Cover	1
	Title Page	3
	Copyright	6
	Contents	9
	Preface	19
	Chapter 1 Historical Overview and Future Perspective	23
	1.1 Use of Fermentation Procedures Before the Discovery of Microorganisms (Neolithic Era &equals	23
	1.2 Investigation of Microorganisms and Beginning of Industrial Microbiology (1850 Until 1940)	29
	1.3 Development of New Products and Procedures: Antibiotics and Other Biomolecules (From 1940)	33
	1.4 Genetic Engineering Is Introduced into Industrial Microbiology (From Roughly 1980)	37
	1.5 Future Perspectives: Synthetic Microbiology	40
	References	42
	Further Reading	43
	Chapter 2 Bioprocess Engineering	45
	2.1 Introduction	45
	2.1.1 Role of Bioreactors	47
	2.1.2 Basic Bioreactor Configurations	48
	2.1.3 Types of Growth Media	49
	2.2 Nonstructured Models	50
	2.2.1 Nonstructured Growth Models	50
	2.2.1.1 Unstructured Models	51
	2.2.1.2 Biotechnical Processes	52
	2.2.2 Modeling Fermentations	54
	2.2.3 Metabolic Pathways	61
	2.2.4 Manipulation of Metabolic Pathways	62
	2.2.5 Future of Pathway Design	64
	2.3 Oxygen Transport	65
	2.3.1 Aerobic versus Anaerobic Conditions	65
	2.3.2 kLa – Volumetric Mass Transfer Coefficient	66
	2.4 Heat Generating Aerobic Processes	68
	2.5 Product Recovery	71
	2.5.1 Basics	71
	2.5.2 In Situ Product Recovery (ISPR)	71
	2.6 Modeling and Simulation of Reactor Behavior	73
	2.6.1 Basic Approaches and Software	73
	2.6.2 Numerical Simulation of Bioreactor Function	73
	2.6.3 Contamination of Bioreactors	74
	2.7 Scale?up	75
	References	76
	Further Reading	79
	Chapter 3 Food	81
	3.1 Fermented Foods	81
	3.1.1 Food Preservation	81
	3.1.2 Flavor and Texture	82
	3.1.3 Health Benefits	82
	3.1.4 Economic Impact	84
	3.2 Microorganisms and Metabolism	84
	3.2.1 Fermentation Processes	86
	3.2.2 Starter Cultures	87
	3.3 Yeast Fermentations – Industrial Application of Saccharomyces Species	87
	3.3.1 Grain Fermentation for Ethanol Production – Beer	88
	3.3.2 Grain Fermentation for CO2 Production – Bread	91
	3.3.2.1 Yeast Preparation	91
	3.3.3 Fruit Fermentation – Wines and Ciders	93
	3.4 Vinegar – Incomplete Ethanol Oxidation by Acetic Acid Bacteria Such as Gluconobacter oxydans	97
	3.4.1 Substrates: Wine, Cider, and Malt	97
	3.4.2 Distilled (White) Vinegar	99
	3.4.3 Balsamic and Other Specialty Vinegars	99
	3.5 Bacterial and Mixed Fermentations – Industrial Application of Lactic Acid Bacteria, With or Without Yeast or Molds	100
	3.5.1 Milk – Cultured Milks – Buttermilk, Yogurt, Kefir, and Cheese	100
	3.5.1.1 Bacteriophage Contamination – Death of a Culture	103
	3.5.2 Meats – Sausages, Fish Sauces, and Pastes	104
	3.5.3 Vegetables – Sauerkrauts and Pickles, Olives	105
	3.5.4 Grains and Legumes – Soy Sauce, Miso, Natto, and Tempeh	108
	3.5.5 Cocoa and Coffee	109
	3.6 Fungi as Food	110
	3.6.1 Mushrooms	110
	3.6.2 Single?Cell Protein – Fusarium venenatum	112
	3.7 Conclusions and Outlook	113
	References	114
	Further Reading	114
	Chapter 4 Technical Alcohols and Ketones	117
	4.1 Introduction	117
	4.2 Ethanol Synthesis by Saccharomyces cerevisiae and Clostridium autoethanogenum	119
	4.2.1 Application	119
	4.2.2 Metabolic Pathways and Regulation	119
	4.2.3 Production Strains	120
	4.2.4 Production Processes	120
	4.2.5 Ethanol – Fuel of the Future?	122
	4.2.6 Alternative Substrates for Ethanol Fermentation by Cellulolytic Bacteria and Clostridium autoethanogenum	122
	4.3 1,3?Propanediol Synthesis by Escherichia coli	123
	4.3.1 Application	123
	4.3.2 Metabolic Pathways and Regulation	124
	4.3.3 Production Strains	124
	4.3.4 Production Processes	126
	4.4 Butanol and Isobutanol Synthesis by Clostridia and Yeast	127
	4.4.1 History of Acetone–Butanol–Ethanol (ABE) Fermentation by Clostridium acetobutylicum and C. beijerinckii	127
	4.4.2 Application	128
	4.4.3 Metabolic Pathways and Regulation	129
	4.4.4 Production Strains	132
	4.4.5 Production Processes	132
	4.4.6 Product Toxicity	135
	4.5 Acetone Synthesis by Solventogenic Clostridia	135
	4.5.1 Application	135
	4.5.2 Metabolic Pathways and Regulation	135
	4.5.3 Production Strains	136
	4.5.4 Production Processes	136
	4.6 Outlook	137
	Further Reading	137
	Chapter 5 Organic Acids	139
	5.1 Introduction	139
	5.2 Citric Acid	141
	5.2.1 Economic Impact and Applications	142
	5.2.2 Biochemistry of Citric Acid Accumulation	142
	5.2.3 Industrial Production by the Filamentous Fungus Aspergillus niger	144
	5.2.4 Yarrowia lipolytica: A Yeast as an Alternative Production Platform	145
	5.3 Lactic Acid	146
	5.3.1 Economic Impact and Applications	146
	5.3.2 Anaerobic Bacterial Metabolism Generating Lactic Acid	147
	5.3.3 Lactic Acid Production by Bacteria	147
	5.3.4 Lactic Acid Production by Yeasts	148
	5.4 Gluconic Acid	149
	5.4.1 Economic Impact and Applications	149
	5.4.2 Extracellular Biotransformation of Glucose to Gluconic Acid by Aspergillus niger	150
	5.4.3 Production of Gluconic Acid by Bacteria	151
	5.5 Succinic Acid	151
	5.5.1 Economic Impact and Applications	152
	5.5.2 Pilot Plants for Anaerobic or Aerobic Microbes	152
	5.6 Itaconic Acid	154
	5.6.1 Economic Impact and Applications	154
	5.6.2 Decarboxylation as a Driver in Itaconic Acid Accumulation	154
	5.6.3 Production Process by Aspergillus terreus	154
	5.6.4 Metabolic Engineering for Itaconic Acid Production	154
	5.7 Downstream Options for Organic Acids	156
	5.8 Perspectives	157
	5.8.1 Targeting Acrylic Acid – Microbes Can Replace Chemical Process Engineering	158
	5.8.2 Lignocellulose?Based Biorefineries	158
	Further Reading	159
	Chapter 6 Amino Acids	161
	6.1 Introduction	161
	6.1.1 Importance and Areas of Application	161
	6.1.2 Amino Acids in the Feed Industry	162
	6.1.3 Economic Significance	163
	6.2 Production of Amino Acids	164
	6.2.1 Conventional Development of Production Strains	164
	6.2.2 Advanced Development of Production Strains	166
	6.3 l?Glutamate Synthesis by Corynebacterium glutamicum	167
	6.3.1 Synthesis Pathway and Regulation	167
	6.3.2 Production Process	170
	6.4 l?Lysine	170
	6.4.1 Synthesis Pathway and Regulation	170
	6.4.2 Production Strains	172
	6.4.3 Production Process	174
	6.5 l?Threonine Synthesis by Escherichia coli	175
	6.5.1 Synthesis Pathway and Regulation	175
	6.5.2 Production Strains	176
	6.5.3 Production Process	177
	6.6 l?Phenylalanine	177
	6.6.1 Synthesis Pathway and Regulation	177
	6.6.2 Production Strains	178
	6.6.3 Production Process	179
	6.7 Outlook	180
	Further Reading	181
	Chapter 7 Vitamins, Nucleotides, and Carotenoids	183
	7.1 Application and Economic Impact	183
	7.2 l?Ascorbic Acid (Vitamin C)	185
	7.2.1 Biochemical Significance, Application, and Biosynthesis	185
	7.2.2 Regioselective Oxidation with Bacteria in the Production Process	186
	7.3 Riboflavin (Vitamin B2)	188
	7.3.1 Significance as a Precursor for Coenzymes and as a Pigment	188
	7.3.2 Biosynthesis by Fungi and Bacteria	189
	7.3.3 Production by Ashbya gossypii	190
	7.3.4 Production by Bacillus subtilis	193
	7.3.5 Downstream Processing and Environmental Compatibility	195
	7.4 Cobalamin (Vitamin B12)	196
	7.4.1 Physiological Relevance	196
	7.4.2 Biosynthesis	198
	7.4.3 Production with Pseudomonas denitrificans	198
	7.5 Purine Nucleotides	200
	7.5.1 Impact as Flavor Enhancer	200
	7.5.2 Development of Production Strains	200
	7.5.3 Production of Inosine or Guanosine with Subsequent Phosphorylation	201
	7.6 ??Carotene	202
	7.6.1 Physiological Impact and Application	202
	7.6.2 Production with Blakeslea trispora	203
	7.7 Perspectives	203
	Further Reading	205
	Chapter 8 Antibiotics and Pharmacologically Active Compounds	207
	8.1 Microbial Substances Active Against Infectious Disease Agents or Affecting Human Cells	207
	8.1.1 Distribution and Impacts	207
	8.1.2 Diversity of Antibiotics Produced by Bacteria and Fungi	211
	8.2 ??Lactams	212
	8.2.1 History, Effect, and Application	212
	8.2.2 ??Lactam Biosynthesis	212
	8.2.3 Penicillin Production by Penicillium chrysogenum	215
	8.2.4 Cephalosporin Production by Acremonium chrysogenum	215
	8.3 Lipopeptides	215
	8.3.1 History, Effect, and Application	215
	8.3.2 Lipopeptide Biosynthesis	216
	8.3.3 Daptomycin Production by Streptomyces roseosporus	216
	8.3.4 Cyclosporine Production by Tolypocladium inflatum	216
	8.4 Macrolides	219
	8.4.1 History, Effect, and Application	219
	8.4.2 Macrolide Biosynthesis	219
	8.4.3 Erythromycin Production by Saccharopolyspora erythraea	219
	8.5 Tetracyclines	222
	8.5.1 History, Effect, and Application	222
	8.5.2 Tetracycline Biosynthesis	222
	8.5.3 Tetracycline Production by Streptomyces rimosus	223
	8.6 Aminoglycosides	223
	8.6.1 History, Effect, and Application	223
	8.6.2 Aminoglycoside Biosynthesis	223
	8.6.3 Tobramycin Production by Streptomyces tenebrarius	225
	8.7 Claviceps Alkaloids	225
	8.7.1 History, Effect, and Application	225
	8.7.2 Alkaloid Biosynthesis	225
	8.7.3 Ergotamine Production by Claviceps purpurea	225
	8.8 Perspectives	225
	8.8.1 Antibiotic Resistance	225
	8.8.2 New Research Model for Compound Identification	228
	8.8.3 Future Opportunities	229
	Further Reading	233
	Chapter 9 Pharmaceutical Proteins	235
	9.1 History, Main Areas of Application, and Economic Importance	235
	9.2 Industrial Expression Systems, Cultivation and Protein Isolation, and Legal Framework	237
	9.2.1 Development of Production Strains	237
	9.2.2 Isolation of Pharmaceutical Proteins	243
	9.2.3 Regulatory Requirements for the Production of Pharmaceutical Proteins	244
	9.3 Insulins	245
	9.3.1 Application and Structures	245
	9.3.2 Manufacturing Processes by Escherichia coli and Saccharomyces cerevisiae	247
	9.3.2.1 Production of a Fusion Protein in E. coli	248
	9.3.2.2 Production of a Precursor Protein, the So?Called Mini Proinsulin with the Host Strain S. cerevisiae	250
	9.4 Somatropin	252
	9.4.1 Application	252
	9.4.2 Manufacturing Process	253
	9.5 Interferons – Application and Manufacturing	254
	9.6 Human Granulocyte Colony?Stimulating Factor	256
	9.6.1 Application	256
	9.6.2 Manufacturing Process	257
	9.7 Vaccines	257
	9.7.1 Application	257
	9.7.2 Manufacturing Procedure Using the Example of Gardasil™	258
	9.7.3 Manufacturing Process Based on the Example of a Hepatitis B Vaccine	259
	9.8 Antibody Fragments	260
	9.9 Enzymes	261
	9.10 Peptides	262
	9.11 View – Future Economic Importance	262
	Further Reading	264
	Chapter 10 Enzymes	265
	10.1 Fields of Application and Economic Impacts	265
	10.1.1 Enzymes are Biocatalysts	265
	10.1.2 Advantages and Limitations of Using Enzymatic Versus Chemical Methods	266
	10.1.3 Brief History of Enzyme Used for the Industrial Production of Valuable Products	267
	10.1.4 Diverse Ways That Enzymes Are Used in Industry	268
	10.2 Enzyme Discovery and Improvement	272
	10.2.1 Screening for New Enzymes and Optimization of Enzymes by Protein Engineering	272
	10.2.2 Classical Development of Production Strains	273
	10.2.3 Genetic Engineering of Producer Strains	275
	10.3 Production Process for Bacterial or Fungal Enzymes	277
	10.4 Polysaccharide?Hydrolyzing Enzymes	277
	10.4.1 Starch?Cleaving Enzymes Produced by Bacillus and Aspergillus Species	279
	10.4.2 Cellulose?Cleaving Enzymes: A Domain of Trichoderma reesei	281
	10.4.3 Production Strains	283
	10.5 Enzymes Used as Cleaning Agents	285
	10.5.1 Subtilisin?Like Protease	286
	10.5.2 Bacillus sp. Production Strains and Production Process	287
	10.6 Feed Supplements – Phytases	288
	10.6.1 Fields of Applications of Phytase	289
	10.6.2 Phytase in the Animals Intestine	289
	10.6.3 Production of a Bacterial Phytase in Aspergillus niger	291
	10.7 Enzymes for Chemical and Pharmaceutical Industry	293
	10.7.1 Examples for Enzymatic Chemical Production	293
	10.7.2 Production of (S)?Profens by Fungal Lipase	293
	10.8 Enzymes as Highly Selective Tools for Research and Diagnostics	294
	10.8.1 Microbial Enzymes for Analysis and Engineering of Nucleic Acids	294
	10.8.2 Specific Enzymes for Quantitative Metabolite Assays	297
	10.9 Perspectives	298
	10.9.1 l?DOPA by Tyrosine Phenol Lyase	298
	10.9.2 Activation of Alkanes	298
	10.9.3 Enzyme Cascades	298
	References	299
	Further Reading	299
	Chapter 11 Microbial Polysaccharides	301
	11.1 Introduction	301
	11.2 Heteropolysaccharides	304
	11.2.1 Xanthan: A Product of the Bacterium Xanthomonas campestris	304
	11.2.1.1 Introduction	304
	11.2.1.2 Regulatory Status	304
	11.2.1.3 Structure	304
	11.2.1.4 Biosynthesis	306
	11.2.1.5 Industrial Production of Xanthan	308
	11.2.1.6 Physicochemical Properties	309
	11.2.1.7 Applications	311
	11.2.2 Sphingans: Polysaccharides from Sphingomonas sp.	313
	11.2.3 Hyaluronic Acid: A High?Value Polysaccharide for Cosmetic Applications	315
	11.2.4 Alginate: Alternatives to Plant?Based Products by Pseudomonas and Azotobacter sp.	316
	11.2.5 Succinoglycan: Acidic Polysaccharide from Rhizobium sp.	316
	11.3 Homopolysaccharides	317
	11.3.1 ??Glucans	318
	11.3.1.1 Pullulan	318
	11.3.1.2 Dextran	318
	11.3.2 ??Glucans	319
	11.3.2.1 Linear ??glucans like cellulose and curdlan	319
	11.3.2.2 Branched ??Glucans Like Scleroglucan and Schizophyllan	319
	11.3.3 Fructosylpolymers like Levan	320
	11.4 Perspectives	320
	Further Reading	321
	Chapter 12 Steroids	323
	12.1 Fields of Applications and Economic Importance	323
	12.2 Advantages of Biotransformations During Production of Steroids	325
	12.3 Development of Production Strains and Production Processes	327
	12.4 Applied Types of Biotransformation	329
	12.5 Synthesis of Steroids in Organic – Aqueous Biphasic System	332
	12.6 Side?chain Degradation of Phytosterols by Mycobacterium to Gain Steroid Intermediates	333
	12.7 Biotransformation of Cholesterol to Gain Key Steroid Intermediates	335
	12.8 11?Hydroxylation by Fungi During Synthesis of Corticosteroids	335
	12.9 ?1?Dehydrogenation by Arthrobacter for the Production of Prednisolone	338
	12.10 17?Keto Reduction by Saccharomyces in Testosterone Production	339
	12.11 Double?Bond Isomerization of Steroids	340
	12.12 Perspectives	341
	References	342
	Further Reading	343
	Chapter 13 Bioleaching	345
	13.1 Acidophilic Microorganisms Dissolve Metals from Sulfide Ores	345
	13.1.1 Brief Overview on the Diversity of Acidophilic Mineral?Oxidizing Microorganisms	347
	13.1.2 Natural and Man?Made Habitats of Mineral?oxidizing Microorganisms	347
	13.1.3 Biological Catalysis of Metal Sulfide Oxidation	350
	13.1.4 Importance of Biofilm Formation and Extracellular Polymeric Substances for Bioleaching by Acidithiobacillus ferrooxidans and Leptospirillum ferrooxidans	352
	13.2 Bioleaching of Copper, Nickel, Zinc, and Cobalt	356
	13.2.1 Economic Impact	356
	13.2.2 Heap, Dump, or Stirred?tank Bioleaching of Copper, Nickel, Zinc, and Cobalt	359
	13.3 Gold	364
	13.3.1 Economic Impact	365
	13.3.2 Unlocking Gold by Biooxidation of the Mineral Matrix	365
	13.4 Uranium	368
	13.4.1 Economic Impact	368
	13.4.2 In Situ Biomining of Uranium	368
	13.5 Perspectives	369
	13.5.1 Urban Mining – Processing of Electronic Waste and Industrial Residues	369
	13.5.2 Microbial Iron Reduction for Dissolution of Mineral Oxides	370
	13.5.3 Biomining Goes Underground – In Situ Leaching as a Green Mining Technology?	370
	References	373
	Further Reading	373
	Chapter 14 Wastewater Treatment Processes	375
	14.1 Introduction	376
	14.1.1 Historical Development of Sewage Treatment	376
	14.1.2 Resources from Wastewater Treatment	379
	14.1.3 Wastewater and Storm Water Drainage	380
	14.1.4 Wastewater Characterization and Processes for Effective Wastewater Treatment	380
	14.1.5 Suspended or Immobilized Bacteria as Biocatalysts for Effective Sewage Treatment	382
	14.2 Biological Basics of Carbon, Nitrogen, and Phosphorus Removal from Sewage	384
	14.2.1 Aerobic and Anaerobic Degradation of Carbon Compounds	384
	14.2.1.1 Mass and Energy Balance	388
	14.2.2 Fundamentals of Nitrification	390
	14.2.3 Elimination of Nitrate by Denitrification	393
	14.2.4 New Nitrogen Elimination Processes	393
	14.2.5 Microbial Phosphate Elimination	394
	14.3 Wastewater Treatment Processes	396
	14.3.1 Typical Process Sequence in Municipal Sewage Treatment Plants	396
	14.3.2 Activated Sludge Process	398
	14.3.3 Trickling Filters	400
	14.3.4 Technical Options for Denitrification	401
	14.3.5 Biological Phosphate Elimination	403
	14.3.6 Sewage Sludge Treatment	404
	14.3.6.1 Aerobic and Anaerobic Sewage Sludge Treatment	404
	14.3.6.2 Sanitation and Quality Assurance of Sewage Sludge	406
	14.4 Advanced Wastewater Treatment	406
	14.4.1 Elimination of Micropollutants	407
	14.4.2 Wastewater Disinfection	407
	14.5 Future Perspectives	408
	References	408
	Further Reading	410
	Index	411
	EULA	420