BIOCHEMICAL PATHWAYS: AN ATLAS OF BIOCHEMISTRY AND MOLECULAR BIOLOGY Biochemical Pathways Posters available from Roche Applied Science Gerhard Michal’s famous biochemical pathways posters have been a valuable resource for the global biochemistry community since 1968. Updated and revised, the Biochemical Pathways Wallcharts are an ideal companion to this text. Paired together, the book and wallcharts are perfect for researchers and students in biochemistry, biology, medicine, and physiology. The wallcharts are also a great gift for anyone interested in following the myriad chemical reactions in our cells.To obtain this pair of large, detailed wall charts, contact Roche at https://www.roche-applied-science.com/techresources/index.jsp BIOCHEMICAL PATHWAYS: An Atlas of Biochemistry and Molecular Biology Second Edition Edited by Gerhard Michal Dietmar Schomburg A JOHN WILEY & SONS, INC., PUBLICATION Copyright © 2012 John Wiley & Sons, Inc. All rights reserved. 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QP171.B685 2012 612.3'9--dc23 2011041441 Printed in the Singapore 10 9 8 7 6 5 4 3 2 1 V Contents Preface to the Second Edition IX 2.8 Polymeric Carbohydrates 31 From the Preface to the First Edition X 2.8.1 Polymeric Carbohydrates in Energy Storage 31 2.8.2 Polymeric Carbohydrates as Structural Elements 32 Contributors XI 2.9 Glycosylated Proteins and Peptides 32 2.9.1 Glycoproteins 33 1 Introduction and General Aspects 1 2.9.2 Proteoglycans 33 Gerhard Michal and Dietmar Schomburg 2.9.3 Peptidoglycans 35 1.1 Organization of This Book 1 2.10 Lipid Aggregates and Membranes 35 1.1.1 Conventions Used in This Book 3 1.1.2 Common Abbreviations 3 3 Metabolism 37 1.2 Carbohydrate Chemistry and Structure 4 1.2.1 Structure and Classification 4 3.1 Carbohydrate Metabolism and Citrate Cycle 37 1.2.2 Glycosidic Bonds 5 Röbbe Wünschiers 1.3 Amino Acid Chemistry and Structure 5 3.1.1 Glycolysis and Gluconeogenesis 37 3.1.2 Polysaccharide Metabolism 42 1.3.1 Structure and Classification 6 3.1.3 Pyruvate Turnover and Acetyl-Coenzyme A 46 1.3.2 Peptide Bonds 6 3.1.4 Di- and Oligosaccharides 48 1.4 Lipid Chemistry and Structure 6 3.1.5 Metabolism of Hexose Derivatives 48 1.4.1 Fatty acids 6 3.1.6 Pentose Metabolism 51 1.4.2 Acylglycerols and Derivatives 7 3.1.7 Amino Sugars 54 1.4.3 Waxes 7 3.1.8 Citrate Cycle 55 1.4.4 Glycerophospholipids 7 3.1.9 Glyoxylate Metabolism 57 1.4.5 Plasmalogens 7 3.2 Amino Acids and Derivatives 58 1.4.6 Sphingolipids 7 1.4.7 Steroids 8 Röbbe Wünschiers 1.4.8 Lipoproteins 8 3.2.1 Nitrogen Fixation and Metabolism 58 3.2.2 Glutamate, Glutamine, Alanine, Aspartate, Asparagine and 1.5 Physico-Chemical Aspects of Biochemical Processess 8 Ammonia Turnover 59 1.5.1 Energetics of Chemical Reactions 8 3.2.3 Proline and Hydroxyproline 62 1.5.2 Redox Reactions 9 3.2.4 Serine and Glycine 62 1.5.3 Transport Through Membranes 9 3.2.5 Lysine, Threonine, Methionine, Cysteine and 1.5.4 Enzyme Kinetics 10 Sulfur Metabolism 65 3.2.6 Leucine, Isoleucine and Valine 72 3.2.7 Phenylalanine, Tyrosine, Tryptophan and 2 The Cell and Its Contents 14 Derivatives 74 Gerhard Michal and Dietmar Schomburg 3.2.8 Histidine 79 3.2.9 Urea Cycle, Arginine and Associated 2.1 Classification of Living Organisms 14 Reactions 80 2.2 Structure of Cells 14 3.3 Tetrapyrroles 82 2.2.1 Prokaryotic Cells 14 Martina Jahn and Dieter Jahn 2.2.2 General Characteristics of Eukaryotic Cells 15 2.2.3 Special Structures of Plant Cells 17 3.3.1 Pathways for the Biosynthesis of 2.2.4 Special Structures of Animal Cells 18 Tetrapyrroles 82 3.3.2 Heme and Cytochrome Biosynthesis 86 2.3 Protein Structure and Function 18 3.3.3 Linear Tetrapyrroles 87 2.3.1 Levels of Organization 19 3.3.4 Biosynthesis of Chlorophylls 90 2.3.2 Protein Function 21 3.3.5 Biosynthesis of Cobalamins 91 3.3.6 Siroheme Biosynthesis 91 2.4 Enzymes 21 2.4.1 Catalytic Mechanism 21 3.4 Lipids and Glycolipids 93 2.4.2 Isoenzymes 23 Röbbe Wünschiers 2.4.3 Multienzyme Complexes 23 2.4.4 Reaction Rate 23 3.4.1 Fatty Acids and Acyl-CoA 93 2.4.5 Classification of Enzymes 23 3.4.2 Triacylglycerols (Triglycerides) 98 3.4.3 Phospholipids 100 2.5 Regulation of the Enzyme Activity 24 3.4.4 Glycolipids 104 2.5.1 Regulation of the Quantity of Enzymes 24 2.5.2 Regulation of the Activity of Enzymes 24 3.5 Steroids and Isoprenoids 107 2.5.3 Site of Regulation 26 Röbbe Wünschiers 2.6 Nucleic Acid Structure 26 3.5.1 Cholesterol 107 2.6.1 Components of Nucleic Acids 26 3.5.2 Hopanoids, Steroids of Plants and 2.6.2 Properties of RNA Chains 27 Insects 110 2.6.3 Properties of DNA Chains 27 3.5.3 Isoprenoids 111 2.6.4 Compaction Levels of DNA Chains 28 3.5.4 Steroid Hormones 114 3.5.5 Gestagen 115 2.7 Genetic Code and the Flow of Information 30 3.5.6 Androgens 116 2.7.1 From DNA to RNA 30 3.5.7 Estrogens 117 2.7.2 From Nucleic Acids to Proteins – The Genetic Code 30 3.5.8 Corticosteroids 119 2.7.3 Influence of Errors 31 3.5.9 Bile Acids 121 VI Contents 3.6 Nucleotides and Nucleosides 124 4.1.3 Bacterial Protein Synthesis 214 Röbbe Wünschiers 4.1.4 Degradation of Nucleic Acids 217 3.6.1 Purine Nucleotides and Nucleosides 124 4.2 Protein Biosynthesis in Eukarya 219 3.6.2 Pyrimidine Nucleotides and Nucleosides 130 Röbbe Wünschiers 3.7 Cofactors and Vitamins 133 4.2.1 Eukaryotic Transcription 219 Ida Schomburg 4.2.2 Regulation of Eukaryotic Transcription 226 4.2.3 Eukaryotic Translation 228 3.7.1 Retinol (Vitamin A) 133 4.2.4 Translational Regulation 231 3.7.2 Thiamin (Vitamin B) 134 1 4.2.5 mRNA Degradation 231 3.7.3 Riboflavin (Vitamin B), FMN and FAD 135 2 3.7.4 Pyridoxine (Vitamin B) 136 6 4.3 Cell Cycle in Eukarya 232 3.7.5 Cobalamin (Coenzyme B , Vitamin B ) 137 12 12 Stefan Ries 3.7.6 Folate and Pterines 138 3.7.7 Pantothenate, Coenzyme A and Acyl Carrier 4.3.1 Core Components of the Cell Cycle Machinery 232 Protein (ACP) 141 4.3.2 Cell Cycle Regulation in Yeast 234 3.7.8 Biotin 141 4.3.3 G to S Transition in Mammalian Cells 234 1 3.7.9 Nicotinate, NAD+ and NADP+ 143 4.3.4 G to M Transition in Mammalian Cells 235 2 3.7.10 Ascorbate (Vitamin C) 145 4.3.5 Mitosis in Mammalian Cells 235 3.7.11 Calciferol (Vitamin D) 146 4.3.6 Cell Cycle Checkpoints 236 3.7.12 Tocopherol (Vitamin E) 148 3.7.13 Phylloquinone and Menaquinone (Vitamin K) 148 4.4 Posttranslational Modification of Proteins 238 3.7.14 Other Compounds 149 Röbbe Wünschiers 4.4.1 Protein Processing in the Endoplasmic Reticulum 238 3.8 Nucleic Acid Metabolism in Bacteria 149 4.4.2 Glycosylation Reactions in the Golgi Apparatus 241 Susanne Peifer and Elmar Heinzle 4.4.3 Terminal Carbohydrate Structures of 3.8.1 Bacterial DNA Replication 149 Glycoconjugates 243 3.8.2 Bacterial DNA Repair 151 3.8.3 Degradation of Nucleic Acids 156 4.5 Protein Folding, Transport / Targeting and Degradation 244 3.9 Nucleic Acid Metabolism in Eukarya 157 Petra Dersch Helmut Burtscher 4.5.1 Folding of Proteins 244 3.9.1 Eukaryotic DNA Replication 157 4.5.2 Vesicular Transport and Secretion of Proteins 248 3.9.2 Eukaryotic DNA Repair 162 4.5.3 Protein Transport into the Nucleus 249 4.5.4 Protein Transport into Mitochondria 252 3.10 Special Bacterial Metabolism and Biosynthesis of 4.5.5 Protein Transport into Chloroplasts 254 Antimicrobials 164 4.5.6 Protein Degradation 256 Julia Garbe, Annika Steen and Max Schobert 4.5.7 Protein Degradation by the Ubiquitin-Proteasome 3.10.1 Bacterial Envelope 164 System 258 3.10.2 Bacterial Protein Export across the Cytoplasmic Membrane 166 3.10.3 Protein Transport across the Outer Membrane of Gram-Negative Bacteria 167 5 Viruses 261 3.10.4 Bacterial Transport Systems 168 Klaus Klumpp 3.10.5 Bacterial Fermentations 169 3.10.6 Anaerobic Respiration 173 5.1 General Characteristics of Viruses 261 3.10.7 Chemolithotrophy 175 5.1.1 Genomic Characteristics of Viruses 261 3.10.8 Quinoenzymes, Alkane and Methane Oxidation 178 5.1.2 Structure 263 3.10.9 Antibiotics 179 5.2 DNA Viruses 264 3.11 Electron Transfer Reactions and Oxidative 5.2.1 Papillomavirus 264 Phosphorylation 183 Martina Jahn and Dieter Jahn 5.3 RNA Viruses 267 5.3.1 Hepatitis C Virus 267 3.11.1 General Principles 183 3.11.2 Different types of electron transport chains 183 5.4 Retroviruses 268 3.11.3 The Energetic Basis of the Oxidative Phosphorylation 183 5.4.1 Human Immunodeficiency Virus (HIV) 268 3.11.4 Electron Transport System in Mitochondria and Bacteria 184 3.12 Photosynthesis 188 6 Transport 272 Dieter Oesterhelt and Josef Wachtveitl 3.12.1 Light Reaction 188 6.1 Transport Through Membranes 272 3.12.2 Dark Reactions 192 Wilhelm Just 6.1.1 Systems of Eukaryotic Membrane Passage 272 3.13 Plant Secondary Metabolism 193 6.1.2 Channels / Pores 272 Antje Chang 6.1.3 Solute Carriers 276 3.13.1 Phenolics 194 6.1.4 Primary Active Transport Systems 277 3.13.2 Terpenoids 198 6.1.5 Import by Endocytosis and Pinocytosis 278 3.13.3 Nitrogen-containing Secondary Metabolites 201 6.1.6 The Cytoskeleton as Means for Intracellular Transport and Cellular Movements in Eukarya 278 4 Protein Biosynthesis, Modifications and 6.2 Transport of Lipids in Plasma 279 Degradation 210 Horst Klima 6.2.1 Apolipoproteins (Apo) 279 4.1 Protein Synthesis in Bacteria 210 6.2.2 Plasma Lipoprotein Metabolism 279 Martina Jahn and Dieter Jahn 6.2.3 Lipid Transport Proteins 281 4.1.1 Bacterial Transcription 210 6.2.4 Lipoprotein Receptors 281 4.1.2 Regulation of Bacterial Gene Expression 212 6.2.5 Lipid Metabolic Disorders 282 Contents VII 6.3 Oxygen Transport by Hemoglobin 282 8.1.3 Development and Maturation of the Cellular Gerhard Michal Components 328 8.1.4 Antigen Receptor of B Lymphocytes, 6.3.1 Biosynthesis and Properties of Hemoglobin and Antibodies 330 Myoglobin 282 8.1.5 Complement System 334 6.3.2 Oxygen Binding to Hemo- and Myoglobin 283 8.1.6 Antigen Receptor of T Lymphocytes 336 6.3.3 Hemoglobin Diseases in Humans 285 8.1.7 Antigen Presentation by MHC Molecules 337 8.1.8 Cytokines, Chemokines and Receptors 338 7 Signal Transduction and Cellular 8.2 Generation of a Specific Immune Communication 286 Response 343 Gerhard Niederfellner 8.2.1 Activation of T Cells 343 8.2.2 CD4+ T Effector Cells, Regulation of the Immune 7.1 Intercellular Signal Transmission by Hormones 286 Response 344 7.1.1 General Characteristics of Hormones 286 8.2.3 Activation of B Cells 345 7.1.2 General Characteristics of Receptors 286 8.2.4 Lymphocyte Circulation and Generation of Cellular and 7.1.3 Insulin and Glucagon 287 Humoral Immune Responses in Lymphoid Tissue 345 7.1.4 Epinephrine and Norepinephrine (Catecholamines) 287 8.2.5 Cellular Cytotoxicity and Apoptosis 347 7.1.5 Hypothalamus-Anterior Pituitary Hormone System 287 8.2.6 Interactions between the Immune System and the 7.1.6 Placental Hormones 291 Neuroendocrine System 350 7.1.7 Hormones Regulating the Extracellular Ca++, Mg++ and 8.2.7 Immunological Tolerance 350 Phosphate Concentrations 292 8.2.8 Induction of Specific Immune Responses against 7.1.8 Hormones Regulating the Na+ Concentration and the Water Pathogens 351 Balance 292 7.1.9 Hormones of the Gastrointestinal Tract 293 8.3 Pathologic Immune responses 352 8.3.1 IgE-Mediated Hypersensitivity of the 7.2 Nerve Conduction and Synaptic Transmission 294 Immediate Type 352 7.2.1 Membrane Potential 294 8.3.2 Autoimmunity 353 7.2.2 Conduction of the Action Potential along the Axon 294 7.2.3 Transmitter Gated Signalling at the Synapse 294 8.4 Adhesion of Leukocytes 354 7.2.4 Voltage Gated Signalling at the Synapse 296 Anton Haselbeck 7.2.5 Postsynaptic Receptors 296 7.2.6 Axonal Transport 296 7.3 Principles of Intracellular Communication 296 9 Blood Coagulation and Fibrinolysis 357 Peter Müller 7.4 Receptors Coupled to Heterotrimeric G-Proteins 299 7.4.1 Mechanism of Heterotrimeric G-Protein Action 300 9.1 Hemostasis 357 7.4.2 cAMP Metabolism, Activation of Adenylate Cyclase and Protein Kinase A 302 9.2 Initial Reactions 358 7.4.3 Activation of Phospholipase C and Protein Kinase C 302 9.2.1 Reactions Initiated by the Tissue Factor 358 7.4.4 Metabolic Role of Inositol Phosphates and Ca++ 303 9.2.2 Contact Activation 358 7.4.5 Muscle Contraction 305 9.2.3 Generation of Binding Surfaces 358 7.4.6 Visual Process 307 9.3 Coagulation Propagation and Control 359 7.4.7 Olfactory and Gustatory Processes 308 7.4.8 Arachidonate Metabolism and Eicosanoids 309 9.3.1 Requirements for Protease Activity 359 9.3.2 Pathways Leading to Thrombin 359 7.5 Receptors Acting Through Tyrosine Kinases 311 9.3.3 Key Events 359 7.5.1 Regulatory Factors for Cell Growth and Function 311 9.3.4 Controlled Propagation 360 7.5.2 Components of the Signal Cascades 311 9.3.5 Generation of Fibrin 361 7.5.3 Receptor Tyrosine Kinases 312 9.4 Platelets (Thrombocytes) 362 7.5.4. Tyrosine Kinase-Associated Receptors (TKaR) 315 7.6 Programmed Cell Death (Apoptosis) 319 9.5 Fibrinolysis 364 9.5.1 Pathways of Plasminogen Activation 364 7.7 Receptors for Steroid and Thyroid Hormones, for 9.5.2 Control of Fibrinolysis 365 Retinoids and Vitamin D 321 7.8 Cyclic GMP Dependent Pathways and Effects of 10 Biochemical Networks, Bioinformatics and Systems Nitric Oxide (NO) 322 Biology 366 7.8.1 Membrane Bound Guanylate Cyclases 323 Dietmar Schomburg 7.8.2 Soluble Guanylate Cyclases and Their Activation by Nitric Oxide (NO) 323 10.1 Systems Biology and Networks 366 7.8.3 Protein Kinase G 323 10.2 Modeling of Metabolic Fluxes 366 8 Immune System 325 10.3 Biochemical Pathways Information Ernst Peter Rieber Resources 366 10.3.1 Overview 366 8.1 Components of the Immune System 325 10.3.2 Detailed Description of Some Databases 367 8.1.1 Innate, Non Adaptive Immune System 325 8.1.2 Specific, Adaptive Immune System 328 Index 374 IX Preface to the Second Edition Since the publication of the fi rst edition of ‘Biochemical Pathways’ in first edition of the ‘Biochemical Pathways’ book, which has become 1999 the molecular life sciences (encompassing biology, biochemis- the standard book of reference in his and many other labs since then. try, pharmacy and medicine) have undergone dramatic changes. With In its focus on pathways and networks it is unique and was published the extremely rapid development in the ‘OMICS’ analytical tech- exactly at a time when pathways, networks and systems became the niques (Genomics, transcriptomics, proteomics, metabolimics) we are focus of biochemical research. These areas have become the major in principle able to determine the genome of a microorganism in one fields of DS’s research work in the last decade. day and a human genome for a couple of thousand dollars. We have The fields of activities on both sides encouraged us to combine also seen the advent of ‘systems biology’, which, based on the meas- our experiences in writing and publishing the second edition of this ured OMICS-data, aims at analysis and even prediction of biologi- book. The task became larger than expected on the first glance. Since cal functions by the construction of computer models. These models the publication of the first edition our knowledge has increased simulate the reaction of biological systems, including whole cells, to tremendously. The selection of the facts to be dealt with and their con- changes in the environment, genetic disorders or mutations. densation into a short, but legible form was no easy task. We could Based on the annotation of the genome and experimental data, persuade expert authors to help us with the book. We both had a highly metabolic, regulatory and signal transduction pathways and networks enjoyable cooperation and could now finally finish this work. We are constructed and mathematically formulated. They depend entirely want to thank all authors for their contributions. In addition, Robbe on our knowledge of biochemical pathways, as they are presented in Wünschiers likes to express his gratitude to Dr. Rainer Lemke for this book. supporting the revision of the chapters. As outlined in the preface to the first edition, one of us (GM) began The book not only gained one half in volume, but every sentence early in the 1960s to combine an extract of the biochemical knowledge and every figure had to be checked and often modified. More than half in a wall chart. The other of us (DS), towards the end of his student of the many hundreds of figures in the book had to replaced, modified life saw the ‘Biochemical Pathways’ wall chart or ‘Boehringer chart’ or added in this second edition. in almost every lab working in the field of biochemistry or molecu- We hope that it will help students and researchers to obtain a deeper lar biology. (At present, it is distributed as the 4th edition by Roche understanding of the pathways and networks that determine biological Diagnostics GmbH, Mannheim). He was impressed by the puzzle functions. work biochemists had performed for almost one century. This pres- Gerhard Michal entation of important features of biochemistry was extended in the Dietmar Schomburg X From the Preface to the First Edition This book is not intended to be a textbook of biochemistry in the con- in various kingdoms of biology, etc. This form of presentation facili- ventional sense. There is no shortage of good biochemistry textbooks. tates a rapid overview. A standard set of conventions is used in all which outline how biochemical knowledge has been gained, trace illustrations (representation of formulas, symbols for proteins, the use the logical and experimental developments in this fi eld and present of colors, the shape of arrows, etc. - the rare exceptions are indicated), advances in their historical sequence. and this assists in finding the facts quickly. In contrast, this book tries to condense important aspects of current Tables have been added to provide more detailed information. They knowledge. Its goal is to give concise information on the metabolic list additional properties of the system components, homologies, etc. sequences in the pathways, the chemistry and enzymology of con- The text plays only a supportive role. It gives a concise description versions, the regulation of turnover and the effect of disorders. This of the reactions and their regulation, and puts them into the general concentration on the sequence of facts has entailed the omission of metabolic context. researchers’ names, experimental methods and the discussion of how In many cases, current knowledge focuses on a limited in number results have been obtained. For information on these aspects, and for of species. A rough classification of the occurrence of pathways is an introduction to the fundamentals of biological science, it is neces- given by the color or the reaction arrows in the illustrations, but both sary to consult textbooks. generalizations and specialization are expected to be found in the The scope of this book is general biochemistry, encompassing future, which will necessitate modification of the picture. bacteria (and to some extent archaea), plants, yeasts and animals. The literature references have been limited in number and they usu- Although a balanced representation is intended, personal interest nat- ally cite recent review articles and books, if possible, from readily urally plays a role in the selection of topics. In a number of cases, the accessible sources. They were selected to provide more detailed infor- chemistry of the reactions is given in more detail, especially at meta- mation on new developments and additional references for the inter- bolic key and branching points. Human metabolism, its regulation and ested reader. There are no references to long-established biochemical disorders as a result of disease is a frequent topic. On the other hand, facts which can be found in any textbook. I hope that this restriction some chapters are especially devoted to bacterial metabolism. will be acceptable to readers, since a complete listing of all sources This book grew out of my interest in metabolic interrelationships for the statements presented here would take up a major portion of this and regulation which was stimulated by my professional work at volume. To compensate for the omission of such general references, a Boehringer Mannheim GmbH, Germany. Previously, this interest led special chapter on electronic data banks and major printed sources has me to compile the ‘Biochemical Pathways’ wall chart, the first edi- been added at the end of the book. tion of which appeared 40 years ago. Three more editions followed, Most of all I want to thank my wife Dea, who has often encouraged which have been widely distributed. As a result of this experience, I me during the long time required to fiish this work. She has given me developed a preference for the graphic presentation of scientific facts. valuable advice and support in checking the text of the English edi- In contrast to texts, illustrations allow the simultaneous display of dif- tion. Without her understanding and her help this book would not have ferent aspects, such as structural formulas, enzyme catalysis and its been brought to completion. regulation, the involvement of cofactors, the occurrence of enzymes Gerhard Michal XI Contributors Helmut Burtscher, Roche Diagnostics GmbH, D-82372 Penzberg Gerhard Niederfellner, Roche Diagnostics GmbH, D-82372 Penzberg Antje Chang, Enzymeta GmbH, D-50374 Erftstadt Dieter Oesterheldt, Max-Planck Institute for Biochemistry, D-82152 Petra Dersch, Helmholtz Center for Infection Research, Dept. of Martinsried Molecular Infection Biology, D-38124 Braunschweig Susanne Peifer, Technical Biochemistry, Universität des Saarlandes, Julia Garbe, Institute for Microbiology, Technische Universität, D-66123 Saarbrücken D-38106 Braunschweig Ernst Peter Rieber, Institute for Immunology, Technische Universität, Anton Haselbeck, MAB Discovery GmbH, D-82061 Neuried D-01011 Dresden Elmar Heinzle, Technical Biochemistry, Universität des Saarlandes, Stefan Ries, Roche Diagnostics GmbH, D-82372 Penzberg D-66123 Saarbrücken Max Schobert, Institute for Microbiology, Technische Universität, Dieter Jahn, Institute for Microbiology, Technische Universität, D-38106 Braunschweig D-38106 Braunschweig Dietmar Schomburg, Institute of Biochemistry, Biotechnology & Martina Jahn, Institute for Microbiology, Technische Universität, Bioinformatics, Technische Universität, D-38106 Braunschweig D-38106 Braunschweig Ida Schomburg, Enzymeta GmbH, D-50374 Erftstadt Wilhelm Just, Biochemistry Center, University, D-69120 Heidelberg Annika Steen, Institute for Microbiology, Technische Universität, Horst Klima, Roche Diagnostics GmbH, D-82372 Penzberg D-38106 Braunschweig Klaus Klumpp, Hoffmann-La Roche Inc., Nutley NJ 07110 Josef Wachtveitl, Institute for Physical and Theoretical Chemistry, University, D-60438 Frankfurt/M. Gerhard Michal, Roche Diagnostics GmbH, D-82372 Penzberg, Röbbe Wünschiers, Biotechnology/Computational Biology, University formerly Boehringer Mannheim GmbH (ret.) of Applied Sciences, D-09648 Mittweida Peter Müller, Helmholtz Centre for Infection Research, Dept. Gene Regulation & Differentiation, D-38124 Braunschweig