the simple country folk,
and to blackmail on the part of crafty informers. The discontent,
fomented by the clergy and the local magistrates, culminated in a
petition to Louis XVI., imploring his Majesty to expel the accursed
race from Alsace. But it was too late in the day. The movement in
favour of toleration had made too much headway. An enquiry was
instituted, and the ringleader of the anti-Jewish agitation—a legal
rogue rejoicing in the name of Hell—was convicted of blackmail and
banished from the province, instead of the Jews. At the
1780
same time the latter presented to the King a memorial,
drawn up by Dohm, and obtained a considerable alleviation of the
burdens under which they groaned, of the restrictions which
hampered their commercial activity, and of the missionary zeal of the
Catholic priests, which threatened the religion of their children.
Finally, they were relieved of the odious capitation tax in 1784, the
year which witnessed the triumph of Beaumarchais’ Mariage de
Figaro at the Theatre Français—a rapier thrust at the dotard giant of
feudalism, none the less deadly because inflicted amid peals of
laughter; to be followed by the fall of the Bastille and of other things.
In the same year a Royal Commission was appointed to revise the
laws concerning the Jews and to remove their disabilities.
The Revolution did not stem the current of toleration. In 1789 the
National Assembly met in Paris: a council of twelve hundred spiritual
and secular fathers patriotically sworn to formulate a new creed—an
object which, despite pandemonic wrangling and jangling and
chaotic disorder of thought and action, they contrived to achieve in
that memorable document, the Declaration of the Rights of Man. The
National or, as it now calls itself, Constituent Assembly is the “station
for all augury,” whither repair all mortals in distress and doubt.
Petitions pour in from every side, and among these is one from the
Jews, especially the down-trodden Jews of Alsace. They also come
forward to claim a share in the new Elysium, to assert their rights as
men. Mirabeau, who already towers high above his brother-
councillors, and is looked upon as the one seer among many
speakers—the one living force among fleeting shades—espouses
the Jewish claim. Three years earlier he had published a work On
Mendelssohn and the Political Reform of the Jews. He now sets
himself to demolish the remnants of the ancient prejudice still
cherished by some of the clerical friends of mankind.
The task was not an easy one. Besides Mirabeau, the Abbé
Grégoire, and Clermont-Tonnerre, there were scarcely any politicians
of note in France who cared for the Jews. The Declaration of the
Rights of Man, while abolishing the religious disabilities of
Protestants, made no provision for the Jews. Even the French public
of 1789 was not yet quite ripe for so revolutionary a measure as the
admission of the Jew to that equality of citizenship which it declared
to be the birthright of every human being. A statute of January 28th,
1790, enfranchised the Jews of the south of France who had always
held a privileged position; but this exception on behalf of a few only
emphasised the disabilities of the many. The bulk of the race,
especially in Alsace, continued to be treated as outcasts, until the
more advanced section of the Parisian public, under the leadership
of the advocate Godard, appealed to the people of the capital for its
opinion on the matter. Fifty-three out of the sixty
1790 Feb. 25
districts voted in favour of the Jews, and the Commune
gave a practical expression to the feelings of the majority in the form
of an address laid before the Assembly. But it was not till nineteen
months after that a definite decision was arrived at, partly by the
eloquent advocacy of Talleyrand, who pointed out to the Assembly
that the only difference between ordinary Frenchmen and French
Jews was their religion. In every other respect they were fellow-
countrymen and brothers. If, therefore, religion were allowed to
interfere with their enfranchisement, that would be a denial of the
principles of the Revolution—a flagrant breach of all those laws of
humanity and civil equality for which the French people were fighting.
These arguments prevailed in the end, and the French
1791 Sept. 27
Jews were formally enfranchised. For the first time
since the destruction of the Temple the children of
Israel, who had hitherto sojourned as strangers in foreign realms,
hated, baited, and hunted from place to place, without a country,
without a home, without civil or political rights, are citizens.
Henceforth the name Juif, made hateful by the horrors of centuries,
is to be forgotten in the new appellation of Israelite.
The storm that raged during the next three years left the French
Jews comparatively unscathed. Israel had long taken to heart the
lesson embodied in the oriental proverb, “The head that is bent is
spared by the sword.” In some districts, it is true, the enemies of all
religion also tried to suppress the Jewish “superstition”; but on the
whole the Jews came through the ordeal better than might have
been expected. The Constitution of 1795 confirmed the decrees of
the National Assembly.
Holland, as we have seen, had long been a home for the
persecuted sons of Israel. But the full rights of citizenship were not
conceded to them until 1796, when closer relations with France
enabled the gospel of liberty, equality, and fraternity to complete the
work of toleration begun by enlightened commercial policy. The gift,
however, was not welcomed by the heads of the community. The
jealous Synagogue, which had persecuted poor Uriel Acosta to
death, and excommunicated Spinoza in the preceding century, was
still determined to guard its masterful hold upon its members. The
new duties and rights which accompanied the gift, it was feared,
would render the Jews less dependent upon their religious pastors.
The Rabbis, supported by the Portuguese element which formed the
aristocracy of the community and, like all aristocracies, abhorred
innovation, offered a strenuous resistance to emancipation. They
indited a circular epistle declaring that the Jews renounced their
rights of citizenship as contrary to the commands of Holy Writ. They
endorsed all the objections raised by the enemies of Jewish
emancipation—namely, that the Jews, owing to their traditions of the
past and their expectation of the Messiah, are and shall ever be
strangers in the land—and they prevented their flock from accepting
the invitation to vote in the elections to the National Assembly. On
the other hand, the Liberal party, led by Jews of German descent,
endeavoured to weaken the power of the Rabbis. The two sections
banned each other heartily, and the distance between them grew
wider as the Liberals went further and further along the path of
reform. This difference of views led to a schism between the lovers
of the new and the slaves of the old.
In England prejudice was still so strong that as late as 1783 we
find the Jews excluded from the benefit of the Irish Naturalisation
Act, passed that year. Yet there appears a faint reflection of
Lessing’s teaching in some of the writings which bring the century to
a close. Richard Cumberland, the friend of Burke and Reynolds,
Garrick and Goldsmith, banteringly eulogized by the last-named
author as “the Terence of England, the mender of hearts,” wrote, in
collaboration with Burgess, the Exodiad, a long epic, consisting of
eight dull books, wherein the two bards sing the deliverance of Israel
from Egypt and their journey through the desert. The work begins,
after the fashion of epics, with the orthodox invocation of the Muse in
a single breathless period:
 “Of Israel, by Jehovah’s mighty power
From long captivity redeem’d, with loss
And total overthrow of Egypt’s host,
What time the chosen servant of the Lord
From Goshen to the land of promise led
Through the divided sea the ransom’d tribes,
Sing, heavenly Muse, and prop those mortal powers,
Which but for thy sustaining aid must sink
Under the weight of argument so vast,
Scenes so majestic, subject so sublime.”

It ends with a parting speech from Moses at the point of death:

“‘My ministry is finish’d; in thine hands,

Blest of the Lord, O Joshua! I have put
The book of life, and in thine arms expire.’

He ceas’d, and instantly the hand of death

Press’d on his heart and stopp’d its vital pulse;
His eye-lids dropt upon their sightless balls:
One deep-drawn sigh dismiss’d his parting soul;
To heaven it rose; his body sank to earth,
And God’s archangel guarded his remains.”

In charming contrast to this portentous rhapsody stands

Goldsmith’s own tender oratorio, The Captivity. It deals with the sons
of Israel in exile, working and weeping on the banks of the
Euphrates; yet keeping their hearts turned longingly to the fields of
Sharon, the plains of Kedron, the cedar-clad hills of Lebanon, and
Zion. “Insulted, chained, and all the world their foe,” the captives
nourish their faith in the God of their fathers:

“Our God is all we boast below,

To him we turn our eyes;
 And every added weight of woe
Shall make our homage rise.”

Thus sings the chorus of Prophets in Exile. Yet, even in the midst
of their woes, they see cause for pride and self-glorification: They
are the only worshippers of the true God; the rest of the world
worships idle idols:

“Are not, this very morn, those feasts begun,

Where prostrate Error hails the rising sun?
Do not our tyrant lords this day ordain
For superstitious rites and mirth profane?
And should we mourn? should coward Virtue fly,
When vaunting Folly lifts her head on high?
No! rather let us triumph still the more,
And as our fortune sinks, our spirit soar.”

Faith has its reward. While the captives bewail their lot,
deliverance is close at hand. The star of Cyrus has risen; Babylon
the proud falls, and the prophecy concerning the restoration of Israel
is fulfilled.
But strong as is the sympathy with the fortunes and the spirit of
Israel in both these works, neither of them can be legitimately
considered as bearing directly on the Jewish question. The Shylock
tradition is still powerful in England, for want of a Lessing. It is not
ponderous poetasters, like Cumberland and Burgess, nor yet sweet
singers like the gentle Goldsmith, who will overthrow a convention
hallowed by the genius of a Shakespeare.
 CHAPTER XX

PALINGENESIA

The French Revolution is over. For a while the volcanic forces, which
had long groaned in subterranean bondage, broke their prison, burst
into the light of day, and brought death and desolation upon the face
of the earth. But their task is done. Nemesis has obtained the due
and forfeit of her bond, and the Titans have returned to their
Tartarean abode, until such time as their services may be needed
again. A sentimentalist will, no doubt, find much to lament in the
unsparing fury of the avengers. Their hand has struck down
everything that stood high—good, evil, and indifferent alike—with
elemental impartiality. But the philosopher may, on the whole, see
reason to rejoice. At all events, he will, if he happens to be a Jew.
For among the ruins of tyranny he will recognise the rusty chains
which had for centuries weighed upon the limbs of Israel. They are
gone, whatever may have survived. Whatever may be said of the
rest, they were an evil. The Jew sees nothing but the hand of God in
the desolation wrought by another. For him the Powers of Darkness
had broken their prison; for him the proud ones of the earth had
been laid low; for him the dreams of freedom dreamt by the poets
and thinkers of France had been turned into a reality of despotism.
What matter? Cyrus was a despot, and yet a deliverer of Israel;
Alexander was another; and Napoleon was doubtless destined to be
the third. Strange, indeed, are the ways of the Lord, but His mercy
endureth for ever toward Israel.
The hopes of the Jews were not disappointed. The work of
enfranchisement, commenced by philosophers like Montesquieu,
and carried on by patriots like Mirabeau, was completed by
Napoleon. Though deeply sensible of the disagreeable fact that
usury and extortion had been the favourite pursuits of the Jews from
time immemorial, Napoleon did not allow himself to be biassed by
the mediaeval view of the matter. Like Alexander the Great, Caesar,
Charlemagne, and Cromwell, he saw the advantage of securing the
support of so numerous, so opulent, and so scattered a nation as the
Israelites, and one at least of his motives undoubtedly was to
conciliate the Jews of Old Prussia, Poland, and Southern Russia, in
the hope of profiting by their sympathy and assistance in the contest
in which he was then engaged. While depriving individual Jews,
notorious for rapacity, of their civil rights, and restricting the
operations of the Jews of the north-east of France by temporarily
refusing to them the right to sequester the goods of their debtors, the
Emperor decided to hear the Jewish side of the question. By his
order an assembly of Hebrew notables from the
1806 July
French and German departments, as well as from Italy,
was summoned in Paris. Twelve questions were put to the delegates
concerning the Jew’s attitude towards the Gentile, the authority of
the Rabbis, usury and conscription; and, on the answers proving
satisfactory, Napoleon astonished the assembly with an
announcement which no Jewish ear had ever hoped to hear in
Europe. The Sanhedrin, or National Council of Israel, after a
prorogation of seventeen centuries, was once more convoked. The
Hebrew polity had outlasted the heathen Roman Empire, the Holy
Roman Empire, Feudalism, and the French Monarchy. Time and the
seismic convulsions which had overthrown these mighty fabrics,
once regarded as eternal, had respected the humble institutions of
the outcasts of humanity. The constitutions of other nations were
built upon the earth and were subject to the laws which govern
earthly things; the constitution of the Jews was preserved in the
archives of Heaven, and was therefore immortal. And
1807 Feb. 9
so, at a word from Napoleon, seventy-one delegates of
the French and Italian Jewries were gathered together in Paris,
elected by the synagogues of the two countries in accordance with
the ancient forms and usages of Israel.
1807 March 2 The fruit of the Sanhedrin’s deliberations was a
charter which defined the relations between Jew and
Gentile in France. While retaining the essential
features of Judaism, the Rabbis wisely conceded much to the
demands of the country which so generously adopted them. The
Nine Responses of the document form a rational compromise
between the rights of God and the rights of Caesar: polygamy is
forbidden; divorce is allowed in accordance with the civil law of the
land; intermarriage with the Gentiles is tolerated, though not
sanctioned, by the Synagogue; French Jews are bidden to regard
the French people as brethren; acts of justice and charity are
recommended towards all believers in the Creator, without distinction
of creed; Jews born in France are exhorted to look upon the country
as their fatherland, to educate their children in its language, to
acquire real property in it, to renounce pursuits hated by their
neighbours, and in every way to endeavour to earn the esteem and
goodwill of the latter; usury is forbidden towards the stranger as
towards the brother; and the interest raised on loans is not, in any
case, to exceed the legal rate. Thus an effective answer was given
to all the legal arguments which had been advanced by the
opponents of Jewish emancipation, and an honest attempt was
made by the doctors and chiefs of the nation to remove from the
children of Israel a portion at least of that odium under which they
had so long laboured.
1808 March 1 When the Sanhedrin had brought its labours to an
7 end, the Emperor repealed the exceptional measures
of 1806 and recognised the Consistorial organisation
which for a century fixed the status of Israel in France. Every two
thousand Jews were to form a community under a synagogue and a
board of trustees, with Paris for their centre. Napoleon, it is true,
while granting this liberal charter, was compelled to yield to the anti-
Jewish prejudices of the people of Alsace and other parts of Eastern
France, where the Jew was hated more than ever, for the disasters
of the Reign of Terror and the distress caused by Napoleon’s
campaigns, by impoverishing the peasants, had delivered them up to
the tender mercies of the money-lender. In accordance with the
wishes of the inhabitants of those districts Napoleon took some
steps highly detrimental to Jewish interests. He enacted, for
example, that loans to minors, women, soldiers and domestic
servants, as well as loans raised on agricultural implements, should
be null; that no more Jews should be allowed to enter Alsace; that
every Jew should serve in the army; and that no Jew should engage
in trade without permission from the Prefect. The duration of this
decree was limited to ten years. But, such local disadvantages and
the indignation aroused thereby notwithstanding, the well-earned
gratitude of Israel was expressed in many Hebrew hymns composed
in honour of the Deliverer whom the Lord had raised for His people.
A few years afterwards even these enactments were withdrawn,
and the Jews were accorded complete equality, civil and political.
From 1814 till 1831 French legislation, despite certain fluctuations
under the brief restoration of the Bourbons, was enriched with
various Acts, all tending to lift the Israelites to a position worthy of
their country, and schools were established for the education of the
Rabbis, who since the latter date until recently were regarded as
138
1833 public functionaries and were paid by the State.
Two years later the French Government gave a signal
proof of its interest in the welfare of the Jewish portion of the French
people by suspending relations with a Swiss canton which had
denied justice to a French Israelite on account of his religion. For in
Switzerland, when the French domination expired, the old prejudices
came to life again, and it was not till 1874 that political equality was
accorded to the Swiss Jews.
1805 Meanwhile Napoleon’s arms had carried on, even
outside France, the work begun by the philosophers of
the preceding generation. The Inquisition was crushed in every
Catholic country under the Emperor’s heel, while in Germany
Napoleon’s conquest brought to the Jews a relief which departed
with the French legions, to return by slow degrees in the succeeding
years. It was one of the bitterest examples of irony presented by
history. The French autocrat had given to the German Jews freedom,
and the people whom the Jews aided with their lives to throw off the
French autocrat’s yoke robbed them of it. In Frankfort, where the
ghetto had been abolished in 1811, immediately on the French
garrison’s withdrawal a clamour arose demanding its restoration. In
other “free towns” also, where rights of equality had been granted to
Israel while the fear of Napoleon hung over them, the ancient hatred
revived immediately on his downfall, and the old state of bondage
was restored. Even in Prussia, where the law recognised the equality
of the Jews in theory, slavery was their lot in reality: many trades and
industries were prohibited to them, the road to academic distinction
was barred to them, and Jews who had attained to the rank of
officers during the War of Liberation were forced to resign their
commissions. Nor were these disabilities removed even when the
German Diet, which, by the Act signed in Vienna on June 8, 1815,
was to manage the affairs of the German Confederacy, had
established the principle of religious freedom among the Christians,
and had pledged itself to consider measures for improving the lot of
the Jews.
This reaction was partly due to an exaggerated sentiment of
nationality and hatred of everything foreign, aroused by the presence
of the French legions in the country, and strengthened by the
sacrifices and the success of the struggle for independence. National
consciousness found an ally in the Christian revolt against the
French Religion of Reason. Enthusiasm for the faith, which the
French had overthrown, added zest to the enthusiasm for the
fatherland, which the French had overrun. “Christian Germanism”
became, not only a patriotic motto, but a veritable cult of a novel and
jealous god to whom everything that was non-Christian and non-
German, including the Jew, ought to be immolated.
1819
“Hep, hep!” (Hierosolyma est perdita) became the
battle-cry of the Jew-baiters in many German towns, and the
persecution spread even into Denmark, where the Jews had been
placed on a footing of equality since 1814. The
1828–30
Prussian Government proposed a plan for the
improvement of the social and political condition of the Jews, but the
measure had to be abandoned owing to the opposition which it met
with on the part of the representatives of the Prussian people. This
return to mediaeval intolerance once assumed in
1840
Prussia the mediaeval form of a blood-accusation; but
the charge only served to establish the innocence of the Jews and
the stupid credulity of their assailants. None the less, it supplied a
striking illustration of the retrogression of the public mind. For the
prejudice, even when its basis was proved false, continued to subsist
in a more or less latent condition among the lower intellectual strata
of society—as prejudices have a way of doing for long centuries after
they have vanished from the surface—and during the revolution of
1848, on the Upper Rhine, it led to a general persecution of the
Jews, who sought refuge in the neighbouring territory of Switzerland.
But the reaction was temporary, and the revolutionary movement
proved, in the main, favourable to the cause of Jewish emancipation.
Although the Prussians, fired by patriotism, had rallied round
their king and unanimously supported him in the effort to deliver the
country from French domination, they had not been left untouched
by the lessons of the French Revolution. To the Prussian patriots
individual freedom was as precious as national independence. So
strong was this feeling that Frederick William III. had been obliged to
promise that at the end of the struggle he would reward his subjects’
sacrifices by granting to them a representative form of government.
But few monarchs have ever parted with power except under
compulsion. When the War of Liberation was over, and the country’s
independence assured, the king forgot his promises. Hence there
arose between the prince and his people a bitter conflict, which
continued under his successor. Frederick William IV. as Crown
Prince had evinced a lively sympathy with the popular demand for a
Constitution; but with the sceptre he inherited the absolutist
principles of his ancestors, and strove to prop up the authority of the
throne by the help of religion. The German Liberals, however, had
outgrown the mediaeval notion that kings rule by the grace of God.
They claimed that the will of the people should be the supreme law
of the State, and laughed at the Sovereign’s antiquated pretensions.
The fate of the German Jews was naturally bound up in that of
German Liberalism.
The year 1846 was chiefly distinguished by the agitation which
prevailed in Prussia and all Northern Germany in favour of religious
toleration and liberty of conscience; and the emancipation of the
Jews was one of the demands submitted to the King of Prussia by
the Prussian Estates, especially those of Cologne, Posen and Berlin,
for various measures of domestic and social improvement, as, for
example, the reform of criminal justice, the publication of the
procedure of trials and of the debates of the Estates, and the
extension of the representation of towns and rural communities. In
the following year the question of Jewish emancipation
1847
was again introduced into the Prussian Chambers and
found only two opponents, one of them being Bismarck, who then
declared that he was “no enemy of the Jews, and if they are my
enemies,” he said, “I forgive them. Under some circumstances I even
like them. I willingly accord them every right, only not that of an
important official power in a Christian State. For me the words, ‘By
the grace of God,’ are no mere empty sounds, and I call that a
Christian State which makes the end and aim of its teaching the
truths of Christianity. If I should see a Jew a representative of the
King’s most sacred Majesty, I should feel deeply humiliated.”
However, the National Parliament which met at Frankfort-on-the-
Main in 1848, under Liberal auspices, among other steps which it
took in order to secure popular freedom, removed all religious
disabilities. The Prussian Constitution of 1850 imitated the example;
and the establishment of the new régime, in 1871, threw the doors
open to the Jews throughout the German Empire. The Reichstag
now contains many distinguished members of the Jewish faith.
In Austria the edifice of toleration reared by Joseph II. was
overthrown by his successors, Leopold II. and Francis I., who
revived most of the antiquated restrictions and regulations against
the Jews, and again confined them within special quarters. This
barbarous policy lasted far into the nineteenth century. In many parts
of the country the Jews were forbidden to own, or even to rent land,
except that on which their houses stood, or to migrate from one
province to another without special permission. In Austrian Poland,
or Galicia, the Jews were especially hated. There, as elsewhere in
Poland, they formed a vast multitude, settled in the chief towns and
villages. The greater part of their emoluments was derived from the
sale of intoxicating liquors, to which the Poles, like all northern
nations, were immoderately addicted. From the time of Joseph II. the
Jews had been by repeated laws prohibited from trading in alcohol.
But these laws were disregarded. The landowners possessed the
exclusive rights of distilling, and they had from the first coming of the
Jews to Poland farmed out these rights to the latter. Deplorably
enough, a number of the Jews, in despair of finding other means of
livelihood, allowed themselves to become the go-betweens in this
demoralising traffic, and thus the most temperate race of Europe laid
itself open to the hostility and scorn of those who would feign have
seen a check put to the intemperate propensities of the people and
its consequent impoverishment.
The condition of the Jews was incomparably better in the parts
of the Empire upon which the rule of the Hapsburgs weighed less
heavily. In Hungary and Transylvania they had long enjoyed freedom
of tenure under the protection of the Magyar nobles. These were in
the habit of employing Jewish bailiffs, and did not consider it beneath
their dignity even to obey the orders of Jewish officers in the war for
independence, in which the Jews took an important part. After the
suppression of the rebellion the latter were made by
1848
the Imperial Government to pay for their patriotic
ardour; but when the day came for the distribution of prizes they
secured their reward. By the Austrian Constitution of 1860, which
received its finishing touches eight years later, the Jews obtained full
liberty. At present several Jews sit in the Legislature, and the race
flourishes not only in Vienna, Budapesth, and other great towns, but
even in the Austrian section of Poland.
The daylight of a tolerant and liberal administration has chased
the ghosts of the past out of Galicia. Even the most orthodox
followers of the Synagogue are fast forgetting their ancient wrongs
and prejudices. In olden times Jewish boys on their birth were
imprisoned by their parents within a pair of stays, laced tighter and
tighter every year, that the child’s chest might remain too narrow for
military service—a suicidal training, the evil consequences of which
are to this day visible in the form of chest diseases and consumption
among the Galician Jews. But the practice has long been
abandoned. Humaner conditions in the army, and the spread of
education among the Austro-Polish Jews, have reconciled them to
the service, and now one half of the Galicia contingent of the Austro-
Hungarian Army consists of Jewish recruits. The Empire has gained
loyal defenders, and the Jews the benefit of a disciplinary and
patriotic education.
In Italy the Papal States were the last retreat of the Middle Age.
The Holy Office had disappeared from Parma, Tuscany, and Sicily in
the eighteenth century, but in Rome it continued to flourish; and
where the Inquisition held sway there was no peace for Israel. The
Roman Jews, liberated by Napoleon, were thrust back
1809
into slavery after his fall. Then the reign of darkness
was restored under the double crown of Dogmatism and Despotism.
The temporal power enforced the doctrines of the spiritual, and the
spiritual was abused to sanctify the decrees of the temporal. How
could the lot of the infidel Jew be other than what it was? The
Roman Ghetto continued to be the home of squalor and sorrow far
into the nineteenth century. As late as 1847 decrees were issued
forbidding the inmates to quit their cage, the Jews were still
compelled to hear sermons at church, and everything that bigotry
could do was done to bring about their conversion.
It is true that Pope Pius IX. inaugurated his reign with a display
of toleration till then unparalleled in the annals of the Papacy. In
1846 a general amnesty was proclaimed by which thousands of
prisoners and exiles were pardoned for crimes which they had never
committed, or of which they had never been legally convicted; two
years later the Jews were relieved from the necessity of listening to
sermons; and daylight seemed at last to have dawned upon Rome.
But this period of liberalism proved as transient as it was
unprecedented. The reaction soon set in, and the influence of the
Jesuits and of obscurantism was re-established. In 1856 the Pope
issued an encyclical condemning somnambulism and clairvoyance,
and bidding all bishops to suppress the anti-Christian practices. Nine
years later he hurled an anathema against the Freemasons—the
deadly enemies of the Inquisition. In brief, the pontificate of Pius IX.,
despite its promising beginning, is chiefly distinguished for two fresh
victories over reason: the discovery of the Immaculate Conception
and the invention of Papal Infallibility.
1858 Under such conditions it is not surprising that the
Church should not hesitate to allow a nurse to baptize
her Jewish charge secretly, and then, on the ground that the child
was a Christian, to tear it from the arms of its parents, and rear it to
be a monk and a persecutor of its own people. Obscurantism and
oppression vanished from Rome only with the Pope’s authority. For
the Jews, as for the Christians of Rome, light came in the train of
Italian unity. Among other mediaeval barbarities which ceased on the
day on which the Italian Army entered Rome were the Inquisition and
the bondage of the Jews. Israel has outlived Temporal Power also. In
the Vatican all facilities are now given for the study of Rabbinic and
Talmudic literature, once condemned to the flames. The pestilent
slums of the Ghetto have been wiped off the face of the earth, and
there is nothing left to recall the days of darkness, save the grey old
synagogue and, close by, the Tiber, murmuring the sad tales of a
world that is past.
1808 In Spain also the Inquisition, suppressed by
Napoleon, revived after his fall; but only as the shade
of its former self. Its last victims were a Quaker and a
1826
Jew, the former hanged, the latter roasted. But even
Spain had to follow the tide of the times. The Jews,
1837
pitilessly driven out of the country when Catholicism
ruled the Peninsula, were readmitted as soon as Catholicism faded
into a mere name. In 1881 the Spanish Government actually invited
the Jews who fled from Russia to settle in its dominions. Seville,
where the Holy Office had instituted its human sacrifices in 1480,
now boasts a Hebrew synagogue. Israel has outlived the Spanish
Inquisition also.
1821 In Portugal, when early in the nineteenth century
liberty of conscience was proclaimed, strange
individuals from the interior of the country appeared at the
synagogues of Lisbon and Oporto. They were the descendants of
the old Marranos. For three centuries they had eluded the ferrets of
the Holy Office and, Christians in appearance, had remained Jews at
heart, waiting, as only a Jew can wait, for the blessed day of
deliverance. They now emerged, and came to participate with their
brethren in the worship of their God after the fashion of their fathers.