David Wilson, PhD, was a Professor of Biochemistry, Molecular and Cell Biology at Cornell University in Ithaca (USA).Hermann Sahm, PhD, is Emeritus Professor of Biotechnology at the University of Düsseldorf (Germany).Peter Stahmann, PhD, is Professor for Technical Microbiology at the Brandenburg Technical University in Senftenberg (Germany).Mattheos Koffas, PhD, is Professor of Biology at Rensselaer Polytechnic Institute in Troy (USA).

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• Preface xvii1 Historical Overview and Future Perspective 1Bernhard Eikmanns, Marcella Eikmanns, and Christopher J. Paddon1.1 Use of Fermentation Procedures Before the Discovery of Microorganisms (Neolithic Era = New Stone Age Until 1850) 11.2 Investigation of Microorganisms and Beginning of Industrial Microbiology (1850 Until 1940) 71.3 Development of New Products and Procedures: Antibiotics and Other Biomolecules (From 1940) 111.4 Genetic Engineering is Introduced into Industrial Microbiology (From Roughly 1980) 151.5 Future Perspectives: Synthetic Microbiology 18References 20Further Reading 212 Bioprocess Engineering 23Michael R. Ladisch, Eduardo Ximenes, Nathan Mosier, Abigail S. Engelberth, Kevin Solomon, and Robert Binkley2.1 Introduction 232.1.1 Role of Bioreactors 252.1.2 Basic Bioreactor Configurations 262.1.3 Types of Growth Media 272.2 Nonstructured Models 282.2.1 Nonstructured Growth Models 282.2.1.1 Unstructured Models 292.2.1.2 Biotechnical Processes 302.2.2 Modeling Fermentations 322.2.3 Metabolic Pathways 392.2.4 Manipulation of Metabolic Pathways 402.2.5 Future of Pathway Design 422.3 Oxygen Transport 432.3.1 Aerobic versus Anaerobic Conditions 432.3.2 kL a – Volumetric Mass Transfer Coefficient 442.4 Heat Generating Aerobic Processes 462.5 Product Recovery 492.5.1 Basics 492.5.2 In Situ Product Recovery (ISPR) 492.6 Modeling and Simulation of Reactor Behavior 512.6.1 Basic Approaches and Software 512.6.2 Numerical Simulation of Bioreactor Function 512.6.3 Contamination of Bioreactors 522.7 Scale-up 53References 54Further Reading 573 Food 59Gülhan Ünlü and Barbara Nielsen3.1 Fermented Foods 593.1.1 Food Preservation 593.1.2 Flavor and Texture 603.1.3 Health Benefits 603.1.4 Economic Impact 623.2 Microorganisms and Metabolism 623.2.1 Fermentation Processes 643.2.2 Starter Cultures 653.3 Yeast Fermentations – Industrial Application of Saccharomyces Species 653.3.1 Grain Fermentation for Ethanol Production – Beer 663.3.2 Grain Fermentation for CO2 Production – Bread 693.3.2.1 Yeast Preparation 693.3.3 Fruit Fermentation –Wines and Ciders 713.4 Vinegar – Incomplete Ethanol Oxidation by Acetic Acid Bacteria Such as Gluconobacter oxydans 753.4.1 Substrates: Wine, Cider, and Malt 753.4.2 Distilled (White) Vinegar 773.4.3 Balsamic and Other Specialty Vinegars 773.5 Bacterial and Mixed Fermentations – Industrial Application of Lactic Acid Bacteria, with or without Yeast or Molds 783.5.1 Milk – Cultured Milks – Buttermilk, Yogurt, Kefir, and Cheese 783.5.1.1 Bacteriophage Contamination – Death of a Culture 813.5.2 Meats – Sausages, Fish Sauces, and Pastes 823.5.3 Vegetables – Sauerkrauts and Pickles, Olives 833.5.4 Grains and Legumes – Soy Sauce, Miso, Natto, and Tempeh 863.5.5 Cocoa and Coffee 873.6 Fungi as Food 883.6.1 Mushrooms 883.6.2 Single-Cell Protein – Fusarium venenatum 903.7 Conclusions and Outlook 91References 92Further Reading 924 Technical Alcohols and Ketones 95Peter Dürre4.1 Introduction 954.2 Ethanol Synthesis by Saccharomyces cerevisiae and Clostridium autoethanogenum 974.2.1 Application 974.2.2 Metabolic Pathways and Regulation 974.2.3 Production Strains 984.2.4 Production Processes 984.2.5 Ethanol – Fuel of the Future? 1004.2.6 Alternative Substrates for Ethanol Fermentation by Cellulolytic Bacteria and Clostridium autoethanogenum 1004.3 1,3-Propanediol Synthesis by Escherichia coli 1014.3.1 Application 1014.3.2 Metabolic Pathways and Regulation 1024.3.3 Production Strains 1024.3.4 Production Processes 1044.4 Butanol and Isobutanol Synthesis by Clostridia and Yeast 1054.4.1 History of Acetone–Butanol–Ethanol (ABE) Fermentation by Clostridium acetobutylicum and C. beijerinckii 1054.4.2 Application 1064.4.3 Metabolic Pathways and Regulation 1074.4.4 Production Strains 1104.4.5 Production Processes 1104.4.6 Product Toxicity 1134.5 Acetone Synthesis by Solventogenic Clostridia 1134.5.1 Application 1134.5.2 Metabolic Pathways and Regulation 1134.5.3 Production Strains 1144.5.4 Production Processes 1144.6 Outlook 115Further Reading 1155 Organic Acids 117Michael Sauer and Diethard Mattanovich5.1 Introduction 1175.2 Citric Acid 1195.2.1 Economic Impact and Applications 1205.2.2 Biochemistry of Citric Acid Accumulation 1205.2.3 Industrial Production by the Filamentous Fungus Aspergillus niger 1225.2.4 Yarrowia lipolytica: A Yeast as an Alternative Production Platform 1235.3 Lactic Acid 1245.3.1 Economic Impact and Applications 1245.3.2 Anaerobic Bacterial Metabolism Generating Lactic Acid 1255.3.3 Lactic Acid Production by Bacteria 1255.3.4 Lactic Acid Production by Yeasts 1265.4 Gluconic Acid 1275.4.1 Economic Impact and Applications 1275.4.2 Extracellular Biotransformation of Glucose to Gluconic Acid by Aspergillus niger 1285.4.3 Production of Gluconic Acid by Bacteria 1295.5 Succinic Acid 1295.5.1 Economic Impact and Applications 1305.5.2 Pilot Plants for Anaerobic or Aerobic Microbes 1305.6 Itaconic Acid 1325.6.1 Economic Impact and Applications 1325.6.2 Decarboxylation as a Driver in Itaconic Acid Accumulation 1325.6.3 Production Process by Aspergillus terreus 1325.6.4 Metabolic Engineering for Itaconic Acid Production 1325.7 Downstream Options for Organic Acids 1345.8 Perspectives 1355.8.1 Targeting Acrylic Acid – Microbes Can Replace Chemical Process Engineering 1365.8.2 Lignocellulose-Based Biorefineries 136Further Reading 1376 Amino Acids 139Lothar Eggeling6.1 Introduction 1396.1.1 Importance and Areas of Application 1396.1.2 Amino Acids in the Feed Industry 1406.1.3 Economic Significance 1416.2 Production of Amino Acids 1426.2.1 Conventional Development of Production Strains 1426.2.2 Advanced Development of Production Strains 1446.3 l-Glutamate Synthesis by Corynebacterium glutamicum 1456.3.1 Synthesis Pathway and Regulation 1456.3.2 Production Process 1486.4 l-Lysine 1486.4.1 Synthesis Pathway and Regulation 1486.4.2 Production Strains 1506.4.3 Production Process 1526.5 l-Threonine Synthesis by Escherichia coli 1536.5.1 Synthesis Pathway and Regulation 1536.5.2 Production Strains 1546.5.3 Production Process 1556.6 l-Phenylalanine 1556.6.1 Synthesis Pathway and Regulation 1556.6.2 Production Strains 1566.6.3 Production Process 1576.7 Outlook 158Further Reading 1597 Vitamins, Nucleotides, and Carotenoids 161Klaus-Peter Stahmann and Hans-Peter Hohmann7.1 Application and Economic Impact 1617.2 l-Ascorbic Acid (Vitamin C) 1637.2.1 Biochemical Significance, Application, and Biosynthesis 1637.2.2 Regioselective Oxidation with Bacteria in the Production Process 1647.3 Riboflavin (Vitamin B2) 1667.3.1 Significance as a Precursor for Coenzymes and as a Pigment 1667.3.2 Biosynthesis by Fungi and Bacteria 1677.3.3 Production by Ashbya gossypii 1687.3.4 Production by Bacillus subtilis 1717.3.5 Downstream Processing and Environmental Compatibility 1737.4 Cobalamin (Vitamin B12) 1747.4.1 Physiological Relevance 1747.4.2 Biosynthesis 1767.4.3 Production with Pseudomonas denitrificans 1767.5 Purine Nucleotides 1787.5.1 Impact as Flavor Enhancer 1787.5.2 Development of Production Strains 1787.5.3 Production of Inosine or Guanosine with Subsequent Phosphorylation 1797.6 β-Carotene 1807.6.1 Physiological Impact and Application 1807.6.2 Production with Blakeslea trispora 1817.7 Perspectives 181Further Reading 1838 Antibiotics and Pharmacologically Active Compounds 185Lei Fang, Guojian Zhang, and Blaine A. Pfeifer8.1 Microbial Substances Active Against Infectious Disease Agents or Affecting Human Cells 1858.1.1 Distribution and Impacts 1858.1.2 Diversity of Antibiotics Produced by Bacteria and Fungi 1898.2 β-Lactams 1908.2.1 History, Effect, and Application 1908.2.2 β-Lactam Biosynthesis 1908.2.3 Penicillin Production by Penicillium chrysogenum 1938.2.4 Cephalosporin Production by Acremonium chrysogenum 1938.3 Lipopeptides 1938.3.1 History, Effect, and Application 1938.3.2 Lipopeptide Biosynthesis 1948.3.3 Daptomycin Production by Streptomyces roseosporus 1948.3.4 Cyclosporine Production by Tolypocladium inflatum 1948.4 Macrolides 1978.4.1 History, Effect, and Application 1978.4.2 Macrolide Biosynthesis 1978.4.3 Erythromycin Production by Saccharopolyspora erythraea 1978.5 Tetracyclines 2008.5.1 History, Effect, and Application 2008.5.2 Tetracycline Biosynthesis 2008.5.3 Tetracycline Production by Streptomyces rimosus 2018.6 Aminoglycosides 2018.6.1 History, Effect, and Application 2018.6.2 Aminoglycoside Biosynthesis 2018.6.3 Tobramycin Production by Streptomyces tenebrarius 2038.7 Claviceps Alkaloids 2038.7.1 History, Effect, and Application 2038.7.2 Alkaloid Biosynthesis 2038.7.3 Ergotamine Production by Claviceps purpurea 2038.8 Perspectives 2038.8.1 Antibiotic Resistance 2038.8.2 New Research Model for Compound Identification 2068.8.3 Future Opportunities 207Further Reading 2119 Pharmaceutical Proteins 213Heinrich Decker, Susanne Dilsen, and Jan Weber9.1 History, Main Areas of Application, and Economic Importance 2139.2 Industrial Expression Systems, Cultivation and Protein Isolation, and Legal Framework 2159.2.1 Development of Production Strains 2159.2.2 Isolation of Pharmaceutical Proteins 2219.2.3 Regulatory Requirements for the Production of Pharmaceutical Proteins 2229.3 Insulins 2239.3.1 Application and Structures 2239.3.2 Manufacturing Processes by Escherichia coli and Saccharomyces cerevisiae 2259.3.2.1 Production of a Fusion Protein in E. coli 2269.3.2.2 Production of a Precursor Protein, the So-Called Mini Proinsulin with the Host Strain S. cerevisiae 2289.4 Somatropin 2309.4.1 Application 2309.4.2 Manufacturing Process 2319.5 Interferons – Application and Manufacturing 2329.6 Human Granulocyte Colony-Stimulating Factor 2349.6.1 Application 2349.6.2 Manufacturing Process 2359.7 Vaccines 2359.7.1 Application 2359.7.2 Manufacturing Procedure Using the Example of GardasilTM 2369.7.3 Manufacturing Process Based on the Example of a Hepatitis B Vaccine 2379.8 Antibody Fragments 2389.9 Enzymes 2399.10 Peptides 2409.11 View – Future Economic Importance 240Further Reading 24210 Enzymes 243David B.Wilson, Maxim Kostylev, Karl-Heinz Maurer, Marina Schramm, Wolfgang Kronemeyer, and Klaus-Peter Stahmann10.1 Fields of Application and Economic Impacts 24310.1.1 Enzymes are Biocatalysts 24310.1.2 Advantages and Limitations of Using Enzymatic Versus Chemical Methods 24410.1.3 Brief History of Enzyme Used for the Industrial Production of Valuable Products 24510.1.4 Diverse Ways That Enzymes are Used in Industry 24610.2 Enzyme Discovery and Improvement 25010.2.1 Screening for New Enzymes and Optimization of Enzymes by Protein Engineering 25010.2.2 Classical Development of Production Strains 25110.2.3 Genetic Engineering of Producer Strains 25310.3 Production Process for Bacterial or Fungal Enzymes 25510.4 Polysaccharide-Hydrolyzing Enzymes 25510.4.1 Starch-Cleaving Enzymes Produced by Bacillus and Aspergillus Species 25710.4.2 Cellulose-Cleaving Enzymes: A Domain of Trichoderma reesei 25910.4.3 Production Strains 26110.5 Enzymes Used as Cleaning Agents 26310.5.1 Subtilisin-Like Protease 26410.5.2 Bacillus sp. Production Strains and Production Process 26510.6 Feed Supplements – Phytases 26610.6.1 Fields of Applications of Phytase 26710.6.2 Phytase in the Animals Intestine 26710.6.3 Production of a Bacterial Phytase in Aspergillus niger 26910.7 Enzymes for Chemical and Pharmaceutical Industry 27110.7.1 Examples for Enzymatic Chemical Production 27110.7.2 Production of (S)-Profens by Fungal Lipase 27110.8 Enzymes as Highly Selective Tools for Research and Diagnostics 27210.8.1 Microbial Enzymes for Analysis and Engineering of Nucleic Acids 27210.8.2 Specific Enzymes for Quantitative Metabolite Assays 27510.9 Perspectives 27610.9.1 l-DOPA by Tyrosine Phenol Lyase 27610.9.2 Activation of Alkanes 27610.9.3 Enzyme Cascades 276References 277Further Reading 27711 Microbial Polysaccharides 279Volker Sieber, Jochen Schmid, and Gerd Hublik11.1 Introduction 27911.2 Heteropolysaccharides 28211.2.1 Xanthan: A Product of the Bacterium Xanthomonas campestris 28211.2.1.1 Introduction 28211.2.1.2 Regulatory Status 28211.2.1.3 Structure 28211.2.1.4 Biosynthesis 28411.2.1.5 Industrial Production of Xanthan 28611.2.1.6 Physicochemical Properties 28711.2.1.7 Applications 28911.2.2 Sphingans: Polysaccharides from Sphingomonas sp. 29111.2.3 Hyaluronic Acid: A High-Value Polysaccharide for Cosmetic Applications 29311.2.4 Alginate: Alternatives to Plant-Based Products by Pseudomonas and Azotobacter sp. 29411.2.5 Succinoglycan: Acidic Polysaccharide from Rhizobium sp. 29411.3 Homopolysaccharides 29511.3.1 α-Glucans 29611.3.1.1 Pullulan 29611.3.1.2 Dextran 29611.3.2 β-Glucans 29711.3.2.1 Linear β-glucans like cellulose and curdlan 29711.3.2.2 Branched β-Glucans Like Scleroglucan and Schizophyllan 29711.3.3 Fructosylpolymers like Levan 29811.4 Perspectives 298Further Reading 29912 Steroids 301Shuvendu Das and Sridhar Gopishetty12.1 Fields of Applications and Economic Importance 30112.2 Advantages of Biotransformations During Production of Steroids 30312.3 Development of Production Strains and Production Processes 30512.4 Applied Types of Biotransformation 30712.5 Synthesis of Steroids in Organic – Aqueous Biphasic System 31012.6 Side-chain Degradation of Phytosterols by Mycobacterium to Gain Steroid Intermediates 31112.7 Biotransformation of Cholesterol to Gain Key Steroid Intermediates 31312.8 11-Hydroxylation by Fungi During Synthesis of Corticosteroids 31312.9 Δ1-Dehydrogenation by Arthrobacter for the Production of Prednisolone 31612.10 17-Keto Reduction by Saccharomyces in Testosterone Production 31712.11 Double-Bond Isomerization of Steroids 31812.12 Perspectives 319References 320Further Reading 32113 Bioleaching 323Sören Bellenberg, Mario Vera Véliz, and Wolfgang Sand13.1 Acidophilic Microorganisms Dissolve Metals from Sulfide Ores 32313.1.1 Brief Overview on the Diversity of Acidophilic Mineral-Oxidizing Microorganisms 32513.1.2 Natural and Man-Made Habitats of Mineral-oxidizing Microorganisms 32513.1.3 Biological Catalysis of Metal Sulfide Oxidation 32813.1.4 Importance of Biofilm Formation and Extracellular Polymeric Substances for Bioleaching by Acidithiobacillus ferrooxidans and Leptospirillum ferrooxidans 33013.2 Bioleaching of Copper, Nickel, Zinc, and Cobalt 33413.2.1 Economic Impact 33413.2.2 Heap, Dump, or Stirred-tank Bioleaching of Copper, Nickel, Zinc, and Cobalt 33713.3 Gold 34213.3.1 Economic Impact 34313.3.2 Unlocking Gold by Biooxidation of the Mineral Matrix 34313.4 Uranium 34613.4.1 Economic Impact 34613.4.2 In Situ Biomining of Uranium 34613.5 Perspectives 34713.5.1 Urban Mining – Processing of Electronic Waste and Industrial Residues 34713.5.2 Microbial Iron Reduction for Dissolution of Mineral Oxides 34813.5.3 Biomining Goes Underground – In Situ Leaching as a Green Mining Technology? 348References 351Further Reading 35114 Wastewater Treatment Processes 353Claudia Gallert and Josef Winter14.1 Introduction 35414.1.1 Historical Development of Sewage Treatment 35414.1.2 Resources from Wastewater Treatment 35714.1.3 Wastewater and Storm Water Drainage 35814.1.4 Wastewater Characterization and Processes for Effective Wastewater Treatment 35814.1.5 Suspended or Immobilized Bacteria as Biocatalysts for Effective Sewage Treatment 36014.2 Biological Basics of Carbon, Nitrogen, and Phosphorus Removal from Sewage 36214.2.1 Aerobic and Anaerobic Degradation of Carbon Compounds 36214.2.1.1 Mass and Energy Balance 36614.2.2 Fundamentals of Nitrification 36814.2.3 Elimination of Nitrate by Denitrification 37114.2.4 New Nitrogen Elimination Processes 37114.2.5 Microbial Phosphate Elimination 37214.3 Wastewater Treatment Processes 37414.3.1 Typical Process Sequence in Municipal Sewage Treatment Plants 37414.3.2 Activated Sludge Process 37614.3.3 Trickling Filters 37814.3.4 Technical Options for Denitrification 37914.3.5 Biological Phosphate Elimination 38114.3.6 Sewage Sludge Treatment 38214.3.6.1 Aerobic and Anaerobic Sewage Sludge Treatment 38214.3.6.2 Sanitation and Quality Assurance of Sewage Sludge 38414.4 Advanced Wastewater Treatment 38414.4.1 Elimination of Micropollutants 38514.4.2 Wastewater Disinfection 38514.5 Future Perspectives 386References 386Further Reading 388Index 389

David Wilson, PhD, was a Professor of Biochemistry, Molecular and Cell Biology at Cornell University in Ithaca (USA).Hermann Sahm, PhD, is Emeritus Professor of Biotechnology at the University of Düsseldorf (Germany).Peter Stahmann, PhD, is Professor for Technical Microbiology at the Brandenburg Technical University in Senftenberg (Germany).Mattheos Koffas, PhD, is Professor of Biology at Rensselaer Polytechnic Institute in Troy (USA).

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• Preface xvii1 Historical Overview and Future Perspective 1Bernhard Eikmanns, Marcella Eikmanns, and Christopher J. Paddon1.1 Use of Fermentation Procedures Before the Discovery of Microorganisms (Neolithic Era = New Stone Age Until 1850) 11.2 Investigation of Microorganisms and Beginning of Industrial Microbiology (1850 Until 1940) 71.3 Development of New Products and Procedures: Antibiotics and Other Biomolecules (From 1940) 111.4 Genetic Engineering is Introduced into Industrial Microbiology (From Roughly 1980) 151.5 Future Perspectives: Synthetic Microbiology 18References 20Further Reading 212 Bioprocess Engineering 23Michael R. Ladisch, Eduardo Ximenes, Nathan Mosier, Abigail S. Engelberth, Kevin Solomon, and Robert Binkley2.1 Introduction 232.1.1 Role of Bioreactors 252.1.2 Basic Bioreactor Configurations 262.1.3 Types of Growth Media 272.2 Nonstructured Models 282.2.1 Nonstructured Growth Models 282.2.1.1 Unstructured Models 292.2.1.2 Biotechnical Processes 302.2.2 Modeling Fermentations 322.2.3 Metabolic Pathways 392.2.4 Manipulation of Metabolic Pathways 402.2.5 Future of Pathway Design 422.3 Oxygen Transport 432.3.1 Aerobic versus Anaerobic Conditions 432.3.2 kL a – Volumetric Mass Transfer Coefficient 442.4 Heat Generating Aerobic Processes 462.5 Product Recovery 492.5.1 Basics 492.5.2 In Situ Product Recovery (ISPR) 492.6 Modeling and Simulation of Reactor Behavior 512.6.1 Basic Approaches and Software 512.6.2 Numerical Simulation of Bioreactor Function 512.6.3 Contamination of Bioreactors 522.7 Scale-up 53References 54Further Reading 573 Food 59Gülhan Ünlü and Barbara Nielsen3.1 Fermented Foods 593.1.1 Food Preservation 593.1.2 Flavor and Texture 603.1.3 Health Benefits 603.1.4 Economic Impact 623.2 Microorganisms and Metabolism 623.2.1 Fermentation Processes 643.2.2 Starter Cultures 653.3 Yeast Fermentations – Industrial Application of Saccharomyces Species 653.3.1 Grain Fermentation for Ethanol Production – Beer 663.3.2 Grain Fermentation for CO2 Production – Bread 693.3.2.1 Yeast Preparation 693.3.3 Fruit Fermentation –Wines and Ciders 713.4 Vinegar – Incomplete Ethanol Oxidation by Acetic Acid Bacteria Such as Gluconobacter oxydans 753.4.1 Substrates: Wine, Cider, and Malt 753.4.2 Distilled (White) Vinegar 773.4.3 Balsamic and Other Specialty Vinegars 773.5 Bacterial and Mixed Fermentations – Industrial Application of Lactic Acid Bacteria, with or without Yeast or Molds 783.5.1 Milk – Cultured Milks – Buttermilk, Yogurt, Kefir, and Cheese 783.5.1.1 Bacteriophage Contamination – Death of a Culture 813.5.2 Meats – Sausages, Fish Sauces, and Pastes 823.5.3 Vegetables – Sauerkrauts and Pickles, Olives 833.5.4 Grains and Legumes – Soy Sauce, Miso, Natto, and Tempeh 863.5.5 Cocoa and Coffee 873.6 Fungi as Food 883.6.1 Mushrooms 883.6.2 Single-Cell Protein – Fusarium venenatum 903.7 Conclusions and Outlook 91References 92Further Reading 924 Technical Alcohols and Ketones 95Peter Dürre4.1 Introduction 954.2 Ethanol Synthesis by Saccharomyces cerevisiae and Clostridium autoethanogenum 974.2.1 Application 974.2.2 Metabolic Pathways and Regulation 974.2.3 Production Strains 984.2.4 Production Processes 984.2.5 Ethanol – Fuel of the Future? 1004.2.6 Alternative Substrates for Ethanol Fermentation by Cellulolytic Bacteria and Clostridium autoethanogenum 1004.3 1,3-Propanediol Synthesis by Escherichia coli 1014.3.1 Application 1014.3.2 Metabolic Pathways and Regulation 1024.3.3 Production Strains 1024.3.4 Production Processes 1044.4 Butanol and Isobutanol Synthesis by Clostridia and Yeast 1054.4.1 History of Acetone–Butanol–Ethanol (ABE) Fermentation by Clostridium acetobutylicum and C. beijerinckii 1054.4.2 Application 1064.4.3 Metabolic Pathways and Regulation 1074.4.4 Production Strains 1104.4.5 Production Processes 1104.4.6 Product Toxicity 1134.5 Acetone Synthesis by Solventogenic Clostridia 1134.5.1 Application 1134.5.2 Metabolic Pathways and Regulation 1134.5.3 Production Strains 1144.5.4 Production Processes 1144.6 Outlook 115Further Reading 1155 Organic Acids 117Michael Sauer and Diethard Mattanovich5.1 Introduction 1175.2 Citric Acid 1195.2.1 Economic Impact and Applications 1205.2.2 Biochemistry of Citric Acid Accumulation 1205.2.3 Industrial Production by the Filamentous Fungus Aspergillus niger 1225.2.4 Yarrowia lipolytica: A Yeast as an Alternative Production Platform 1235.3 Lactic Acid 1245.3.1 Economic Impact and Applications 1245.3.2 Anaerobic Bacterial Metabolism Generating Lactic Acid 1255.3.3 Lactic Acid Production by Bacteria 1255.3.4 Lactic Acid Production by Yeasts 1265.4 Gluconic Acid 1275.4.1 Economic Impact and Applications 1275.4.2 Extracellular Biotransformation of Glucose to Gluconic Acid by Aspergillus niger 1285.4.3 Production of Gluconic Acid by Bacteria 1295.5 Succinic Acid 1295.5.1 Economic Impact and Applications 1305.5.2 Pilot Plants for Anaerobic or Aerobic Microbes 1305.6 Itaconic Acid 1325.6.1 Economic Impact and Applications 1325.6.2 Decarboxylation as a Driver in Itaconic Acid Accumulation 1325.6.3 Production Process by Aspergillus terreus 1325.6.4 Metabolic Engineering for Itaconic Acid Production 1325.7 Downstream Options for Organic Acids 1345.8 Perspectives 1355.8.1 Targeting Acrylic Acid – Microbes Can Replace Chemical Process Engineering 1365.8.2 Lignocellulose-Based Biorefineries 136Further Reading 1376 Amino Acids 139Lothar Eggeling6.1 Introduction 1396.1.1 Importance and Areas of Application 1396.1.2 Amino Acids in the Feed Industry 1406.1.3 Economic Significance 1416.2 Production of Amino Acids 1426.2.1 Conventional Development of Production Strains 1426.2.2 Advanced Development of Production Strains 1446.3 l-Glutamate Synthesis by Corynebacterium glutamicum 1456.3.1 Synthesis Pathway and Regulation 1456.3.2 Production Process 1486.4 l-Lysine 1486.4.1 Synthesis Pathway and Regulation 1486.4.2 Production Strains 1506.4.3 Production Process 1526.5 l-Threonine Synthesis by Escherichia coli 1536.5.1 Synthesis Pathway and Regulation 1536.5.2 Production Strains 1546.5.3 Production Process 1556.6 l-Phenylalanine 1556.6.1 Synthesis Pathway and Regulation 1556.6.2 Production Strains 1566.6.3 Production Process 1576.7 Outlook 158Further Reading 1597 Vitamins, Nucleotides, and Carotenoids 161Klaus-Peter Stahmann and Hans-Peter Hohmann7.1 Application and Economic Impact 1617.2 l-Ascorbic Acid (Vitamin C) 1637.2.1 Biochemical Significance, Application, and Biosynthesis 1637.2.2 Regioselective Oxidation with Bacteria in the Production Process 1647.3 Riboflavin (Vitamin B2) 1667.3.1 Significance as a Precursor for Coenzymes and as a Pigment 1667.3.2 Biosynthesis by Fungi and Bacteria 1677.3.3 Production by Ashbya gossypii 1687.3.4 Production by Bacillus subtilis 1717.3.5 Downstream Processing and Environmental Compatibility 1737.4 Cobalamin (Vitamin B12) 1747.4.1 Physiological Relevance 1747.4.2 Biosynthesis 1767.4.3 Production with Pseudomonas denitrificans 1767.5 Purine Nucleotides 1787.5.1 Impact as Flavor Enhancer 1787.5.2 Development of Production Strains 1787.5.3 Production of Inosine or Guanosine with Subsequent Phosphorylation 1797.6 β-Carotene 1807.6.1 Physiological Impact and Application 1807.6.2 Production with Blakeslea trispora 1817.7 Perspectives 181Further Reading 1838 Antibiotics and Pharmacologically Active Compounds 185Lei Fang, Guojian Zhang, and Blaine A. Pfeifer8.1 Microbial Substances Active Against Infectious Disease Agents or Affecting Human Cells 1858.1.1 Distribution and Impacts 1858.1.2 Diversity of Antibiotics Produced by Bacteria and Fungi 1898.2 β-Lactams 1908.2.1 History, Effect, and Application 1908.2.2 β-Lactam Biosynthesis 1908.2.3 Penicillin Production by Penicillium chrysogenum 1938.2.4 Cephalosporin Production by Acremonium chrysogenum 1938.3 Lipopeptides 1938.3.1 History, Effect, and Application 1938.3.2 Lipopeptide Biosynthesis 1948.3.3 Daptomycin Production by Streptomyces roseosporus 1948.3.4 Cyclosporine Production by Tolypocladium inflatum 1948.4 Macrolides 1978.4.1 History, Effect, and Application 1978.4.2 Macrolide Biosynthesis 1978.4.3 Erythromycin Production by Saccharopolyspora erythraea 1978.5 Tetracyclines 2008.5.1 History, Effect, and Application 2008.5.2 Tetracycline Biosynthesis 2008.5.3 Tetracycline Production by Streptomyces rimosus 2018.6 Aminoglycosides 2018.6.1 History, Effect, and Application 2018.6.2 Aminoglycoside Biosynthesis 2018.6.3 Tobramycin Production by Streptomyces tenebrarius 2038.7 Claviceps Alkaloids 2038.7.1 History, Effect, and Application 2038.7.2 Alkaloid Biosynthesis 2038.7.3 Ergotamine Production by Claviceps purpurea 2038.8 Perspectives 2038.8.1 Antibiotic Resistance 2038.8.2 New Research Model for Compound Identification 2068.8.3 Future Opportunities 207Further Reading 2119 Pharmaceutical Proteins 213Heinrich Decker, Susanne Dilsen, and Jan Weber9.1 History, Main Areas of Application, and Economic Importance 2139.2 Industrial Expression Systems, Cultivation and Protein Isolation, and Legal Framework 2159.2.1 Development of Production Strains 2159.2.2 Isolation of Pharmaceutical Proteins 2219.2.3 Regulatory Requirements for the Production of Pharmaceutical Proteins 2229.3 Insulins 2239.3.1 Application and Structures 2239.3.2 Manufacturing Processes by Escherichia coli and Saccharomyces cerevisiae 2259.3.2.1 Production of a Fusion Protein in E. coli 2269.3.2.2 Production of a Precursor Protein, the So-Called Mini Proinsulin with the Host Strain S. cerevisiae 2289.4 Somatropin 2309.4.1 Application 2309.4.2 Manufacturing Process 2319.5 Interferons – Application and Manufacturing 2329.6 Human Granulocyte Colony-Stimulating Factor 2349.6.1 Application 2349.6.2 Manufacturing Process 2359.7 Vaccines 2359.7.1 Application 2359.7.2 Manufacturing Procedure Using the Example of GardasilTM 2369.7.3 Manufacturing Process Based on the Example of a Hepatitis B Vaccine 2379.8 Antibody Fragments 2389.9 Enzymes 2399.10 Peptides 2409.11 View – Future Economic Importance 240Further Reading 24210 Enzymes 243David B.Wilson, Maxim Kostylev, Karl-Heinz Maurer, Marina Schramm, Wolfgang Kronemeyer, and Klaus-Peter Stahmann10.1 Fields of Application and Economic Impacts 24310.1.1 Enzymes are Biocatalysts 24310.1.2 Advantages and Limitations of Using Enzymatic Versus Chemical Methods 24410.1.3 Brief History of Enzyme Used for the Industrial Production of Valuable Products 24510.1.4 Diverse Ways That Enzymes are Used in Industry 24610.2 Enzyme Discovery and Improvement 25010.2.1 Screening for New Enzymes and Optimization of Enzymes by Protein Engineering 25010.2.2 Classical Development of Production Strains 25110.2.3 Genetic Engineering of Producer Strains 25310.3 Production Process for Bacterial or Fungal Enzymes 25510.4 Polysaccharide-Hydrolyzing Enzymes 25510.4.1 Starch-Cleaving Enzymes Produced by Bacillus and Aspergillus Species 25710.4.2 Cellulose-Cleaving Enzymes: A Domain of Trichoderma reesei 25910.4.3 Production Strains 26110.5 Enzymes Used as Cleaning Agents 26310.5.1 Subtilisin-Like Protease 26410.5.2 Bacillus sp. Production Strains and Production Process 26510.6 Feed Supplements – Phytases 26610.6.1 Fields of Applications of Phytase 26710.6.2 Phytase in the Animals Intestine 26710.6.3 Production of a Bacterial Phytase in Aspergillus niger 26910.7 Enzymes for Chemical and Pharmaceutical Industry 27110.7.1 Examples for Enzymatic Chemical Production 27110.7.2 Production of (S)-Profens by Fungal Lipase 27110.8 Enzymes as Highly Selective Tools for Research and Diagnostics 27210.8.1 Microbial Enzymes for Analysis and Engineering of Nucleic Acids 27210.8.2 Specific Enzymes for Quantitative Metabolite Assays 27510.9 Perspectives 27610.9.1 l-DOPA by Tyrosine Phenol Lyase 27610.9.2 Activation of Alkanes 27610.9.3 Enzyme Cascades 276References 277Further Reading 27711 Microbial Polysaccharides 279Volker Sieber, Jochen Schmid, and Gerd Hublik11.1 Introduction 27911.2 Heteropolysaccharides 28211.2.1 Xanthan: A Product of the Bacterium Xanthomonas campestris 28211.2.1.1 Introduction 28211.2.1.2 Regulatory Status 28211.2.1.3 Structure 28211.2.1.4 Biosynthesis 28411.2.1.5 Industrial Production of Xanthan 28611.2.1.6 Physicochemical Properties 28711.2.1.7 Applications 28911.2.2 Sphingans: Polysaccharides from Sphingomonas sp. 29111.2.3 Hyaluronic Acid: A High-Value Polysaccharide for Cosmetic Applications 29311.2.4 Alginate: Alternatives to Plant-Based Products by Pseudomonas and Azotobacter sp. 29411.2.5 Succinoglycan: Acidic Polysaccharide from Rhizobium sp. 29411.3 Homopolysaccharides 29511.3.1 α-Glucans 29611.3.1.1 Pullulan 29611.3.1.2 Dextran 29611.3.2 β-Glucans 29711.3.2.1 Linear β-glucans like cellulose and curdlan 29711.3.2.2 Branched β-Glucans Like Scleroglucan and Schizophyllan 29711.3.3 Fructosylpolymers like Levan 29811.4 Perspectives 298Further Reading 29912 Steroids 301Shuvendu Das and Sridhar Gopishetty12.1 Fields of Applications and Economic Importance 30112.2 Advantages of Biotransformations During Production of Steroids 30312.3 Development of Production Strains and Production Processes 30512.4 Applied Types of Biotransformation 30712.5 Synthesis of Steroids in Organic – Aqueous Biphasic System 31012.6 Side-chain Degradation of Phytosterols by Mycobacterium to Gain Steroid Intermediates 31112.7 Biotransformation of Cholesterol to Gain Key Steroid Intermediates 31312.8 11-Hydroxylation by Fungi During Synthesis of Corticosteroids 31312.9 Δ1-Dehydrogenation by Arthrobacter for the Production of Prednisolone 31612.10 17-Keto Reduction by Saccharomyces in Testosterone Production 31712.11 Double-Bond Isomerization of Steroids 31812.12 Perspectives 319References 320Further Reading 32113 Bioleaching 323Sören Bellenberg, Mario Vera Véliz, and Wolfgang Sand13.1 Acidophilic Microorganisms Dissolve Metals from Sulfide Ores 32313.1.1 Brief Overview on the Diversity of Acidophilic Mineral-Oxidizing Microorganisms 32513.1.2 Natural and Man-Made Habitats of Mineral-oxidizing Microorganisms 32513.1.3 Biological Catalysis of Metal Sulfide Oxidation 32813.1.4 Importance of Biofilm Formation and Extracellular Polymeric Substances for Bioleaching by Acidithiobacillus ferrooxidans and Leptospirillum ferrooxidans 33013.2 Bioleaching of Copper, Nickel, Zinc, and Cobalt 33413.2.1 Economic Impact 33413.2.2 Heap, Dump, or Stirred-tank Bioleaching of Copper, Nickel, Zinc, and Cobalt 33713.3 Gold 34213.3.1 Economic Impact 34313.3.2 Unlocking Gold by Biooxidation of the Mineral Matrix 34313.4 Uranium 34613.4.1 Economic Impact 34613.4.2 In Situ Biomining of Uranium 34613.5 Perspectives 34713.5.1 Urban Mining – Processing of Electronic Waste and Industrial Residues 34713.5.2 Microbial Iron Reduction for Dissolution of Mineral Oxides 34813.5.3 Biomining Goes Underground – In Situ Leaching as a Green Mining Technology? 348References 351Further Reading 35114 Wastewater Treatment Processes 353Claudia Gallert and Josef Winter14.1 Introduction 35414.1.1 Historical Development of Sewage Treatment 35414.1.2 Resources from Wastewater Treatment 35714.1.3 Wastewater and Storm Water Drainage 35814.1.4 Wastewater Characterization and Processes for Effective Wastewater Treatment 35814.1.5 Suspended or Immobilized Bacteria as Biocatalysts for Effective Sewage Treatment 36014.2 Biological Basics of Carbon, Nitrogen, and Phosphorus Removal from Sewage 36214.2.1 Aerobic and Anaerobic Degradation of Carbon Compounds 36214.2.1.1 Mass and Energy Balance 36614.2.2 Fundamentals of Nitrification 36814.2.3 Elimination of Nitrate by Denitrification 37114.2.4 New Nitrogen Elimination Processes 37114.2.5 Microbial Phosphate Elimination 37214.3 Wastewater Treatment Processes 37414.3.1 Typical Process Sequence in Municipal Sewage Treatment Plants 37414.3.2 Activated Sludge Process 37614.3.3 Trickling Filters 37814.3.4 Technical Options for Denitrification 37914.3.5 Biological Phosphate Elimination 38114.3.6 Sewage Sludge Treatment 38214.3.6.1 Aerobic and Anaerobic Sewage Sludge Treatment 38214.3.6.2 Sanitation and Quality Assurance of Sewage Sludge 38414.4 Advanced Wastewater Treatment 38414.4.1 Elimination of Micropollutants 38514.4.2 Wastewater Disinfection 38514.5 Future Perspectives 386References 386Further Reading 388Index 389

David Wilson, PhD, was a Professor of Biochemistry, Molecular and Cell Biology at Cornell University in Ithaca (USA).Hermann Sahm, PhD, is Emeritus Professor of Biotechnology at the University of Düsseldorf (Germany).Peter Stahmann, PhD, is Professor for Technical Microbiology at the Brandenburg Technical University in Senftenberg (Germany).Mattheos Koffas, PhD, is Professor of Biology at Rensselaer Polytechnic Institute in Troy (USA).

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• Preface xvii1 Historical Overview and Future Perspective 1Bernhard Eikmanns, Marcella Eikmanns, and Christopher J. Paddon1.1 Use of Fermentation Procedures Before the Discovery of Microorganisms (Neolithic Era = New Stone Age Until 1850) 11.2 Investigation of Microorganisms and Beginning of Industrial Microbiology (1850 Until 1940) 71.3 Development of New Products and Procedures: Antibiotics and Other Biomolecules (From 1940) 111.4 Genetic Engineering is Introduced into Industrial Microbiology (From Roughly 1980) 151.5 Future Perspectives: Synthetic Microbiology 18References 20Further Reading 212 Bioprocess Engineering 23Michael R. Ladisch, Eduardo Ximenes, Nathan Mosier, Abigail S. Engelberth, Kevin Solomon, and Robert Binkley2.1 Introduction 232.1.1 Role of Bioreactors 252.1.2 Basic Bioreactor Configurations 262.1.3 Types of Growth Media 272.2 Nonstructured Models 282.2.1 Nonstructured Growth Models 282.2.1.1 Unstructured Models 292.2.1.2 Biotechnical Processes 302.2.2 Modeling Fermentations 322.2.3 Metabolic Pathways 392.2.4 Manipulation of Metabolic Pathways 402.2.5 Future of Pathway Design 422.3 Oxygen Transport 432.3.1 Aerobic versus Anaerobic Conditions 432.3.2 kL a – Volumetric Mass Transfer Coefficient 442.4 Heat Generating Aerobic Processes 462.5 Product Recovery 492.5.1 Basics 492.5.2 In Situ Product Recovery (ISPR) 492.6 Modeling and Simulation of Reactor Behavior 512.6.1 Basic Approaches and Software 512.6.2 Numerical Simulation of Bioreactor Function 512.6.3 Contamination of Bioreactors 522.7 Scale-up 53References 54Further Reading 573 Food 59Gülhan Ünlü and Barbara Nielsen3.1 Fermented Foods 593.1.1 Food Preservation 593.1.2 Flavor and Texture 603.1.3 Health Benefits 603.1.4 Economic Impact 623.2 Microorganisms and Metabolism 623.2.1 Fermentation Processes 643.2.2 Starter Cultures 653.3 Yeast Fermentations – Industrial Application of Saccharomyces Species 653.3.1 Grain Fermentation for Ethanol Production – Beer 663.3.2 Grain Fermentation for CO2 Production – Bread 693.3.2.1 Yeast Preparation 693.3.3 Fruit Fermentation –Wines and Ciders 713.4 Vinegar – Incomplete Ethanol Oxidation by Acetic Acid Bacteria Such as Gluconobacter oxydans 753.4.1 Substrates: Wine, Cider, and Malt 753.4.2 Distilled (White) Vinegar 773.4.3 Balsamic and Other Specialty Vinegars 773.5 Bacterial and Mixed Fermentations – Industrial Application of Lactic Acid Bacteria, with or without Yeast or Molds 783.5.1 Milk – Cultured Milks – Buttermilk, Yogurt, Kefir, and Cheese 783.5.1.1 Bacteriophage Contamination – Death of a Culture 813.5.2 Meats – Sausages, Fish Sauces, and Pastes 823.5.3 Vegetables – Sauerkrauts and Pickles, Olives 833.5.4 Grains and Legumes – Soy Sauce, Miso, Natto, and Tempeh 863.5.5 Cocoa and Coffee 873.6 Fungi as Food 883.6.1 Mushrooms 883.6.2 Single-Cell Protein – Fusarium venenatum 903.7 Conclusions and Outlook 91References 92Further Reading 924 Technical Alcohols and Ketones 95Peter Dürre4.1 Introduction 954.2 Ethanol Synthesis by Saccharomyces cerevisiae and Clostridium autoethanogenum 974.2.1 Application 974.2.2 Metabolic Pathways and Regulation 974.2.3 Production Strains 984.2.4 Production Processes 984.2.5 Ethanol – Fuel of the Future? 1004.2.6 Alternative Substrates for Ethanol Fermentation by Cellulolytic Bacteria and Clostridium autoethanogenum 1004.3 1,3-Propanediol Synthesis by Escherichia coli 1014.3.1 Application 1014.3.2 Metabolic Pathways and Regulation 1024.3.3 Production Strains 1024.3.4 Production Processes 1044.4 Butanol and Isobutanol Synthesis by Clostridia and Yeast 1054.4.1 History of Acetone–Butanol–Ethanol (ABE) Fermentation by Clostridium acetobutylicum and C. beijerinckii 1054.4.2 Application 1064.4.3 Metabolic Pathways and Regulation 1074.4.4 Production Strains 1104.4.5 Production Processes 1104.4.6 Product Toxicity 1134.5 Acetone Synthesis by Solventogenic Clostridia 1134.5.1 Application 1134.5.2 Metabolic Pathways and Regulation 1134.5.3 Production Strains 1144.5.4 Production Processes 1144.6 Outlook 115Further Reading 1155 Organic Acids 117Michael Sauer and Diethard Mattanovich5.1 Introduction 1175.2 Citric Acid 1195.2.1 Economic Impact and Applications 1205.2.2 Biochemistry of Citric Acid Accumulation 1205.2.3 Industrial Production by the Filamentous Fungus Aspergillus niger 1225.2.4 Yarrowia lipolytica: A Yeast as an Alternative Production Platform 1235.3 Lactic Acid 1245.3.1 Economic Impact and Applications 1245.3.2 Anaerobic Bacterial Metabolism Generating Lactic Acid 1255.3.3 Lactic Acid Production by Bacteria 1255.3.4 Lactic Acid Production by Yeasts 1265.4 Gluconic Acid 1275.4.1 Economic Impact and Applications 1275.4.2 Extracellular Biotransformation of Glucose to Gluconic Acid by Aspergillus niger 1285.4.3 Production of Gluconic Acid by Bacteria 1295.5 Succinic Acid 1295.5.1 Economic Impact and Applications 1305.5.2 Pilot Plants for Anaerobic or Aerobic Microbes 1305.6 Itaconic Acid 1325.6.1 Economic Impact and Applications 1325.6.2 Decarboxylation as a Driver in Itaconic Acid Accumulation 1325.6.3 Production Process by Aspergillus terreus 1325.6.4 Metabolic Engineering for Itaconic Acid Production 1325.7 Downstream Options for Organic Acids 1345.8 Perspectives 1355.8.1 Targeting Acrylic Acid – Microbes Can Replace Chemical Process Engineering 1365.8.2 Lignocellulose-Based Biorefineries 136Further Reading 1376 Amino Acids 139Lothar Eggeling6.1 Introduction 1396.1.1 Importance and Areas of Application 1396.1.2 Amino Acids in the Feed Industry 1406.1.3 Economic Significance 1416.2 Production of Amino Acids 1426.2.1 Conventional Development of Production Strains 1426.2.2 Advanced Development of Production Strains 1446.3 l-Glutamate Synthesis by Corynebacterium glutamicum 1456.3.1 Synthesis Pathway and Regulation 1456.3.2 Production Process 1486.4 l-Lysine 1486.4.1 Synthesis Pathway and Regulation 1486.4.2 Production Strains 1506.4.3 Production Process 1526.5 l-Threonine Synthesis by Escherichia coli 1536.5.1 Synthesis Pathway and Regulation 1536.5.2 Production Strains 1546.5.3 Production Process 1556.6 l-Phenylalanine 1556.6.1 Synthesis Pathway and Regulation 1556.6.2 Production Strains 1566.6.3 Production Process 1576.7 Outlook 158Further Reading 1597 Vitamins, Nucleotides, and Carotenoids 161Klaus-Peter Stahmann and Hans-Peter Hohmann7.1 Application and Economic Impact 1617.2 l-Ascorbic Acid (Vitamin C) 1637.2.1 Biochemical Significance, Application, and Biosynthesis 1637.2.2 Regioselective Oxidation with Bacteria in the Production Process 1647.3 Riboflavin (Vitamin B2) 1667.3.1 Significance as a Precursor for Coenzymes and as a Pigment 1667.3.2 Biosynthesis by Fungi and Bacteria 1677.3.3 Production by Ashbya gossypii 1687.3.4 Production by Bacillus subtilis 1717.3.5 Downstream Processing and Environmental Compatibility 1737.4 Cobalamin (Vitamin B12) 1747.4.1 Physiological Relevance 1747.4.2 Biosynthesis 1767.4.3 Production with Pseudomonas denitrificans 1767.5 Purine Nucleotides 1787.5.1 Impact as Flavor Enhancer 1787.5.2 Development of Production Strains 1787.5.3 Production of Inosine or Guanosine with Subsequent Phosphorylation 1797.6 β-Carotene 1807.6.1 Physiological Impact and Application 1807.6.2 Production with Blakeslea trispora 1817.7 Perspectives 181Further Reading 1838 Antibiotics and Pharmacologically Active Compounds 185Lei Fang, Guojian Zhang, and Blaine A. Pfeifer8.1 Microbial Substances Active Against Infectious Disease Agents or Affecting Human Cells 1858.1.1 Distribution and Impacts 1858.1.2 Diversity of Antibiotics Produced by Bacteria and Fungi 1898.2 β-Lactams 1908.2.1 History, Effect, and Application 1908.2.2 β-Lactam Biosynthesis 1908.2.3 Penicillin Production by Penicillium chrysogenum 1938.2.4 Cephalosporin Production by Acremonium chrysogenum 1938.3 Lipopeptides 1938.3.1 History, Effect, and Application 1938.3.2 Lipopeptide Biosynthesis 1948.3.3 Daptomycin Production by Streptomyces roseosporus 1948.3.4 Cyclosporine Production by Tolypocladium inflatum 1948.4 Macrolides 1978.4.1 History, Effect, and Application 1978.4.2 Macrolide Biosynthesis 1978.4.3 Erythromycin Production by Saccharopolyspora erythraea 1978.5 Tetracyclines 2008.5.1 History, Effect, and Application 2008.5.2 Tetracycline Biosynthesis 2008.5.3 Tetracycline Production by Streptomyces rimosus 2018.6 Aminoglycosides 2018.6.1 History, Effect, and Application 2018.6.2 Aminoglycoside Biosynthesis 2018.6.3 Tobramycin Production by Streptomyces tenebrarius 2038.7 Claviceps Alkaloids 2038.7.1 History, Effect, and Application 2038.7.2 Alkaloid Biosynthesis 2038.7.3 Ergotamine Production by Claviceps purpurea 2038.8 Perspectives 2038.8.1 Antibiotic Resistance 2038.8.2 New Research Model for Compound Identification 2068.8.3 Future Opportunities 207Further Reading 2119 Pharmaceutical Proteins 213Heinrich Decker, Susanne Dilsen, and Jan Weber9.1 History, Main Areas of Application, and Economic Importance 2139.2 Industrial Expression Systems, Cultivation and Protein Isolation, and Legal Framework 2159.2.1 Development of Production Strains 2159.2.2 Isolation of Pharmaceutical Proteins 2219.2.3 Regulatory Requirements for the Production of Pharmaceutical Proteins 2229.3 Insulins 2239.3.1 Application and Structures 2239.3.2 Manufacturing Processes by Escherichia coli and Saccharomyces cerevisiae 2259.3.2.1 Production of a Fusion Protein in E. coli 2269.3.2.2 Production of a Precursor Protein, the So-Called Mini Proinsulin with the Host Strain S. cerevisiae 2289.4 Somatropin 2309.4.1 Application 2309.4.2 Manufacturing Process 2319.5 Interferons – Application and Manufacturing 2329.6 Human Granulocyte Colony-Stimulating Factor 2349.6.1 Application 2349.6.2 Manufacturing Process 2359.7 Vaccines 2359.7.1 Application 2359.7.2 Manufacturing Procedure Using the Example of GardasilTM 2369.7.3 Manufacturing Process Based on the Example of a Hepatitis B Vaccine 2379.8 Antibody Fragments 2389.9 Enzymes 2399.10 Peptides 2409.11 View – Future Economic Importance 240Further Reading 24210 Enzymes 243David B.Wilson, Maxim Kostylev, Karl-Heinz Maurer, Marina Schramm, Wolfgang Kronemeyer, and Klaus-Peter Stahmann10.1 Fields of Application and Economic Impacts 24310.1.1 Enzymes are Biocatalysts 24310.1.2 Advantages and Limitations of Using Enzymatic Versus Chemical Methods 24410.1.3 Brief History of Enzyme Used for the Industrial Production of Valuable Products 24510.1.4 Diverse Ways That Enzymes are Used in Industry 24610.2 Enzyme Discovery and Improvement 25010.2.1 Screening for New Enzymes and Optimization of Enzymes by Protein Engineering 25010.2.2 Classical Development of Production Strains 25110.2.3 Genetic Engineering of Producer Strains 25310.3 Production Process for Bacterial or Fungal Enzymes 25510.4 Polysaccharide-Hydrolyzing Enzymes 25510.4.1 Starch-Cleaving Enzymes Produced by Bacillus and Aspergillus Species 25710.4.2 Cellulose-Cleaving Enzymes: A Domain of Trichoderma reesei 25910.4.3 Production Strains 26110.5 Enzymes Used as Cleaning Agents 26310.5.1 Subtilisin-Like Protease 26410.5.2 Bacillus sp. Production Strains and Production Process 26510.6 Feed Supplements – Phytases 26610.6.1 Fields of Applications of Phytase 26710.6.2 Phytase in the Animals Intestine 26710.6.3 Production of a Bacterial Phytase in Aspergillus niger 26910.7 Enzymes for Chemical and Pharmaceutical Industry 27110.7.1 Examples for Enzymatic Chemical Production 27110.7.2 Production of (S)-Profens by Fungal Lipase 27110.8 Enzymes as Highly Selective Tools for Research and Diagnostics 27210.8.1 Microbial Enzymes for Analysis and Engineering of Nucleic Acids 27210.8.2 Specific Enzymes for Quantitative Metabolite Assays 27510.9 Perspectives 27610.9.1 l-DOPA by Tyrosine Phenol Lyase 27610.9.2 Activation of Alkanes 27610.9.3 Enzyme Cascades 276References 277Further Reading 27711 Microbial Polysaccharides 279Volker Sieber, Jochen Schmid, and Gerd Hublik11.1 Introduction 27911.2 Heteropolysaccharides 28211.2.1 Xanthan: A Product of the Bacterium Xanthomonas campestris 28211.2.1.1 Introduction 28211.2.1.2 Regulatory Status 28211.2.1.3 Structure 28211.2.1.4 Biosynthesis 28411.2.1.5 Industrial Production of Xanthan 28611.2.1.6 Physicochemical Properties 28711.2.1.7 Applications 28911.2.2 Sphingans: Polysaccharides from Sphingomonas sp. 29111.2.3 Hyaluronic Acid: A High-Value Polysaccharide for Cosmetic Applications 29311.2.4 Alginate: Alternatives to Plant-Based Products by Pseudomonas and Azotobacter sp. 29411.2.5 Succinoglycan: Acidic Polysaccharide from Rhizobium sp. 29411.3 Homopolysaccharides 29511.3.1 α-Glucans 29611.3.1.1 Pullulan 29611.3.1.2 Dextran 29611.3.2 β-Glucans 29711.3.2.1 Linear β-glucans like cellulose and curdlan 29711.3.2.2 Branched β-Glucans Like Scleroglucan and Schizophyllan 29711.3.3 Fructosylpolymers like Levan 29811.4 Perspectives 298Further Reading 29912 Steroids 301Shuvendu Das and Sridhar Gopishetty12.1 Fields of Applications and Economic Importance 30112.2 Advantages of Biotransformations During Production of Steroids 30312.3 Development of Production Strains and Production Processes 30512.4 Applied Types of Biotransformation 30712.5 Synthesis of Steroids in Organic – Aqueous Biphasic System 31012.6 Side-chain Degradation of Phytosterols by Mycobacterium to Gain Steroid Intermediates 31112.7 Biotransformation of Cholesterol to Gain Key Steroid Intermediates 31312.8 11-Hydroxylation by Fungi During Synthesis of Corticosteroids 31312.9 Δ1-Dehydrogenation by Arthrobacter for the Production of Prednisolone 31612.10 17-Keto Reduction by Saccharomyces in Testosterone Production 31712.11 Double-Bond Isomerization of Steroids 31812.12 Perspectives 319References 320Further Reading 32113 Bioleaching 323Sören Bellenberg, Mario Vera Véliz, and Wolfgang Sand13.1 Acidophilic Microorganisms Dissolve Metals from Sulfide Ores 32313.1.1 Brief Overview on the Diversity of Acidophilic Mineral-Oxidizing Microorganisms 32513.1.2 Natural and Man-Made Habitats of Mineral-oxidizing Microorganisms 32513.1.3 Biological Catalysis of Metal Sulfide Oxidation 32813.1.4 Importance of Biofilm Formation and Extracellular Polymeric Substances for Bioleaching by Acidithiobacillus ferrooxidans and Leptospirillum ferrooxidans 33013.2 Bioleaching of Copper, Nickel, Zinc, and Cobalt 33413.2.1 Economic Impact 33413.2.2 Heap, Dump, or Stirred-tank Bioleaching of Copper, Nickel, Zinc, and Cobalt 33713.3 Gold 34213.3.1 Economic Impact 34313.3.2 Unlocking Gold by Biooxidation of the Mineral Matrix 34313.4 Uranium 34613.4.1 Economic Impact 34613.4.2 In Situ Biomining of Uranium 34613.5 Perspectives 34713.5.1 Urban Mining – Processing of Electronic Waste and Industrial Residues 34713.5.2 Microbial Iron Reduction for Dissolution of Mineral Oxides 34813.5.3 Biomining Goes Underground – In Situ Leaching as a Green Mining Technology? 348References 351Further Reading 35114 Wastewater Treatment Processes 353Claudia Gallert and Josef Winter14.1 Introduction 35414.1.1 Historical Development of Sewage Treatment 35414.1.2 Resources from Wastewater Treatment 35714.1.3 Wastewater and Storm Water Drainage 35814.1.4 Wastewater Characterization and Processes for Effective Wastewater Treatment 35814.1.5 Suspended or Immobilized Bacteria as Biocatalysts for Effective Sewage Treatment 36014.2 Biological Basics of Carbon, Nitrogen, and Phosphorus Removal from Sewage 36214.2.1 Aerobic and Anaerobic Degradation of Carbon Compounds 36214.2.1.1 Mass and Energy Balance 36614.2.2 Fundamentals of Nitrification 36814.2.3 Elimination of Nitrate by Denitrification 37114.2.4 New Nitrogen Elimination Processes 37114.2.5 Microbial Phosphate Elimination 37214.3 Wastewater Treatment Processes 37414.3.1 Typical Process Sequence in Municipal Sewage Treatment Plants 37414.3.2 Activated Sludge Process 37614.3.3 Trickling Filters 37814.3.4 Technical Options for Denitrification 37914.3.5 Biological Phosphate Elimination 38114.3.6 Sewage Sludge Treatment 38214.3.6.1 Aerobic and Anaerobic Sewage Sludge Treatment 38214.3.6.2 Sanitation and Quality Assurance of Sewage Sludge 38414.4 Advanced Wastewater Treatment 38414.4.1 Elimination of Micropollutants 38514.4.2 Wastewater Disinfection 38514.5 Future Perspectives 386References 386Further Reading 388Index 389