High Value Fermentation Products, Volume 1

Saurabh Saran, PhD, is a microbiologist and fermentation scientist with over ten years of experience in industrial microbiology, biotechnology and fermentation technology. He received his doctorate from Delhi University, and he has extensive experience in both the academic and industrial worlds, in multiple countries. He is currently Senior Scientist in the Fermentation Technology Division at the Indian Institute of Integrative Medicine, Jammu. He has three patents and more than 25 international publications in peer reviewed international journals on fermentation technology to his credit. Vikash Babu, PhD, has a doctorate from the Indian Institute of Technology and has over ten years of experience in graduate and postgraduate work and teaching. After working at Mangalayatan University and Graphic Era University, he joined the Indian Institute of Integrative Medicine as a scientist. He has been the editor on one book, also available from Wiley-Scrivener. Asha Chaubey, PhD, is Senior Scientist at the Fermentation Technology Division at the Indian Institute of Integrative Medicine, Jammu, India. Her research interests include exploration and exploitation of microbes for bioactives & enzymes production, immobilization of enzymes, biotransformation, kinetic resolution of racemic drug intermediates, development of biosensors for health care and environmental monitoring.Cover Design: Kris Hackerott

• Foreword xviiAbout the Editors xixList of Contributors xxiPreface xxvAcknowledgement xxvii1 Introduction, Scope and Significance of Fermentation Technology 1Saurabh Saran, Alok Malaviya and Asha Chaubey1.1 Introduction 11.2 Background of Fermentation Technology 21.3 Market of Fermentation Products 31.4 Types of Fermentation 41.4.1 Solid State Fermentation (SSF) 41.4.2 Submerged Fermentation (SmF) 71.4.3 Solid State (SSF) vs. Submerged (SmF) Fermentation 91.5 Classification of Fermentation 91.6 Design and Parts of Fermentors 101.7 Types of Fermentor 151.7.1 Stirred Tank Fermentor 151.7.2 Airlift Fermentor 161.7.3 Bubble Column Fermentor 171.7.4 Fluidized Bed Fermentor 181.7.5 Packed Bed Fermentor 191.7.6 Photo Bioreactor 191.8 Industrial Applications of Fermentation Technology 211.9 Scope and Global Market of Fermentation Technology 221.10 Conclusions 23References 242 Extraction of Bioactive Molecules through Fermentation and Enzymatic Assisted Technologies 27Ramón Larios-Cruz, Liliana Londoño-Hernández, Ricardo Gómez-García, Ivanoe García, Leonardo Sepulveda, Raúl Rodríguez-Herrera and Cristóbal N. Aguilar2.1 Introduction 272.2 Definition of Bioactives Compounds 292.2.1 Polyphenols and Polypeptides 292.2.2 Importance and Applications of Bioactive Compounds 292.2.3 Bioactive Peptides 312.3 Traditional Processes for Obtaining Bioactive Compounds 332.3.1 Soxhlet Extraction 332.3.2 Liquid-Liquid and Solid-Liquid Extraction 342.3.3 Maceration Extraction 352.4 Fermentation and Enzymatic Technologies for Obtaining Bioactive Compounds 352.4.1 Soft Chemistry in Bioactive Compounds 352.4.2 Biotransformation of Bioactive Compounds 362.4.3 Enzymatic and Fermentation Technologies 392.5 Use of Agroindustrial Waste in the Fermentation Process 452.5.1 Cereal Wastes 462.5.2 Fruit and Plant Waste 462.6 General Parameters in the Optimization of Fermentation Processes 492.6.1 Response Surface Methodology 492.6.2 First-Order Model 492.6.3 Second-Order Model 492.7 Final Comments 52Acknowledgements 52References 523 Antibiotics Against Gram Positive Bacteria 61Rahul Vikram Singh, Hitesh Sharma, Anshela Koul and Vikash Babu3.1 Introduction 613.2 Target of Antibiotics Against Gram Positive Bacteria 643.2.1 Cell Wall Synthesis Inhibition 653.2.2 Protein Synthesis Inhibition 703.2.3 DNA Synthesis Inhibition 723.3 Antibiotics Production Processes 723.4 Conclusion 75References 764 Antibiotic Against Gram-Negative Bacteria 79Maryam Faiyaz, Shikha Gupta and Divya Gupta4.1 Introduction 794.2 Gram-Negative Bacteria and Antibiotics 804.2.1 β-Lactam Drugs 814.2.2 Macrolide 824.2.3 Aminoglycosides 844.2.4 Fluoroquinolones 844.3 Production of Antibiotics 854.3.1 Strain Development 854.3.2 Media Formulation and Optimization 884.3.3 Fermentation 904.3.4 Downstream Processing and Purification 924.3.5 Quality Control 954.4 Conclusion 95References 965 Role of Antifungal Drugs in Combating Invasive Fungal Diseases 103Kakoli Dutt5.1 Introduction 1035.2 Antifungal Agents 1055.2.1 Azoles 1145.2.2 Polyenes 1155.2.3 Allylamine/Thiocarbonates 1165.2.4 Other Antifungal Agents 1175.3 Targets of Antifungal Agents 1205.3.1 Cell Wall Biosynthesis Inhibitors 1205.3.2 Sphingolipid Synthesis Inhibitors 1235.3.3 Ergosterol Synthesis Inhibitors 1255.3.4 Protein Synthesis Inhibitors 1265.3.5 Novel Targets 1285.4 Development of Resistance towards Antifungal Agents 1305.4.1 Minimum Inhibitory Concentration 1305.4.2 Antifungal-Drug-Resistance Mechanisms 1315.5 Market and Drug Development 1345.6 Conclusions 136Acknowledgement 137References 1376 Current Update on Rapamycin Production and Its Potential Clinical Implications 145Girijesh K. Patel, Ruchika Goyal1 and Syed M. Waheed6.1 Introduction 1456.2 Biosynthesis of Rapamycin 1466.2.1 Microbial Strain 1476.2.2 Optimization of Carbon, Nitrogen Sources and Salts 1476.2.3 Strain Manipulation to Improve Rapamycin Production 1486.3 Organic Synthesis of Rapamycin 1526.4 Extraction and Quantification of Rapamycin 1526.5 Physiological Factors Affecting Rapamycin Biosynthesis 1536.5.1 Effect of Media Components 1536.5.2 Effect of pH on Rapamycin Production 1536.5.3 Effect of Physical Gravity 1546.5.4 Effect of Morphological Changes 1546.5.5 Effect of Dissolved Oxygen (DO) and Carbon Dioxide (DCO2) 1546.6 Production of Rapamycin Analogs 1546.7 Mechanism of Action of Rapamycin 1556.8 Use of Rapamycin in Medicine 1576.8.1 Anti-Fungal Agent 1576.8.2 Immunosuppression 1586.8.3 Anti-Cancer Agent 1586.8.4 Anti-Aging Agent 1586.8.5 Role in HIV Treatment 1586.8.6 Rheumatoid Arthritis 1596.9 Side Effects of Long-term Use of Rapamycin 1596.10 Conclusions 159Acknowledgements 160References 1607 Advances in Production of Therapeutic Monoclonal Antibodies 165Richi V Mahajan, Subhash Chand, Mahendra Pal Singh, Apurwa Kestwal and Surinder Singh7.1 Introduction 1657.2 Discovery and Clinical Development 1667.3 Structure and Classification 1677.4 Nomenclature of Monoclonal Antibodies 1687.5 Production of Monoclonal Antibodies 1707.5.1 Hybridoma Technology 1707.5.2 Epstein-Barr Virus Technology 1727.5.3 Phage Display Technology 1727.5.4 Cell Line Based Production Techniques 1737.5.5 Chemical Modifications of Monoclonal Antibodies 1837.5.6 Advances in Antibody Technology 1837.6 Conclusions 185References 1868 Antimicrobial Peptides from Bacterial Origin: Potential Alternative to Conventional Antibiotics 193Lipsy Chopra, Gurdeep Singh, Ramita Taggar, Akanksha Dwivedi, Jitender Nandal, Pradeep Kumar and Debendra K. Sahoo8.1 Introduction 1938.2 Classification of Bacteriocins 1948.2.1 Bacteriocins from Gram-Negative Bacteria 1948.2.2 Bacteriocins from Gram-Positive Bacteria 1948.3 Mode of Action 1968.3.1 Pore-Forming Bacteriocins 1968.3.2 Non-Pore-Forming Bacteriocins: Intracellular Targets 1988.4 Applications 1988.4.1 Food Bio Preservative 1988.4.2 Food Packaging (In Packaging Films) 1988.4.3 Hurdle Technology to Enhance Food Safety 1998.4.4 Therapeutic Potential 2008.4.5 Effect of Bacteriocins on Biofilms 2008.5 Conclusions 202Acknowledgments 202Abbreviations 202References 2029 Non-Ribosomal Peptide Synthetases: Nature’s Indispensable Drug Factories 205Richa Sharma, Ravi S. Manhas and Asha Chaubey9.1 Introduction 2059.1.1 Non-Ribosomal Peptides as Natural Products 2059.1.2 Non-Ribosomal Peptides as Drugs 2069.2 NRPS Machinery 2089.3 Catalytic Domains of NRPSs 2089.3.1 Adenylation (A) Domains 2089.3.2 Thiolation (T) or PCP Domains 2099.3.3 Condensation (C) Domains 2099.3.4 Thioesterase (Te) Domains 2099.4 Types of NRPS 2109.4.1 Type A (Linear NRPS) 2109.4.2 Type B (Iterative NRPS) 2109.4.3 Type C (Non-linear NRPS) 2109.5 Working of NRPSs 2109.5.1 Priming Thiolation Domain of NRPS 2119.5.2 Substrate Recognition and Activation 2119.5.3 Peptide Bond Formation between NRP Monomers 2119.5.4 Chain Termination of NRP Synthesis 2129.5.5 NRP Tailoring 2129.6 Sources of NRPs 2139.7 Production of Non-Ribosomal Peptides 2169.8 Future Scope 218Acknowledgements 219References 21910 Enzymes as Therapeutic Agents in Human Disease Management 225Babbal, Adivitiya, Shilpa Mohanty and Yogender Pal Khasa10.1 Introduction 22510.2 Pancreatic Enzymes 23010.2.1 Trypsin (EC 3.4.21.4) 23010.2.2 Pancreatic Lipase (EC 3.1.1.3) 23110.2.3 Amylases (EC 3.2.1.1) 23110.3 Oncolytic Enzymes 23210.3.1 L-Asparaginase (EC 3.5.1.1) 23210.3.2 L-Glutaminase (EC 3.5.1.2) 23310.3.3 Arginine Deiminase (ADI) (EC 3.5.3.6) 23310.4 Antidiabetic Enzymes 23410.4.1 Glucokinase (EC2.7.1.1)10.5 Liver Enzymes 23510.5.1 Superoxide Dismutase (SOD) (EC 1.15.1.1) 23510.5.2 Alkaline Phosphatase (ALP) (EC 3.1.3.1) 23610.6 Kidney Disorder 23710.6.1 Uricase (EC 1.7.3.3) 23710.6.2 Urease (EC 3.5.1.5) 23810.7 DNA- and RNA-Based Enzymes 23810.7.1 Dornase 23910.7.2 Adenosine Deaminase 24010.7.3 Ribonuclease 24010.8 Enzymes for the Treatment of Cardiovascular Disorders 24110.8.1 The Hemostatic System 24210.8.2 Enzymes of the Hemostatic System 24410.9 Lysosomal Storage Disorders 25110.9.1 α-Galactosidase A (EC 3.2.1.22) 25110.9.2 Glucocerebrosidase (EC 3.2.1.45) 25210.9.3 Acid Alpha-Glucosidase (GAA) (EC 3.2.1.20) 25310.9.4 α-L-iduronidase (Laronidase) (EC 3.2.1.76) 25310.10 Miscellaneous Enzymes 25410.10.1 Phenylalanine Hydroxylase (EC 1.14.16.1) 25410.10.2 Collagenase (EC 3.4.24.3) 25510.10.3 Hyaluronidase 25610.10.4 Bromelain 25610.11 Conclusions 256References 25711 Erythritol: A Sugar Substitute 265Kanti N. Mihooliya, Jitender Nandal, Himanshu Verma and Debendra K. Sahoo11.1 Introduction 26511.1.1 Background of Erythritol 26511.1.2 History of Erythritol 26811.1.3 Occurrence of Erythritol 26811.1.4 General Characteristics 26811.2 Chemical and Physical Properties of Erythritol 27111.3 Estimation of Erythritol 27111.3.1 Thin Layer Chromatography (TLC) 27311.3.2 Colorimetric Assay for Detection of Polyols 27311.3.3 High-Performance Liquid Chromatography (HPLC) 27311.3.4 Capillary Electrophoresis (CE) 27311.4 Production Methods for Erythritol 27411.4.1 Chemical Methods for Erythritol Production 27411.4.2 Fermentative Methods for Erythritol Production 27411.5 Optimization of Erythritol Production 27511.5.1 One Factor at a Time 27611.5.2 Statistical Design Approaches 27711.6 Toxicology of Erythritol 27711.7 Applications of Erythritol 27711.7.1 Confectioneries 27811.7.2 Bakery 27911.7.3 Pharmaceuticals 27911.7.4 Cosmetics 27911.7.5 Beverages 27911.8 Precautions for Erythritol Usage 27911.9 Global Market for Erythritol 28011.10 Conclusions 280References 28112 Sugar and Sugar Alcohols: Xylitol 285Bhumica Agarwal and Lalit Kumar Singh12.1 Introduction 28512.1.1 Lignocellulosic Biomass 28612.1.2 Properties of Xylitol 28712.1.3 Occurrence and Production of Xylitol 28912.2 Biomass Conversion Process 28912.2.1 Pretreatment Methodologies 28912.2.2 Enzymatic Hydrolysis 29212.2.3 Detoxification Techniques 29312.3 Utilization of Xylose 29612.3.1 Microorganisms Utilizing Xylose 29612.3.2 Metabolism of Xylose 29712.4 Process Variables 29912.4.1 Temperature and pH 29912.4.2 Substrate Concentration 30012.4.3 Aeration 301References 30313 Trehalose: An Anonymity Turns Into Necessity 309Manali Datta and Dignya Desai13.1 Introduction 30913.2 Trehalose Metabolism Pathways 31013.3 Physicochemical Properties and its Biological Significance 31113.4 Trehalose Production 31213.4.1 Enzymatic Conversion to Trehalose 31213.4.2 Microbe Mediated Fermentation 31413.4.3 Purification and Detection of Trehalose in Fermentation Process 31613.5 Application of Trehalose 31713.5.1 Role of Trehalose in Food Industries 31713.5.2 Role of Trehalose in Cosmetics and Pharmaceutics 31813.6 Conclusions 319References 32014 Production of Yeast Derived Microsomal Human CYP450 Enzymes (Sacchrosomes) in High Yields, and Activities Superior to Commercially Available Microsomal Enzymes 323Ibidapo Stephen Williams and Bhabatosh Chaudhuri14.1 Introduction 32314.1.1 Cytochrome P450 (CYP) Enzymes in Humans 32314.1.2 Human Cytochrome P450 Enzymes and their Role in Drug Metabolism 32414.1.3 Requirement of Activating Proteins to Form Functional Human CYP Enzymes 32514.1.4 Use of Yeast Biased Codons for the Syntheses of Human Cytochrome P450 Genes 32514.1.5 Expression of Human CYP Genes in Baker’s Yeast from an Episomal Plasmid 32514.1.6 Expression of Human CYP Genes in Baker’s Yeast from Integrative Plasmids 32714.1.7 The ADH2 Promoter for Production of Human CYP Enzymes in Baker’s Yeast 32714.1.8 Growth of Yeast Cells Containing Integrated Copies of CYP Gene Expression Cassettes, Driven by the ADH2 Promoter, for Production of CYP Enzymes 32814.2 Amounts of Microsomal CYP Enzyme Isolated from Yeast Strains Containing Chromosomally Integrated CYP Gene Expression Cassettes are far Higher than Strains Harbouring an Episomal Expression Plasmid Encoding a CYP Gene 32814.2.1 Preparation of Microsomal CYP Enzymes 32814.2.2 Measurement of the Amounts of Functional CYPs in Microsomes Isolated from Baker’s Yeast 32914.2.3 Production of Functional Human CYP1A2 Microsomal Enzyme from Baker’s Yeast 33014.2.4 Production of Functional Human CYP3A4 Microsomal Enzyme from Baker’s Yeast 33014.2.5 Production of Functional Human CYP2D6 Microsomal Enzyme from Baker’s Yeast 33114.2.6 Production of Functional Human CYP2C19 Microsomal Enzyme from Baker’s Yeast 33214.2.7 Production of Functional Human CYP2C9 Microsomal Enzyme from Baker’s Yeast 33314.2.8 Production of Functional Human CYP2E1 Microsomal Enzyme from Baker’s Yeast 33314.2.9 Comments on the Production of Human CYP Enzymes from Baker’s Yeast 33414.3 Comparison of CYP Enzyme Activity of Yeast-Derived Microsomes (Sacchrosomes) with Commercially Available Microsomes Isolated from Insect and Bacterial Cells 33614.3.1 Fluorescence-based Assays for Determining CYP Enzyme Activities in Isolated Microsomes 33614.3.2 Comparison of Enzyme Activity of CYP1A2 Sacchrosomes with Commercially Available CYP1A2 Microsomes Isolated from Insect and Bacterial Cells 33614.3.3 Comparison of Enzyme Activity of CYP2C9 Sacchrosomes with Those of Commercially Available CYP2C9 Microsomes from Insect and Bacterial Cells 33714.3.4 Comparison of Enzyme Activity of CYP2C19 Sacchrosomes with Those of Commercially Available CYP2C19 Microsomes from Insect and Bacterial Cells 33714.3.5 Comparison of Enzyme Activity of CYP2D6 Sacchrosomes with Those of Commercially Available CYP2D6 Microsomes from Insect and Bacterial Cells 33814.3.6 Comparison of Enzyme Activity of CYP3A4 Sacchrosomes with Those of Commercially Available CYP3A4 Microsomes from Insect and Bacterial Cells 33814.3.7 Comparison of Enzyme Activity of CYP2E1 Sacchrosomes with One of the Commercial CYP2E1 Microsomes Available from Insect Cells 33914.4 IC50 Values of Known CYP Inhibitors Using Sacchrosomes, Commercial Enzymes and HLMs 33914.5 Stabilisation of Sacchrosomes through Freeze-drying 34014.6 Conclusions 342References 34515 Artemisinin: A Potent Antimalarial Drug 347Alok Malaviya, Karan Malhotra, Anil Agarwal and Katherine Saikia15.1 Introduction 34715.2 Biosynthesis of Artemisinin in Artemisia annua and Pathways Involved 34815.3 Yield Enhancement Strategies in A. annua 35115.4 Artemisinin Production Using Heterologous Hosts 35215.4.1 Microbial Engineering 35215.4.2 Plant Metabolic Engineering 35315.5 Spread of Artemisinin Resistance 35715.6 Challenges in Large-Scale Production 35815.7 Future Prospects 360References 36016 Microbial Production of Flavonoids: Engineering Strategies for Improved Production 365Aravind Madhavan, Raveendran Sindhu, KB Arun, Ashok Pandey, Parameswaran Binod and Edgard Gnansounou16.1 Introduction 36516.2 Flavonoids 36616.3 Flavonoid Chemistry and Classes 36616.4 Health Benefits of Flavonoids 36716.5 Flavonoid Biosynthesis in Microorganism 36816.6 Engineering of Flavonoid Biosynthesis Pathway 37016.7 Metabolic Engineering Strategies 37016.8 Applications of Synthetic Biology in Flavonoid Production 37116.9 Post-modification of Flavonoids 37416.10 Purification of Flavonoids 37416.11 Conclusion 375Acknowledgements 375References 37617 Astaxanthin: Current Advances in Metabolic Engineering of the Carotenoid 381Manmeet Ahuja, Jayesh Varavadekar, Mansi Vora, Piyush Sethia, Harikrishna Reddy and Vidhya Rangaswamy17.1 Introduction 38117.1.1 Structure of Astaxanthin 38217.1.2 Natural vs. Synthetic Astaxanthin 38217.1.3 Uses and Market of Astaxanthin 38317.2 Pathway of Astaxanthin 38417.2.1 Bacteria 38417.2.2 Algae 38417.2.3 Yeast 38517.2.4 Plants 38617.3 Challenges/Current State of the Art in Fermentation/Commercial Production 38617.4 Metabolic Engineering for Astaxanthin 38817.4.1 Bacteria 38817.4.2 Plants 39017.4.3 Synechocystis 39117.4.4 Algae 39117.4.5 Yeast 39217.5 Future Prospects 393References 39518 Exploitation of Fungal Endophytes as Bio-factories for Production of Functional Metabolites through Metabolic Engineering; Emphasizing on Taxol Production 401Sanjog Garyali, Puja Tandon, M. Sudhakara Reddy and Yong Wang18.1 Introduction 40118.2 Taxol: History and Clinical Impact 40318.3 Endophytes 40318.3.1 Biodiversity of Endophytes 40518.3.2 Endophyte vs. Host Plant: the Relationship 40518.4 The Plausibility of Horizontal Gene Transfer (HGT) Hypothesis 40718.5 Endophytes as Biological Factories of Functional Metabolites 40918.6 Taxol Producing Endophytic Fungi 41018.7 Molecular Basis of Taxol Production by Taxus Plants (Taxol Biosynthetic Pathway) 41218.8 Metabolic Engineering for Synthesis of Taxol: Next Generation Tool 41618.8.1 Plant Cell Culture 41718.8.2 Microbial Metabolic Engineering for Synthesis of Taxol and Its Precursors 41818.8.3 Metabolic Engineering in Heterologous Plant for Synthesis of Taxol and Its Precursors 42018.9 Future Perspectives 421Acknowledgements 423References 423Index 431