Comprehensive Natural Products II

Lewis Mander; Hung-Wen Liu

BOOK

Comprehensive Natural Products II

Lewis Mander | Hung-Wen Liu

(2010)

Additional Information

Book Details

ISBN: 978-0-08-045382-8
Edition
Language: English
Pages: 7388
Subjects: Surgical orthopaedics & fractures
Chemistry
Medicinal chemistry
Organic chemistry

Abstract

This work presents a definitive interpretation of the current status of and future trends in natural products—a dynamic field at the intersection of chemistry and biology concerned with isolation, identification, structure elucidation, and chemical characteristics of naturally occurring compounds such as pheromones, carbohydrates, nucleic acids, and enzymes. With more than 1,800 color figures, Comprehensive Natural Products II features 100% new material and complements rather than replaces the original work (©1999).

Reviews the accumulated efforts of chemical and biological research to understand living organisms and their distinctive effects on health and medicine
Stimulates new ideas among the established natural products research community—which includes chemists, biochemists, biologists, botanists, and pharmacologists
Informs and inspires students and newcomers to the field with accessible content in a range of delivery formats
Includes 100% new content, with more than 6,000 figures (1/3 of these in color) and 40,000 references to the primary literature, for a thorough examination of the field
Highlights new research and innovations concerning living organisms and their distinctive role in our understanding and improvement of human health, genomics, ecology/environment, and more
Adds to the rich body of work that is the first edition, which will be available for the first time in a convenient online format giving researchers complete access to authoritative Natural Products content

Advanced praise for Comprehensive Natural Products II: Writing in the preface, renowned natural products chemist Koji Nakanishi praises “Lew Mander and Hung-Wen (Ben) Liu for having assembled an extraordinary team of editors for the nine volumes, who in turn have brought together top natural products scientists to review the respective topics…CONAP II should not be regarded merely as a reference source. Instead, one can take it from the bookshelf, flip through the pages, and go through some sections for one’s entertainment and knowledge enhancement.

Reviews of the first edition: "A marvelous and monumental piece of work." --Journal of the American Chemical Society

"This work is essential for libraries at institutions where natural product research is seriously pursued or contemplated." --Choice

Section Title	Page	Action	Price
e9780080453811v1	1
Cover	1
Title Page	4
Copyright Page	5
Contents	6
Contributors	8
Preface	12
Introduction	14
Editors in Chief	18
Volume Editors	20
1.01 Overview and Introduction	26
1.02 Unsaturated Fatty Acids	30
1.02.1 Introduction	30
1.02.2 Monounsaturated Fatty Acids	32
1.02.3 Methylene-Interrupted Polyunsaturated Fatty Acids	45
1.02.4 Unusual Unsaturated Fatty Acids	49
1.02.5 Summary and Future Prospects	53
Abbreviations	53
References	54
1.03 Prostaglandin Endoperoxide Synthases: Structure, Function, and Synthesis of Novel Lipid Signaling Molecules	60
1.03.1 Introduction	61
1.03.2 Physiological Functions and Regulation of PGHS Isoforms	62
1.03.3 Structural Determinants for Arachidonic Acid Metabolism by PGHS	66
1.03.4 Role of PGHS in the Biosynthesis of Novel Acidic Eicosanoids	72
1.03.5 Biosynthesis, Degradation, and Pharmacology of Prostaglandin-Glycerylesters	78
1.03.6 Biosynthesis, Degradation, and Pharmacology of Prostaglandin-Ethanolamides	80
1.03.7 Metabolism of Other Arachidonoyl Amides by PGHS	81
1.03.8 Conclusions	81
Abbreviations	81
References	82
1.04 Mycolic Acid/Cyclopropane Fatty Acid/Fatty Acid Biosynthesis and Health Relations	90
1.04.1 Introduction	91
1.04.2 Structural Variation, Biosynthesis, and Function of the Core Cell Envelope Mycolic Acids	92
1.04.3 Trehalose-Based Glycolipids	107
1.04.4 Phthiocerol-Based Glycolipids	126
1.04.5 Lipoarabinomannan and Phosphatidylinositides	133
1.04.6 Exotic Glycolipids and Glycopeptidolipids	137
1.04.7 Conclusions and Outlook	156
Abbreviations	156
References	158
1.05 Microbial Type III Polyketide Synthases	172
1.05.1 Introduction	172
1.05.2 Plant Type III PKSs	174
1.05.3 Type III PKSs from Actinobacteria	176
1.05.4 Type III PKSs from Proteobacteria	184
1.05.5 Type III PKSs from Eukaryotic Microbes	188
1.05.6 Conclusions and Future Perspectives	190
Abbreviations	192
References	193
1.06 Plant Type III PKS	196
1.06.1 Introduction	196
1.06.2 Functional Diversity and Catalytic Potential	199
1.06.3 Enzyme Structure and Site-Directed Mutagenesis	230
1.06.4 Protein Engineering	239
1.06.5 Combinational Biosynthesis	240
1.06.6 Conclusions	245
Acknowledgments	245
Abbreviations	245
References	246
1.07 Type II PKS	252
1.07.1 Introduction	253
1.07.2 Enzymes of Type II PKS-Derived Natural Products	253
1.07.3 Natural Structural Diversity	264
1.07.4 Artificial Structural Diversity through Combinatorial Biosynthesis	295
1.07.5 Conclusions	317
Acknowledgments	317
Glossary	317
References	318
1.08 Structural Enzymology of Polyketide Synthase: The Structure–Sequence–Function Correlation	330
1.08.1 Introduction	330
1.08.2 Fatty Acid Biosynthesis and Fatty Acid Synthase	332
1.08.3 The Type II PKS	335
1.08.4 Structural Enzymology of Individual Type II PKS Enzymes	339
1.08.5 Protein–Protein Interactions and Transport of Polyketide Intermediates between Enzymes	364
1.08.6 Summary and Future Prospects	365
Acknowledgments	365
Glossary	366
Abbreviations	366
Nomenclature	367
References	367
1.09 Fungal Type I Polyketides	372
1.09.1 Introduction	372
1.09.2 Diversity of Fungal Polyketides	373
1.09.3 Biosynthesis of Fungal Polyketides	379
1.09.4 Mixed Polyketide/Nonribosomal Peptides	397
1.09.5 Meroterpenoids	399
1.09.6 Post-PKS Reactions in Fungi	401
1.09.7 Conclusions	403
References	405
1.10 Type I Modular PKS	410
1.10.1 Introduction to Polyketides	411
1.10.2 Fatty Acid Biosynthesis – Reactions and Enzymes	413
1.10.3 Polyketide Biosynthesis – Reactions and Enzymes	417
1.10.4 Mechanism and Structural Specificity of Precursor Loading within the Modules of the DEBS	424
1.10.5 Experimental Investigation of Stereospecificity of the Reactions of the DEBS Chain-Extension Cycles	428
1.10.6 Studies of the Quaternary Structure of the Type I FAS	434
1.10.7 Studies of the Structure of the DEBS Modules	440
1.10.8 Current Proposals for the Topology of the DEBS Modules and Multienzymes	443
1.10.9 Other Polyketide Synthases	448
1.10.10 Commercial Applications of Genetic Engineering of Modular Polyketide Synthases	463
1.10.11 Future Perspectives	469
Abbreviations	471
Nomenclature	472
References	472
1.11 NRPS/PKS Hybrid Enzymes and Their Natural Products	478
1.11.1 Introduction	479
1.11.2 Medicinally Important PK/NRP Natural Products and Pathways	483
1.11.3 Trans-AT Domain Pathways – a Rich Source of Unusual Biochemistry	492
1.11.4 Engineering, Technology Development, and Other Future Directions for Hybrid PK/NRP Systems	506
1.11.5 Conclusions	508
Acknowledgment	509
Abbreviations	509
References	510
1.12 Mevalonate Pathway in Bacteria and Archaea	518
1.12.1 Introduction	518
1.12.2 Overview of the Mevalonate Pathway	519
1.12.3 Two Classes of HMG-CoA Reductase	522
1.12.4 Two Types of IPP Isomerase	527
1.12.5 Biosynthetic Gene Clusters of Secondary Metabolites from Actinomycetes	535
1.12.6 Mevalonate Fermentation	536
1.12.7 Conclusions	537
Abbreviations	537
Nomenclature	537
References	538
1.13 Methylerythritol Phosphate Pathway	542
1.13.1 Introduction	543
1.13.2 Identification of the Genes and the Enzymes	547
1.13.3 Distribution of the MEP Pathway	567
1.13.4 Openings and Further Developments	569
Acknowledgments	573
Abbreviations	573
References	574
1.14 Prenyltransferase	582
1.14.1 Introduction	582
1.14.2 (E)-Prenyltransferases	586
1.14.3 (Z)-Prenyl Diphosphate Synthases	594
1.14.4 Conclusions	604
Glossary	605
References	605
1.15 Advances in the Enzymology of Monoterpene Cyclization Reactions	610
1.15.1 Introduction	610
1.15.2 Cyclization Chemistry	613
1.15.3 Structural Studies	620
1.15.4 Conclusions	630
Acknowledgments	630
References	631
1.16 Sesquiterpenes	634
1.16.1 Introduction	634
1.16.2 Classification of Sesquiterpenes	635
1.16.3 Decorating the Sesquiterpene Scaffolds	655
1.16.4 Future Challenges	660
Glossary	661
References	663
1.17 Diterpenes	668
1.17.1 Introduction	668
1.17.2 Labdane-Type Diterpenes	669
1.17.3 Clerodane- and Halimane-Type Diterpenes	685
1.17.4 Other types of Diterpenes	687
1.17.5 Summary and Future Prospects	693
Abbreviations	694
References	694
1.18 Triterpenes	698
1.18.1 Introduction	698
1.18.2 Cyclization Mechanism	699
1.18.3 Lanosterol/Cycloartenol Synthases	701
1.18.4 Plant Triterpene Synthases	709
1.18.5 Triterpene Tailoring Steps	726
1.18.6 Summary and Future Perspectives	729
Abbreviations	730
References	730
1.19 Bacterial Squalene Cyclase	734
1.19.1 Introduction	734
1.19.2 The Reaction Mechanism	736
1.19.3 The Enzyme Structure	737
1.19.4 Site-Directed Mutagenesis	741
1.19.5 Substrate Recognition and Catalytic Potential	744
1.19.6 Conclusions	754
Acknowledgments	755
Abbreviations	755
References	755
1.20 Carotenoids	758
1.20.1 Introduction	758
1.20.2 Biosynthesis of Basic Structures of Carotenoids	759
1.20.3 Biosynthesis of C30 Carotenoids	761
1.20.4 Biosynthesis of C40 Carotenoids	761
1.20.5 Pathway Engineering for Useful Carotenoid Formation in Escherichia coli	770
1.20.6 Pathway Engineering for Useful Carotenoid Formation in Higher Plants	771
1.20.7 Conclusion	775
Acknowledgment	775
Nomenclature	775
References	775
1.21 Sterol and Steroid Biosynthesis and Metabolism in Plants and Microorganisms	780
1.21.1 Introduction	780
1.21.2 Sterol and Steroid Biosynthetic Pathways	781
1.21.3 Sterol and Steroid Conjugates	799
1.21.4 Sterol Degradation	801
1.21.5 Transport	801
1.21.6 Molecular Regulation of Sterol Biosynthesis	802
1.21.7 Functions of Steroids	803
Abbreviations	804
References	805
1.22 Isoprenoid in Actinomycetes	814
1.22.1 Introduction	814
1.22.2 Cyclic Isoprenoids	815
1.22.3 Hybrid Isoprenoids	826
Abbreviations	836
References	836
1.23 Lignans (Neolignans) and Allyl/Propenyl Phenols: Biogenesis, Structural Biology, and Biological/Human Health Considerations	840
1.23.1 Introduction	842
1.23.2 Definition and Nomenclature	843
1.23.3 Chemotaxonomical Diversity: Evolutionary Considerations	846
1.23.4 Lignan Early Biosynthetic Steps: 8–89 Phenylpropanoid Coupling	872
1.23.5 Downstream Lignan Metabolism	881
1.23.6 Other Phenylpropanoid Coupling Modes: 8–29, 8–39 (8–59), and 8–O–49-Linked Lignans	903
1.23.7 Allylic (Phenylpropenal) Double Bond Reductases and Phenylcoumaran Benzylic Ether Reductases	905
1.23.8 Norlignan Biosynthesis	914
1.23.9 Allyl-/Propenylphenol Biosynthesis	917
1.23.10 Biological Properties in Planta and in Human Usage	931
Acknowledgments	941
References	941
1.24 Plant Phenolics: Phenylpropanoids	954
1.24.1 Introduction	954
1.24.2 New Enzyme Functions in Phenylpropanoid Metabolism	956
1.24.3 Flavonoids	962
1.24.4 Functional Genomics and Evolution of Phenylpropanoid/Flavonoid Biosynthesis	991
References	993
1.25 Alkaloids	1002
1.25.1 What Is an Alkaloid?	1002
1.25.2 Classes of Alkaloids	1002
1.25.3 Function and Diversity of Alkaloids	1003
1.25.4 Strategies for Elucidating Alkaloid Biosynthesis	1007
1.25.5 Benzylisoquinoline Alkaloid Biosynthesis	1012
1.25.6 Monoterpene Indole Alkaloid Biosynthesis	1017
1.25.7 Tropane Alkaloid Biosynthesis	1024
1.25.8 Purine Alkaloid Biosynthesis	1026
1.25.9 Conclusions and Outlook	1026
Glossary	1028
References	1028
e9780080453811v2	1034
Cover	1034
Title page	1037
Copyright page\r	1038
Contents	1039
Contributors	1041
Preface	1045
Introduction	1047
Editors-In-Chief	1051
Volume Editors	1053
2.01 Overview and Introduction	1059
2.02 Terrestrial Plants as a Source of Novel Pharmaceutical Agents	1063
2.02.1 Introduction	1064
2.02.2 Plants as a Source of Bioactive Compounds	1064
2.02.3 Anticancer Compounds	1064
2.02.4 Anti-HIV Agents	1080
2.02.5 Antimalarial Compounds	1083
2.02.6 Cardiovascular and Metabolic Diseases	1084
2.02.7 CNS Active Agents	1087
2.02.8 Outlook and Future Prospects	1090
References	1090
2.03 Marine Macroalgal Natural Products	1099
2.03.1 Introduction	1099
2.03.2 Isoprenoids	1100
2.03.3 Fatty Acid and Polyketide Metabolites	1109
2.03.4 Shikimate Metabolites	1113
2.03.5 Nonribosomal Peptide Metabolites	1114
2.03.6 Alkaloid Metabolites	1115
2.03.7 Glycolipids	1117
2.03.8 Conclusion	1119
Acknowledgments	1119
Abbreviations	1119
Nomenclature	1120
References	1120
2.04 Insect Natural Products	1125
2.04.1 Introduction	1125
2.04.2 Challenges in Arthropod Natural Products Chemistry	1128
2.04.3 Terpenoids	1129
2.04.4 Fatty Acid and Other Polyacetate Derivatives	1136
2.04.5 Polyketides	1141
2.04.6 Alkaloids and Amines	1143
2.04.7 Nucleoside Derivatives	1157
2.04.8 Miscellaneous Compounds	1158
2.04.9 Outlook	1159
References	1161
2.05 Terrestrial Microorganisms – Filamentous Bacteria	1167
2.05.1 Introduction	1167
2.05.2 Historical Bacterial Metabolites	1168
2.05.3 Newer Compounds or Compounds with Recently Described Mechanism of Action	1174
Abbreviations	1192
References	1192
2.06 The Natural Products Chemistry of Cyanobacteria	1199
2.06.1 Introduction	1200
2.06.2 Trends in the Structures of Cyanobacterial Natural Products	1201
2.06.3 Fatty Acid Derivatives from Cyanobacteria	1208
2.06.4 Terpenes	1211
2.06.5 Saccharides and Glycosides	1212
2.06.6 Peptides	1216
2.06.7 Polyketides	1223
2.06.8 Lipopeptides	1227
2.06.9 Conclusion	1240
Acknowledgments	1241
References	1241
2.07 Myxobacteria – Unique Microbial Secondary Metabolite Factories	1247
2.07.1 Myxobacteria as Producers of Bioactive Secondary Metabolites	1247
2.07.2 Approaches to Exploring the Biosynthetic Potential of Myxobacteria	1250
2.07.3 Biosynthesis of Myxobacterial Secondary Metabolites at the Molecular Level	1253
2.07.4 Deciphering Regulatory Mechanisms of Secondary Metabolism to Increase Productivity	1269
2.07.5 Biotechnological Strategies to Generate Modified Compounds	1272
2.07.6 Conclusions	1276
Acknowledgments	1276
References	1276
2.08 Natural Product Diversity from Marine Fungi	1281
2.08.1 Introduction	1281
2.08.2 Biology of Marine-Derived Fungi	1281
2.08.3 Natural Product Chemistry of Marine-Derived Fungi	1284
2.08.4 Conclusions	1315
Glossary	1315
References	1316
2.09 Bioactive Metabolites from Marine Dinoflagellates	1321
2.09.1 Introduction	1322
2.09.2 Amphidinium sp.	1322
2.09.3 Alexandrium sp.	1352
2.09.4 Dinophysis sp.	1353
2.09.5 Durinskia sp.	1354
2.09.6 Gambierdiscus toxicus	1354
2.09.7 Karenia sp.	1358
2.09.8 Karlodinium veneficum	1360
2.09.9 Ostreopis siamensis	1361
2.09.10 Prorocentrum sp.	1362
2.09.11 Protoceratium reticulatum	1365
2.09.12 Symbiodinium sp.	1368
2.09.13 Biosynthesis of Dinoflagellate Polyketides	1373
2.09.14 Prospects	1376
Glossary	1377
References	1377
2.10 Marine Invertebrates: Sponges	1385
2.10.1 Introduction	1386
2.10.2 Structure and Bioactivities of Metabolites Characteristic to Marine Sponges	1387
2.10.3 Sponge Metabolites as Drug Leads	1410
2.10.4 Roles of Sponge Metabolites in Marine Ecosystems	1413
2.10.5 Conclusions	1414
Abbreviations	1415
2.11 The Natural Products Chemistry of the Gorgonian Genus Pseudopterogorgia (Octocorallia: Gorgoniidae)	1421
2.11.1 Introduction	1421
2.11.2 Natural Products from Pseudopterogorgia spp.	1425
2.11.3 Aspects of Diterpenoid Biosynthesis and Chemical Ecology	1466
2.11.4 Selected Synthetic Transformations Suggesting Plausible Biogenetic Relationships between Different Families of Pseudopterogorgia Diterpenes	1470
2.11.5 Summary and Conclusions	1473
Acknowledgments	1479
Abbreviations	1479
References	1480
2.12 Exploiting Genomics for New Natural Product Discovery in Prokaryotes	1487
2.12.1 Introduction	1487
2.12.2 Overview of the Genetics and Enzymology of Natural Product Biosynthesis	1488
2.12.3 Development of Bioinformatics Tools for Natural Product Discovery by Genome Mining	1492
2.12.4 Experimental Strategies for the Isolation of New Natural Products by Genome Mining	1500
2.12.5 Concluding Remarks	1507
Abbreviations	1509
References	1509
2.13 Unlocking Environmental DNA Derived Gene Clusters Using a Metagenomics Approach	1513
2.13.1 Introduction	1513
2.13.2 Methodologies	1515
2.13.3 Type II PKS KS from Soil Multigenomic DNA	1518
2.13.4 Molecules and Their Biosynthetic Genes Isolated from Metagenomic Libraries	1520
2.13.5 Conclusions	1528
References	1529
2.14 The Chemistry of Symbiotic Interactions	1533
2.14.1 Introduction	1533
2.14.2 Protists	1534
2.14.3 Brown Algae	1535
2.14.4 Green Plants	1535
2.14.5 Fungi	1544
2.14.6 Sponges	1546
2.14.7 Cnidarians	1550
2.14.8 Arthropods	1553
2.14.9 Nematodes	1557
2.14.10 Flatworms	1558
2.14.11 Bryozoans	1558
2.14.12 Molluscs	1559
2.14.13 Tunicates	1559
2.14.14 Conclusions	1562
Abbreviations	1562
References	1563
2.15 Natural Peptide Toxins	1569
2.15.1 Introduction	1569
2.15.2 Cone Snails: Distribution, Diversity, Behavior, Feeding, and Defense	1570
2.15.3 Molecular Diversity of Cone Snail Venom	1571
2.15.4 Neuropharmacology of Cone Snail Toxins	1575
2.15.5 Structure and Activity of Cone Snail Toxins	1580
2.15.6 Cone Snail Toxins as Therapeutics and Drug Leads	1581
2.15.7 Sea Anemones: Distribution, Diversity, Behavior, Feeding, and Defense	1584
2.15.8 Sea Anemone Venom	1585
2.15.9 Structure and Activity of Sea Anemone Toxins	1586
2.15.10 Sea Anemone Toxins as Insecticides	1589
2.15.11 Conclusions	1590
References	1591
2.16 Cyanobactins – Ubiquitous Cyanobacterial Ribosomal Peptide Metabolites	1597
2.16.1 Introduction	1597
2.16.2 Cyanobactin Structures	1597
2.16.3 Sources and Symbiosis	1599
2.16.4 Shape and Metal Binding	1603
2.16.5 Bioactivity	1605
2.16.6 Total Synthesis	1606
2.16.7 Biosynthesis	1606
2.16.8 Ecology and Purpose	1610
2.16.9 Genome Mining and Modification	1611
2.16.10 Summary and Conclusions	1612
Acknowledgment	1612
References	1612
2.17 The Role of Synthesis and Biosynthetic Logic	1617
2.17.1 Introduction	1617
2.17.2 Chemoenzymatic Approaches to Pikromycin Synthesis	1619
2.17.3 Chemoenzymatic Approaches to Tyrocidine Synthesis	1624
2.17.4 Chemoenzymatic Approaches to Cryptophycin Synthesis	1628
2.17.5 Conclusions	1633
Abbreviations	1634
References	1634
2.18 Missasigned Structures: Case Examples from the Past Decade	1639
2.18.1 Introduction	1639
2.18.2 Structure Diversity of Marine Natural Products	1643
2.18.3 Misassigned Marine Natural Products	1643
2.18.4 Difficulties of Molecular Formula Assignments	1643
2.18.5 Difficulties in Assembling Planar Structures	1661
2.18.6 Completion of Structure Elucidation	1673
2.18.7 Conclusions	1676
Abbreviations	1676
References	1676
2.19 Natural Products of Therapeutic Importance	1681
2.19.1 Introduction	1681
2.19.2 Anti-infectives	1682
2.19.3 Anticholestemics	1694
2.19.4 Microbial Products in Cancer	1697
2.19.5 Nonmicrobial Products in Cancer	1702
2.19.6 Summary and Future Prospects	1703
References	1704
2.20 Natural Products as Probes of Selected Targets in Tumor Cell Biology and Hypoxic Signaling	1709
2.20.1 Introduction	1709
2.20.2 Organelle Function and Protein Stability	1711
2.20.3 Oxygen-Regulated Cell Signaling – Interactions between Cellular Processes	1731
2.20.4 Conclusions and Future Directions	1736
Acknowledgments	1736
References	1736
e9780080453811v3	1743
Cover	1743
Title page	1746
Copyright page	1747
Contents	1748
Contributors	1750
Preface	1754
Introduction	1756
Editors in Chief	1760
Volume Editors	1762
3.01 Overview and Introduction	1768
3.01.1 Biodiversity and Chemodiversity	1768
3.01.2 Biodiscovery	1769
3.01.3 Traditional Knowledge	1769
3.01.4 Food and Health	1769
3.01.5 Supply of Natural Products	1770
3.01.6 Chemistry of Some Common Plants and Related Products	1770
3.01.7 Model Plant and the Future	1770
References	1771
3.02 Natural Products as Lead Sources for Drug Development	1772
3.02.1 Introduction – A Historical Perspective	1772
3.02.2 Natural Product Properties	1776
3.02.3 Chemical Space	1781
3.02.4 Natural Product-Based Libraries	1786
3.02.5 Natural Product Drug Development	1794
3.02.6 Natural Products as Source for Leads and Clinical Candidates	1800
3.02.7 Conclusion and Outlook	1805
References	1807
3.03 Topical Chemical Space Relation to Biological Space	1814
3.03.1 Introduction	1814
3.03.2 Chemical Space	1816
3.03.3 Biological Space	1826
3.03.4 Comparing Chemical and Biological Space	1833
3.03.5 Examples of Studies Pursued	1835
3.03.6 Conclusions and Future Prospects	1842
Acknowledgments	1843
References	1843
3.04 The NAPRALERT Database as an Aid for Discovery of Novel Bioactive Compounds	1848
3.04.1 Introduction	1848
3.04.2 Relational Search Strategies	1855
3.04.3 Summary and Future Prospects	1857
3.04.4 NAPRALERT in Perspective	1860
References	1860
3.05 Plant Diversity from Brazilian Cerrado and Atlantic Forest as a Tool for Prospecting Potential Therapeutic Drugs	1862
3.05.1 Introduction	1862
3.05.2 Main Biomes of Brazil	1865
3.05.3 Development of the Brazilian Natural Products Chemistry	1868
3.05.4 Exploring New Approaches for Natural Product Drug Discovery in the Biota/FAPESP: Current Status of Bioprospecting in Brazil	1875
3.05.5 Search for Bioactive Secondary Metabolites from Brazilian Plant Species	1876
3.05.6 Final Remarks and Conclusions	1895
References	1896
3.06 Nature as Source of Medicines; Novel Drugs from Nature; Screening for Antitumor Activity	1902
3.06.1 Introduction	1903
3.06.2 Nature’s Continuing Role in Drug Discovery	1904
3.06.3 Why Nature?	1904
3.06.4 Nature as a Source of Molecular and Mechanistic Diversity in Cancer Chemotherapy	1915
3.06.5 Summary and Future Prospects	1934
References	1934
3.07 The Identification of Bioactive Natural Products by High Throughput Screening (HTS)	1944
3.07.1 Introduction	1944
3.07.2 Biota Collection	1945
3.07.3 Preparation of Natural Product Extracts for High-Throughput Screening	1946
3.07.4 Logistics	1947
3.07.5 Preparation of Plates for High-Throughput Screening	1947
3.07.6 High-Throughput Screening	1948
3.07.7 The Target	1948
3.07.8 The Assay	1948
3.07.9 Essential Components for a Good HTS Assay	1949
3.07.10 Technology	1950
3.07.11 High-Content Screening	1952
3.07.12 Natural Product High-Throughput Screening	1953
3.07.13 Isolation of Bioactive Natural Products	1955
3.07.14 Small-Scale Bioprofiling	1957
3.07.15 Scale-Up Purification	1958
3.07.16 Structure Determination	1959
3.07.17 Automated Structure Determination	1962
3.07.18 Converting a Natural Product Hit into a Drug	1962
References	1965
3.08 Natural Products Drug Discovery	1972
3.08.1 Introduction	1972
3.08.2 The Current Pharmaceutical Scenario	1973
3.08.3 Why Natural Products Are Intrinsically Useful for Drug Discovery	1974
3.08.4 Possible Reasons for the Current Downsizing of Natural Discovery	1981
3.08.5 Strategies in Natural Products Drug Discovery	1990
3.08.6 Conclusions	1998
References	1999
3.09 Natural Product-Based Biopesticides for Insect Control	2004
3.09.1 Introduction	2004
3.09.2 Commercial Insecticides of Plant Origin	2006
3.09.3 New Insecticide Sources	2011
3.09.4 Sustainable Production: Culture Methods	2026
3.09.5 The New Biopesticide Market	2028
3.09.6 Conclusions	2029
Abbreviations	2029
3.10 Natural Products as Sweeteners and Sweetness Modifiers	2036
3.10.1 Introduction	2036
3.10.2 Commercially Used Highly Sweet Natural Products	2037
3.10.3 Discovery of Natural Sweeteners	2041
3.10.4 Structural Types of Highly Sweet Natural Products	2043
3.10.5 Naturally Occurring Sweetness Inducers	2063
3.10.6 Naturally Occurring Triterpenoid Sweetness Inhibitors	2065
3.10.7 Sensory Evaluation of Natural Products for Sweetness and Sweetness-Modifying Properties	2071
3.10.8 Interactions of Natural Products at the Sweet Receptor	2073
3.10.9 Conclusions	2074
Abbreviations	2075
References	2076
3.11 Chemistry of Cosmetics	2084
3.11.1 Introduction	2084
3.11.2 History of Cosmetics and Natural Products	2084
3.11.3 Pharmaceutical Affairs Law in Japan and Its Relevance to Natural Products	2086
3.11.4 Skin-Whitening Cosmetics	2089
3.11.5 Antiaging Cosmetics	2094
3.11.6 Hair Growth Promoters	2100
3.11.7 Plant Cell/Tissue Culture Technology for Natural Produ 3.11.7 Plant Cell/Tissue Culture Technology for Natural Products in cosmeticcs\r	2104
3.11.8 Conclusion	2113
Abbreviations	2113
References	2114
3.12 Ethnopharmacology and Drug Discovery	2118
3.12.1 Introduction	2118
3.12.2 ‘Old’ Drugs – New Medicines	2119
3.12.3 Today’s Core Challenges	2141
3.12.4 Conclusion: People, Plants, and the Future of Medicines	2143
Abbreviations	2144
References	2144
3.13 Chinese Traditional Medicine	2150
3.13.1 Introduction	2150
3.13.2 Radix et Rhizoma Notoginseng (Sanqi, Tianqi, or Sanchi)	2154
3.13.3 Radix et Rhizoma Salviae Miltiorrhizae (Danshen)	2154
3.13.4 Ganoderma (Lingzhi)	2165
3.13.5 Radix et Rhizoma Glycyrrhizae (Licorice, Gancao)	2169
3.13.6 Herba Epimedii (Yinyanghuo)	2177
3.13.7 Flos Carthami (Honghua)	2177
3.13.8 Radix Isatidis (Banlangen)	2177
3.13.9 Radix Astragali (Huangqi)	2219
3.13.10 Herba Cistanches (Roucongrong)	2219
3.13.11 Gamboge (Tenghuang)	2219
3.13.12 Conclusion	2226
Glossary	2232
Abbreviation	2232
References	2232
3.14 Ayurveda in Modern Medicine: Development and Modification of Bioactivity	2246
3.14.1 Introduction	2246
3.14.2 Plant-Based Pharmaceuticals from Ayurveda	2248
3.14.3 Techniques for Development of Bioactivity of Ayurvedic Medicines	2258
3.14.4 Further Development from Phytochemical Leads	2261
3.14.5 Formulation in Ayurveda and Its Value Addition	2262
3.14.6 Quality Control	2265
3.14.7 Safety of Ayurvedic Preparations	2267
3.14.8 Ongoing Research in India on Ayurveda	2268
3.14.9 Conclusion	2268
Acknowledgment	2271
Abbreviations	2271
References	2271
3.15 Biologically Active Compounds in Food Products and Their Effects on Obesity and Diabetes	2276
3.15.1 Introduction	2277
3.15.2 Some Basic Aspects of Food Composition	2278
3.15.3 The Regulatory Categories Conventional Foods, Functional Foods,and Dietary Supplements	2279
3.15.4 Obesity: From Prevention to Metabolic Complications	2281
3.15.5 Natural Compounds in Weight Management and Diabetes – Introduction and Classification	2287
3.15.6 Natural Compounds and Preparations for Appetite Regulation	2288
3.15.7 Natural Compounds and Preparations Claiming to Affect Fat Absorption	2294
3.15.8 Natural Compounds Affecting Lipid Metabolism or Energy Expenditure	2295
3.15.9 Natural Compounds in Type 2 Diabetes	2298
3.15.10 Nutrigenomics – Finding Effects, Pathways, and New Molecules	2303
3.15.11 Conclusions	2306
Abbreviations	2306
References	2307
3.16 Chemistry of Flavonoid-Based Colors in Plants	2314
3.16.1 Introduction	2315
3.16.2 Color Variation Owing to Anthocyanin Structure	2322
3.16.3 Anthocyanin Localization in Plant Tissue	2347
3.16.4 Colors of Aurones and Chalcones	2349
3.16.5 Biosynthesis of Flavonoids	2355
3.16.6 Functions of Flavonoid Pigments in Plants	2358
3.16.7 Anthocyanin Production	2367
Glossary	2370
References	2371
3.17 Production of Pharmaceuticals by Plant Tissue Cultures	2382
3.17.1 Introduction	2382
3.17.2 Methods of Plant Tissue Culture	2383
3.17.3 Production of Pharmaceuticals by Plant Tissue Culture	2388
3.17.4 Perspectives	2391
Abbreviations	2391
References	2391
3.18 Plant Secondary Metabolism Engineering: Methods, Strategies, Advances, and Omics	2396
3.18.1 Introduction	2396
3.18.2 Techniques for the Genetic Manipulation of Plants	2399
3.18.3 Strategies for the Genetic Engineering of Secondary Metabolic Pathways	2401
3.18.4 Metabolic Engineering of Plant Biosynthetic Networks	2408
3.18.5 Influences of Omics Technologies on Metabolic Engineering of Plants	2425
3.18.6 Future Directions	2428
Acknowledgments	2429
References	2429
3.19 Biotransformation of Monoterpenoids	2436
3.19.1 Introduction	2436
3.19.2 Metabolic Pathways of Monoterpenoids	2437
3.19.3 Mosquitocidal and Knockdown Activity	2556
3.19.4 Antimicrobial Activity	2556
3.19.5 Microbial Transformation of Terpenoids as Unit Reaction	2557
References	2560
3.20 Biotransformation of Sesquiterpenoids	2570
3.20.1 Introduction	2570
3.20.2 Biotransformation of Sesquiterpenoids by Microorganisms	2570
3.20.3 Biotransformation of Sesquiterpenoids by Mammals, Insects, and Cytochrome P-450	2648
References	2654
3.21 Biotransformation of Di- and Triterpenoids, Steroids, and Miscellaneous Synthetic Substrates	2660
3.21.1 Biotransformation of Di- and Triterpenoids and Steroids	2660
3.21.2 Biotransformation of Ionones, Damascones, and Adamantanes	2682
3.21.3 Biotransformation of Aromatic Compounds	2690
3.21.4 Biotransformation of Cyclohexane Derivatives and Other Selected Synthetic Compounds by Microorganisms	2713
Acknowledgments	2728
References	2728
3.22 Beer Flavor	2734
3.22.1 Introduction	2735
3.22.2 Hop Chemistry	2741
3.22.3 Hop Processing	2751
3.22.4 Beer Flavors and Off-Flavors	2753
3.22.5 Beer Flavor Deterioration	2758
3.22.6 Microbiological Deterioration	2761
3.22.7 Prospects	2761
Acknowledgments	2761
References	2761
3.23 Chemistry of Tea	2766
3.23.1 Introduction	2767
3.23.2 Manufacture of Tea	2767
3.23.3 Constituents of Tea and Chemical Reactions during Manufacture	2769
3.23.4 Extraction and Storage of Tea	2786
3.23.5 Products	2788
3.23.6 Potential Health Effects of Tea, Its Flavonoids, and Theanine	2788
3.23.7 Analytical Section	2791
Abbreviations	2793
Nomenclature	2794
References	2794
3.24 Chemistry of Cannabis	2800
3.24.1 An Introduction to the Cannabis Plant	2801
3.24.2 Cannabinoids	2806
3.24.3 Sites and Mechanisms of Action of Cannabinoids	2816
3.24.4 Biological Effects of the Cannabinoids	2822
3.24.5 Noncannabinoid Constituents of Cannabis	2827
3.24.6 Cannabis as a Medicine	2835
3.24.7 Practical Aspects of Cannabis Research	2839
3.24.8 Conclusion	2841
Acknowledgements	2844
References	2844
3.25 Chemistry of Coffee	2852
3.25.1 Overview	2852
3.25.2 Botany	2856
3.25.3 Chemistry Components and Processes	2861
3.25.4 Conclusions	2880
3.26 Chemistry of Wine	2886
3.26.2 Chemistry Associated with Wine Fermentations	2888
3.26.3 Chemistry of Aroma Compounds in Wine	2893
3.26.4 Chemistry of Phenolic Compounds in Wine	2901
3.26.5 Conclusion and Future Prospects	2930
Abbreviations	2930
Nomenclature	2931
References	2931
3.27 Trees: A Remarkable Biochemical Bounty	2940
3.27.1 Trees: Human Reliance on Arborescent Life	2941
3.27.2 Evolution of the Woody Growth Habit: Land Colonization and Adaptation	2945
3.27.3 Wood Anatomy and Cellular/Tissue Function: The Living and the Dead	2958
3.27.4 Nature’s Phytochemical Bounty and Tree Biochemical Diversity	2994
3.27.5 Concluding Remarks	3049
Acknowledgments	3051
References	3051
3.28 The Chemistry of Arabidopsis thaliana	3064
3.28.1 Introduction	3064
3.28.2 Secondary Metabolites of Arabidopsis thaliana	3066
3.28.3 Ecological Roles of Secondary Metabolites of Arabidopsis thaliana	3074
3.28.4 Conclusions	3078
References	3079
e9780080453811v4	3084
Cover	3084
Title Page	3087
Copyright Page	3088
Contents	3089
Contributors	3091
Preface	3095
Introduction	3097
Editors in Chief	3101
Volume Editors	3103
4.01 Overview and Introduction	3109
4.01.1 Scope of Volume 4	3109
4.01.2 Comments on Progress in the Chemistry and Biology of Semiochemicals	3109
4.01.3 Future Perspectives in Chemical Ecology	3114
Acknowledgments	3114
Glossary	3114
References	3114
4.02 Plant Hormones	3117
4.02.1 Introduction	3120
4.02.2 Auxins	3121
4.02.3 Gibberellins	3132
4.02.4 Cytokinins	3145
4.02.5 Abscisic Acid	3161
4.02.6 Brassinosteroids	3175
4.02.7 Jasmonates and Oxylipins	3185
4.02.8 Ethylene	3195
4.02.9 Peptide Hormones in Plants	3199
4.02.10 Strigolactones	3204
References	3208
4.03 Insect Hormones	3235
4.03.1 Introduction	3235
4.03.2 Neuropeptides	3236
4.03.3 Moulting Hormone	3236
4.03.4 Juvenile Hormone	3247
4.03.5 Eicosanoids	3253
4.03.6 Conclusion	3255
Glossary	3255
References	3256
4.04 Pheromones of Terrestrial Invertebrates	3261
4.04.1 Introduction	3262
4.04.2 Pheromone Biology	3262
4.04.3 Isolation and Structure Elucidation	3264
4.04.4 Aromatic Compounds	3267
4.04.5 Unbranched Aliphatic Compounds	3271
4.04.6 Terpenes	3291
4.04.7 Propanogenins and Related Compounds	3304
4.04.8 Mixed Structures	3308
4.04.9 Other Structures	3313
References	3315
4.05 Pheromones in Vertebrates	3333
4.05.1 Introduction	3334
4.05.2 Pheromones in Ancient Vertebrates	3338
4.05.3 Pheromones in Advanced (Teleost) Fishes	3342
4.05.4 Pheromones in Amphibians	3348
4.05.5 Pheromones in Reptiles	3352
4.05.6 Pheromones in Birds	3353
4.05.7 Pheromones in Mammals	3354
4.05.8 Overview	3365
References	3366
4.06 Pheromones of Marine Invertebrates and Algae	3371
4.06.1 Introduction	3371
4.06.2 Algal Sex Pheromones	3371
4.06.3 Sperm Chemotaxis in Marine Invertebrates	3376
4.06.4 Sex Pheromones of Marine Invertebrates	3381
4.06.5 Alarm Pheromones	3384
4.06.6 Summary and Future Prospects	3385
References	3386
4.07 Cell-to-Cell Communications among Microorganisms	3391
4.07.1 Introduction	3392
4.07.2 Gamma-Butyrolactones in Streptomyces	3393
4.07.3 Signaling Molecules in High-GC Gram-Positive Bacteria	3403
4.07.4 Signaling Molecules in Low-GC Gram-Positive Bacteria	3406
4.07.5 Signaling Molecules in Gram-Negative Bacteria	3423
References	3438
4.08 Chemical Defence and Toxins of Plants	3447
4.08.1 Chemical Defense against Herbivores	3447
4.08.2 Antimicrobial Chemical Defense	3469
4.08.3 Phytotoxins	3479
References	3485
4.09 Chemical Defense and Toxins of Lower Terrestrial and Freshwater Animals	3495
4.09.1 Introduction	3495
4.09.2 Alveolata	3496
4.09.3 Porifera	3498
4.09.4 Cnidaria	3498
4.09.5 Platyhelminthes (Flatworms)	3499
4.09.6 Nemathelminthes: Nematoda	3499
4.09.7 Rotatoria (Rotifers)	3499
4.09.8 Nemertini	3499
4.09.9 Mollusca	3500
4.09.10 Annelida: Clitellata: Oligochaeta	3501
4.09.11 Annelida: Clitellata: Hirudinea	3502
4.09.12 Arthropoda: Onychophora	3502
4.09.13 Arthropoda: Tardigrada	3503
4.09.14 Arthropoda: Crustacea, Ostracoda	3503
4.09.15 Arthropoda: Crustacea, Decapoda	3503
4.09.16 Arthropoda: Crustacea, Amphipoda	3503
4.09.17 Arthropoda: Crustacea, Isopoda	3503
4.09.18 Arthropoda: Chelicerata, Scorpiones	3504
4.09.19 Arthropoda: Chelicerata, Pseudoscorpiones	3504
4.09.20 Arthropoda: Chelicerata, Acari (Mites)	3504
4.09.21 Arthropoda: Chelicerata, Opiliones	3506
4.09.22 Arthropoda: Chelicerata, Pedipalpi	3508
4.09.23 Arthropoda: Chelicerata, Araneae	3509
4.09.24 Arthropoda: Myriapoda: Opisthogoneata (Centipedes)	3510
4.09.25 Arthropoda: Myriapoda: Progoneata: Diplopoda (Millipedes) and Symphyla	3511
Acknowledgments	3514
References	3515
4.10 Toxins of Microorganisms	3519
4.10.1 Introduction	3519
4.10.2 Insecticides from Microorganisms	3520
4.10.3 Mycotoxins	3527
References	3557
4.11 Terrestrial Natural Products as Antifeedants	3565
4.11.1 Introduction	3565
4.11.2 Bioassays	3566
4.11.3 Plant Terpenes and Derivatives	3568
4.11.4 Alkaloids	3597
4.11.5 Phenylpropanoids	3598
4.11.6 Miscellaneous	3603
4.11.7 Feeding Deterrence in Higher Animals	3604
4.11.8 Conclusion	3605
References	3605
4.12 Marine Natural Products as Antifeedants	3611
4.12.1 Introduction	3611
4.12.2 Microorganisms	3613
4.12.3 Algae	3615
4.12.4 Sponges	3618
4.12.5 Coelenterates	3625
4.12.6 Ascidians	3629
4.12.7 Bryozoans	3631
4.12.8 Mollusks	3632
4.12.9 Other Marine Organisms	3640
4.12.10 Conclusions	3641
References	3641
4.13 Allelochemicals for Plant–Plant and Plant–Microbe Interactions	3647
4.13.1 Allelochemicals in Plant–Plant Interactions	3647
4.13.2 Allelochemicals in Plant–Microbe Interactions	3655
References	3666
4.14 Allelochemicals in Plant–Insect Interactions	3671
4.14.1 Introduction	3671
4.14.2 Host Selection	3672
4.14.3 Flower-Visiting and Foraging	3688
4.14.4 Insect–Plant Interface in Multitrophic Interactions	3693
References	3698
4.15 Human–Environment Interactions (1): Flavor and Fragrance	3703
4.15.1 Introduction	3704
4.15.2 Outline of the Flavor and Fragrance Industry	3704
4.15.3 Analytical Techniques	3709
4.15.4 Flavor and Fragrance of Natural Origin	3713
4.15.5 Perfumery (Fragrances)	3720
4.15.6 Flavor of Foodstuffs	3721
4.15.7 Human Interactions	3726
4.15.8 Outlook	3730
Abbreviations	3731
Nomenclature	3731
References	3731
4.16 Human–Environment Interactions – Taste	3739
4.16.1 Introduction	3740
4.16.2 Natural Products Associated with Sweetness	3741
4.16.3 Bitter-Tasting Natural Products	3752
4.16.4 Pungent Natural Products	3760
4.16.5 Astringent Natural Products	3764
4.16.6 Umami and Kokumi	3767
4.16.7 Sour and Salty Tastes	3770
4.16.8 Conclusion	3772
References	3772
e9780080453811v5	3781
Cover	3781
Title Page	3784
Copyright Page	3785
Contents	3786
Contributors	3788
Preface	3792
Introduction	3794
Editors in Chief	3798
Volume Editors	3800
5.01 Overview and Introduction	3806
5.02 Nonprotein L-Amino Acids	3810
5.02.1 Introduction	3810
5.02.2 Biosynthesis of Amino Acids	3811
5.02.3 Classification of Nonprotein Amino Acids	3817
Abbreviations	3868
References	3869
5.03 Novel Enzymes for Biotransformation and Resolution of Alpha-Amino Acids	3876
5.03.1 Introduction	3877
5.03.2 Amino Acid Oxidases	3877
5.03.3 Amino Acid Dehydrogenases	3881
5.03.4 Aminotransferases	3885
5.03.5 Lipases, Acylases, and Proteinases	3887
5.03.6 L-Amino Acid N-Acylases	3889
5.03.7 Hydantoinases and Carbamoylases	3890
5.03.8 Nitrilases, Nitrile Hydratases, and Amidases	3891
5.03.9 Concluding Remarks	3892
Nomenclature	3892
References	3893
5.04 1-Aminocyclopropane-1-Carboxylate Synthase, an Enzyme of Ethylene Biosynthesis	3896
5.04.1 Introduction	3896
5.04.2 Ethylene Biosynthesis in Higher Plants	3897
5.04.3 Ethylene Signal Transduction Pathway	3912
5.04.4 Ethylene Action	3915
Abbreviations	3920
References	3921
5.05 Specific and Nonspecific Incorporation of Selenium into Macromolecules	3926
5.05.1 Introduction	3926
5.05.2 Nonspecific Incorporation of Selenium into Macromolecules	3928
5.05.3 Specific Utilization of Selenium in Biology	3932
5.05.4 Summary	3947
Abbreviations	3947
References	3948
5.06 Protein Toxins from Bacteria	3954
5.06.1 Introduction: Bacterial Toxins – An Overview	3954
5.06.2 Potent Virulence Factors Directly Attack the Actin Cytoskeleton of Mammalian Cells: Actin-ADP-Ribosylating Toxins	3958
5.06.3 Introduction of a ‘Super’ Microbe	3963
5.06.4 Structural Commonalities/Differences among SEs and TSST-1	3965
5.06.5 Signal Transduction and Cell Responses Induced by SEs and TSST-1	3968
5.06.6 Animal Models: Surprise, Mice are Not Men!	3970
5.06.7 Strategic Countermeasures: An Eternal Battle between Man and Microbe	3971
5.06.8 Conclusions	3972
Abbreviations	3973
References	3973
5.07 Host Defense Peptides: Bridging Antimicrobial and Immunomodulatory Activities	3980
5.07.1 Introduction	3981
5.07.2 Defining Cationic Host Defense Peptides	3981
5.07.3 Host Defense Peptides Distribution and Class	3983
5.07.4 Host Defense Peptide Target Selection and Self-Promoted Uptake	3987
5.07.5 Host Defense Peptides and Cell Death	3992
5.07.6 Structure–Activity Relationship Studies of the Antimicrobial Activities of the Host Defense Peptides	3992
5.07.7 Bacterial Host Defense Peptide Resistance	3994
5.07.8 Direct Antimicrobial Activity of Host Defense Peptides In Vivo	3996
5.07.9 The Role of Peptides in Mammalian Immunity – The In Vivo Evidence	3997
5.07.10 Immunomodulatory Activities of Host Defense Peptides	3998
5.07.11 Host Defense Peptides and the Adaptive Immune Response	4003
5.07.12 Structure–Activity Relationship Studies of Host Defense Peptides – Immunomodulatory Activities	4004
5.07.13 Therapeutic Applications of Host Defense Peptides	4005
5.07.14 Strategies for Host Defense Peptide Selection and Optimization	4009
5.07.15 Conclusions	4011
Abbreviations	4013
References	4014
5.08 Biosynthesis and Mode of Action of Lantibiotics	4022
5.08.1 Introduction	4022
5.08.2 Overview of Lantibiotic Structures	4025
5.08.3 Lantibiotic Biosynthesis	4026
5.08.4 Biological Activities of Lantibiotics	4046
5.08.5 Potential Applications of Lantibiotics	4050
5.08.6 Lantibiotic Engineering and Structure–Activity Studies	4050
5.08.7 Outlook	4053
Abbreviations	4053
References	4054
5.09 Plant Peptide Toxins from Nonmarine Environments	4062
5.09.1 Introduction	4062
5.09.2 Plant Defense Peptides	4064
5.09.3 Plant Peptide Toxins in Biotechnology and Pharmaceutical Applications	4083
5.09.4 Concluding Remarks	4085
References	4085
5.10 Therapeutic Value of Peptides from Animal Venoms	4092
5.10.1 Introduction	4092
5.10.2 Peptides from Scorpion Venoms	4092
5.10.3 Peptides from Snake Venoms	4095
5.10.4 Peptides from Sea Anemone Venoms	4096
5.10.5 Peptides from Spider Venoms	4097
5.10.6 Peptides from Cone Snail Venoms	4099
5.10.7 Peptides from Insect Venoms	4101
5.10.8 Peptides from Worm Venoms	4102
5.10.9 Other Venom Peptides and Toxins of Interest	4102
Abbreviations	4103
References	4104
5.11 Signal Transduction in Gram-Positive Bacteria by Bacterial Peptides	4110
5.11.1 Introduction	4110
5.11.2 Peptide Pheromone Dependent Signaling Systems in Bacteriocin Production	4110
5.11.3 The Signaling Pathway of Plantaricin C11 System and Other Class II Bacteriocins	4112
5.11.4 Peptide-Dependent Regulation of Lantibiotics	4115
5.11.5 Induction of Competence for Natural Genetic Transformation in Streptococci	4115
5.11.6 Virulence Regulation by Peptide Signaling in Staphylococcus aureus	4117
5.11.7 Virulence Regulation in Enterococcus faecalis by Peptide Signaling	4120
5.11.8 Peptide Signaling Regulation of Carbohydrate Metabolism in Lactobacillus plantarum	4121
5.11.9 agr-Like Quorum Sensing Gene Clusters Identified in Other G+ Bacteria	4121
5.11.10 Pheromone-Responding Conjugative Plasmids in Enterococcus faecalis	4121
5.11.11 Perspectives	4122
Abbreviations	4123
References	4123
5.12 A New Generation of Artificial Enzymes: Catalytic Antibodies or ‘Abzymes’	4128
5.12.1 Introduction	4128
5.12.2 The Concept of Catalytic Antibodies or Abzymes	4129
5.12.3 Catalytic Antibodies Generated against Transition State Analogues	4130
5.12.4 ‘Bait and Switch’ Strategy	4141
5.12.5 Reactive Immunization	4142
5.12.6 Antibodies Using Cofactors	4147
5.12.7 Anti-Idiotypic Antibodies	4149
5.12.8 Other Approaches	4151
5.12.9 Conclusion	4152
References	4154
5.13 Recent Progress on Understanding Ribosomal Protein Synthesis	4158
5.13.1 Introduction	4158
5.13.2 Ribosome Structure	4161
5.13.3 Ribosomal Aminoacyl-tRNA Selection	4164
5.13.4 Peptide Bond Formation	4170
5.13.5 Translocation	4174
5.13.6 Termination	4177
5.13.7 Ribosomal Incorporation of Non-Natural Amino Acids	4180
5.13.8 Conclusion	4183
References	4184
5.14 Glutaminyl-tRNA and Asparaginyl-tRNA Biosynthetic Pathways	4188
5.14.1 Introduction	4189
5.14.2 Nonenzymatic Deamidation of Glutaminyl and Asparaginyl Residues in Protein	4192
5.14.3 Introduction of Glutamine to the Genetic Code	4193
5.14.4 Partners of Direct and Indirect Pathways of Asn-tRNA Biosynthesis and their Reaction Mechanism	4202
5.14.5 Evolution of the Enzymes Involved in Gln-tRNA and in Asn-tRNA Biosynthesis	4219
5.14.6 Inhibitors of Enzymes Involved in Gln-tRNA and Asn-tRNA Biosynthesis as Tools for Structural and Mechanistic Studies and Leads for Therapeutic Applications	4221
5.14.7 Conclusions	4228
Abbreviations	4228
Nomenclature	4229
References	4230
5.15 Posttranslational Modification of Proteins	4238
5.15.1 Introduction	4238
5.15.2 Phosphorylation and Sulfation	4241
5.15.3 Cysteine Disulfide Formation	4248
5.15.4 Methylation	4249
5.15.5 N-Acetylation	4252
5.15.6 Hydroxylation	4253
5.15.7 Glycosylation	4254
5.15.8 ADP-Ribosylation	4255
5.15.9 Prenylation	4256
5.15.10 Biotin, Lipoate, and Phosphopantetheine Tethering	4260
5.15.11 Conclusions	4267
Acknowledgments	4268
Abbreviations	4268
References	4270
5.16 Collagen Formation and Structure	4274
5.16.1 Introduction	4275
5.16.2 Molecular Structure and Biological Function of Collagen Types	4275
5.16.3 Biosynthesis of Collagen Molecules	4298
5.16.4 Collagen Peptides as a Model of the Triple Helix	4307
5.16.5 Collagen Chain Selection, Trimerization, and Triple Helix Formation	4311
5.16.6 Atomic Structures of the Collagen Triple Helix and Collagen Trimerization Domains	4315
5.16.7 Other Collagens	4323
References	4323
5.17 Lipidation of Peptides and Proteins	4336
5.17.1 Introduction	4336
5.17.2 Synthesis of Lipidated Peptides	4343
5.17.3 Synthesis of Lipidated Proteins	4371
5.17.4 Conclusions	4383
Acknowledgments	4383
Abbreviations	4383
References	4385
5.18 Genetic Incorporation of Unnatural Amino Acids into Proteins	4392
5.18.1 Introduction	4392
5.18.2 Methodology	4393
5.18.3 Applications	4406
5.18.4 Future Developments	4418
Glossary	4419
References	4420
5.19 Nonribosomal Peptide Synthetases	4424
5.19.1 Introduction: Peptide-Based Natural Products	4425
5.19.2 Nonribosomal Peptide Natural Products	4426
5.19.3 The Canonical Enzymology of NRPS Modules	4426
5.19.4 Classes of Nonribosomal Peptide Synthetases	4428
5.19.5 Noncanonical Features of NRPSs	4437
5.19.6 Additional Enzyme Domains that Function in the NRPS Assembly Line	4440
5.19.7 Structure and Chemistry of NRPS Domains	4443
5.19.8 Pathways to Nonproteinogenic Amino Acids Incorporated into NRP Natural Products	4449
5.19.9 Chemical Approaches Toward Mechanistic Probes and Inhibitors of NRPS Enzymes	4453
5.19.10 Conclusions	4455
References	4456
5.20 The Properties, Formation, and Biological Activity of 2,5-Diketopiperazines	4462
5.20.1 Introduction	4463
5.20.2 What Are Cyclic Dipeptides?	4464
5.20.3 Historical Aspects and Naturally Occurring Diketopiperazines	4465
5.20.4 Structural Types and Classes of Cyclic Dipeptides	4465
5.20.5 Properties of Diketopiperazines	4466
5.20.6 Structural Relevance	4470
5.20.7 Relevance of Amino Acids	4475
5.20.8 Formation of 2,5-Diketopiperazines	4480
5.20.9 Biological Relevance	4486
Glossary	4494
Abbreviations	4495
Nomenclature	4496
References	4497
5.21 Ubiquitin-Dependent Protein Degradation	4504
5.21.1 Discovery of the Ubiquitin–Proteasome Pathway	4505
5.21.2 The Ubiquitin–Proteasome Pathway	4506
5.21.3 Ubiquitin-Conjugating Enzymes: E1, E2, and E3	4507
5.21.4 Regulation of the Ubiquitin–Proteasome Pathway	4511
5.21.5 Combinatorial Coding of Specificity in Ubiquitin Conjugation	4514
5.21.6 The Proteasome	4515
5.21.7 Regulation of the Proteasome	4517
5.21.8 COP9 Signalosome	4519
5.21.9 Deubiquitinating Enzymes	4520
5.21.10 Ubiquitination and Endocytosis	4524
5.21.11 The Ubiquitin–Proteasome Pathway and Endoplasmic Reticulum-Associated Degradation	4528
5.21.12 The Ubiquitin–Proteasome Pathway and Transcription	4528
5.21.13 Ubiquitin-Like Proteins	4535
5.21.14 Unusual Linkages of Ubiquitin	4538
5.21.15 Ubiquitin and Signaling	4539
5.21.16 Physiological Functions of the Ubiquitin–Proteasome Pathway	4539
5.21.17 Diseases Associated with the Ubiquitin–Proteasome Pathway	4542
5.21.18 Future Perspectives	4547
Abbreviations	4547
References	4548
e9780080453811v6	4558
Cover	4558
Title page	4561
Copyright page	4562
Contents	4563
Contributors	4565
Preface	4569
Introduction	4571
Editors-In-Chief	4575
Volume Editors	4577
6.01 Overview and Introduction	4583
6.01.1 Introduction	4583
6.01.2 Overview	4583
6.02 Enzymatic Synthesis of Complex Carbohydrates	4587
6.02.1 Introduction	4587
6.02.2 Glycosidases	4590
6.02.3 Glycosynthases	4597
6.02.4 Glycosyltransferases	4605
6.02.5 Outlook	4629
Abbreviations	4630
Nomenclature	4631
6.03 New Strategies for Glycopeptide, Neoglycopeptide, and Glycoprotein Synthesis	4637
6.03.1 Introduction	4637
6.03.2 Synthesis of Glycopeptides	4640
6.03.3 Synthesis of Neoglycopeptide	4657
6.03.4 Glycoprotein Synthesis	4661
6.03.5 Conclusions	4666
Abbreviations	4666
6.04 Carbohydrate Vaccines	4673
6.04.1 Introduction	4673
6.04.2 Tumor-Associated Carbohydrate Antigens	4674
6.04.3 TACA-Based Cancer Vaccine Development	4676
6.04.4 Conclusion	4697
Acknowledgment	4698
6.05 MS-Based Glycoanalysis	4705
6.05.1 Introduction	4706
6.05.2 Diversity in Eukaryotic Protein Glycosylation	4707
6.05.3 Workflows in MS-Based Protein Glycosylation Analysis	4710
6.05.4 MS/MS Glycan Sequencing	4721
6.05.5 Targeted Glycomics, Glycoproteomics, and the Way Forward	4731
Abbreviations	4734
6.06 Glycoanalysis of Bacterial Glycome	4739
6.06.1 Introduction	4739
6.06.2 Protein Glycosylation	4740
6.06.3 Lipopolysaccharide	4741
6.06.4 Capsular Polysaccharides	4750
6.06.5 Conclusions	4751
Acknowledgments	4751
Abbreviations	4751
Nomenclature	4752
6.07 Chemical Glycobiology	4757
6.07.1 Introduction	4757
6.07.2 Synthetic Glycans with Biological Activity	4758
6.07.3 Chemoenzymatic Synthesis to Study Glycan Structure and Function	4769
6.07.4 Applications of Metabolic Oligosaccharide Engineering	4779
6.07.5 Covalently Trapping Glycan Interactions with Photocross-linkers	4786
Abbreviations	4799
6.08 Alkaloid Glycosidase Inhibitors	4807
6.08.1 Introduction	4807
6.08.2 Chemistry of Alkaloid Glycosidase Inhibitors	4808
6.08.3 Glycosidase Inhibition	4819
6.08.4 Biological Activity of Glycosidase Inhibitors	4821
6.08.5 Structure and Biosynthesis of N-Linked Glycoproteins	4822
6.08.6 Structure and Synthesis of Glycosphingolipids	4828
6.08.7 Therapeutic Activities of Glycosidase Inhibitors	4833
Abbreviations	4836
6.09 Molecular Probes for Protein Glycosylation	4843
6.09.1 Introduction	4843
6.09.2 Protein Glycosylation in Eukaryotes	4845
6.09.3 Protein Glycosylation in Prokaryotes	4850
6.09.4 Chemical Approaches toward Understanding Protein Glycosylation	4850
6.09.5 Production of Homogeneous Glycoproteins	4851
6.09.6 Chemical Probes for Perturbing Protein Glycosylation	4859
6.09.7 Global Analysis of Protein Glycosylation	4864
6.09.8 Microarray Platforms for Glycomics	4872
6.09.9 Conclusions and Future Perspectives	4873
Acknowledgments	4873
Nomenclature	4873
6.10 O Antigen Biosynthesis	4879
6.10.1 Introduction	4879
6.10.2 Biogenesis of O Antigen	4880
6.10.3 Future Prospects	4892
Acknowledgments	4892
6.11 Biosynthesis of Complex Mucin-Type O-Glycans	4897
6.11.1 Introduction	4897
6.11.2 Mucins	4898
6.11.3 Mucin-Type O-Glycans	4900
6.11.4 Functions of O-Glycans and Changes of O-Glycan Structures in Disease	4902
6.11.5 Biosynthesis of O-Glycans	4904
6.11.6 Structures and Mechanisms of Glycosyltransferases	4905
6.11.7 Initiation of O-Glycosylation	4906
6.11.8 Synthesis of Core 1	4908
6.11.9 Synthesis of Core 2	4909
6.11.10 Synthesis of Core 3	4913
6.11.11 Synthesis of Core 4	4914
6.11.12 Synthesis of Minor Core Structures	4915
6.11.13 Extension and Branching Reactions	4915
6.11.14 The \x023- and \x024-Gal-Transferase Families	4917
6.11.15 Sialyltransferases	4918
6.11.16 Fucosyltransferases	4921
6.11.17 Blood Group Transferases	4923
6.11.18 Sulfotransferases	4924
6.11.19 Future Needs and Directions	4925
Acknowledgments	4926
Abbreviations	4926
6.12 Bacterial Protein Glycosylation	4933
6.12.1 Introduction	4933
6.12.2 Protein N-Glycosylation and O-Glycosylation at a Glance	4934
6.12.3 General Protein N-Glycosylation System in Campylobacter jejuni	4935
6.12.4 Protein O-Glycosylation in Gram-Negative Bacteria	4937
6.12.5 Protein O-Glycosylation in Gram-Positive Bacteria	4949
6.12.6 Protein O-Mannosylation in Mycobacteria	4950
6.12.7 Challenges in the Study of Bacterial Protein Glycosylation	4951
6.12.8 Glycoengineering in Bacteria	4951
6.12.9 Concluding Remarks	4956
Abbreviations	4957
6.13 Structure and Biosynthesis of the Mycobacterial Cell Wall	4963
6.13.1 Introduction	4963
6.13.2 Peptidoglycan	4964
6.13.3 Arabinogalactan	4964
6.13.4 Phosphatidylinositol Mannoside, Lipomannan, Lipoarabinomannan, and Arabinomannan Structure	4965
6.13.5 Peptidoglycan Synthesis	4967
6.13.6 Biosynthesis of Arabinogalactan	4970
6.13.7 Biosynthesis of the Phosphatidylinositol Containing Phosphatidylinositol Mannosides, Lipomannans, and Lipoarabinomannans	4977
6.13.8 Mycobacterial Cell Envelope Ultrastructure	4979
Acknowledgment	4983
6.14 Structure, Biosynthesis, and Function\rof Glycosaminoglycans	4989
6.14.1 Introduction	4989
6.14.2 Heparan Sulfate and Heparin	4989
6.14.3 Chondroitin Sulfate and Dermatan Sulfate	5001
6.14.4 Other Glycosaminoglycans	5003
Acknowledgments	5004
Abbreviations	5004
6.15 Biochemistry and Molecular Biology of Glycogen Synthesis in Bacteria and Mammals and Starch Synthesis in Plants	5011
6.15.1 Introduction	5012
6.15.2 The Role of Glycogen and Starch	5013
6.15.3 Synthesis of Bacterial Glycogen and Plant Starch	5014
6.15.4 Properties of the Bacterial and Plant Enzymes Involved in the Synthesis of Glycogen and Starch	5016
6.15.5 Regulation of the Synthesis of Bacterial Glycogen and Starch	5018
6.15.6 Subcellular Localization of ADP-Glc PPase in Plants	5033
6.15.7 Crystal Structure of Potato Tuber ADP-Glc PPase	5033
6.15.8 Bacterial Glycogen Synthase	5034
6.15.9 Starch Synthases	5037
6.15.10 Branching Enzyme	5046
6.15.11 Other Enzymes Involved in Starch Synthesis	5051
6.15.12 Genetic Regulation of Bacterial Glycogen Synthesis	5052
6.15.13 Properties of the Glycogen Biosynthetic Enzymes of Mammals	5054
6.15.14 Regulation of Mammalian Glycogen Synthesis	5058
6.16 Celluloses	5075
6.16.1 Introduction	5075
6.16.2 Structures and States of Aggregation	5076
6.16.3 Structural Studies	5079
6.16.4 New Spectroscopic Methods	5080
6.16.5 The Need for a New Paradigm	5086
6.16.6 Further Studies of Structures in Cellulose	5091
6.16.7 Computational Modeling	5096
6.16.8 Polymorphy in Cellulose	5098
6.16.9 Chemical Implications of Structure	5099
6.16.10 Cellulose Structures in Summary	5102
6.16.11 Cellulose Chemistry	5103
Glossary	5117
Abbreviations	5118
6.17 Vascular Plant Lignification: Biochemical/Structural Biology Considerations of Upstream Aromatic Amino Acid and Monolignol Pathways	5123
6.17.1 Introduction	5124
6.17.2 Biochemistry of Phenylalanine and Tyrosine Formation in Vascular Plants: The Entry Point to Phenylpropanoid Metabolism and to Lignification	5125
6.17.3 Structural Biology Considerations for the Monolignol-F Biosynthetic Pathway Steps	5139
6.17.4 Conclusions	5177
Acknowledgments	5177
6.18 Proanthocyanidins: Chemistry and Biology	5187
6.18.1 Introduction	5187
6.18.2 The Naming Convention	5188
6.18.3 Flavans, Flavan-3-ols, Flavan-4-ols, and Flavan-3,4-diols as Building\rBlocks for Proanthocyanidins	5190
6.18.4 Proanthocyanidins	5204
6.18.5 Nonproanthocyanidins with Flavan or Flavan-3-ol Constituent Units	5233
6.18.6 Conformation of Proanthocyanidins	5233
6.18.7 HPLC–MS Analysis of Proanthocyanidins	5235
6.18.8 Effects of Proanthocyanidins on Human Health and Nutrition	5235
6.19 Nucleoside Analogues	5245
6.19.1 Introduction	5245
6.19.2 Stereoelectronic Factors that Affect Nucleic Acid Stability	5247
6.19.3 2-O-Methyl and 29-Fluoro Modification	5248
6.19.4 Pseudouridine	5250
6.19.5 Base-Modified Nucleosides in tRNA	5254
6.19.6 Summary and Future Prospects	5260
6.20 RNA Modifying Enzymes	5265
6.20.1 Introduction	5265
6.20.2 Methylation	5266
6.20.3 Thiolation and Selenation	5278
6.20.4 Deamination	5282
6.20.5 Alkylation	5287
6.20.6 Reduction/Oxidation	5291
6.20.7 Transglycosylation	5294
6.20.8 Complex Modifications	5305
6.20.9 Conclusions and Perspectives	5313
Abbreviations	5315
6.21 Riboswitches	5325
6.21.1 Introduction	5325
6.21.2 Mechanisms of Gene Regulation	5326
6.21.3 Regulatory Signals	5328
6.21.4 Structure of Riboswitch RNAs	5335
6.21.5 Riboswitches and Gene Identification	5336
6.21.6 Using Riboswitches to Control Gene Expression	5337
6.21.7 Perspectives and Future Directions	5338
Glossary	5339
e9780080453811v7	5343
Cover	5343
Title Page	5346
Copyright Page	5347
Contents	5348
Contributors	5350
Preface	5354
Introduction	5356
Editors in Chief	5360
Volume Editors	5362
7.01 Overview and Introduction	5368
7.02 Riboflavin Biosynthesis	5370
7.02.1 Introduction	5370
7.02.2 GTP Cyclohydrolase II	5371
7.02.3 Deaminase/Reductase	5375
7.02.4 3,4-Dihydroxy-2-Butanone 4-Phosphate Synthase	5378
7.02.5 Lumazine Synthase	5379
7.02.6 Riboflavin Synthase	5382
7.02.7 Pentameric Riboflavin Synthases of Archaea	5389
7.02.8 Lumazine Protein	5390
7.02.9 Regulation of Riboflavin Biosynthesis	5390
7.02.10 Biotechnology	5395
7.02.11 Riboflavin Biosynthesis Genes as Potential Drug Targets	5395
7.02.12 Riboflavin Kinase and FAD Synthetase	5396
7.02.13 Biosynthesis of Deazaflavin Cofactors	5396
7.02.14 Riboflavin as Substrate for Other Biosynthetic Pathways	5396
References	5399
7.03 Flavin-Dependent Enzymes	5404
7.03.1 Introduction	5405
7.03.2 Oxidation of Carbon–Heteroatom Bonds	5409
7.03.3 Oxidation and Reduction of Carbon–Carbon Bonds	5423
7.03.4 Thiol/Disulfide Chemistry	5432
7.03.5 Electron Transfer Reactions	5439
7.03.6 Oxygen Reactions	5443
7.03.7 Nonredox Reactions	5454
7.03.8 Complex Flavoenzymes	5463
7.03.9 Summary	5468
Abbreviations	5468
References	5470
7.04 Biotechnology of Riboflavin Production	5482
7.04.1 Scope	5482
7.04.2 Introduction	5483
7.04.3 Industrial Production	5484
7.04.4 Riboflavin Biosynthesis	5487
7.04.5 Construction of Riboflavin Production Strains	5490
7.04.6 Process Development	5499
7.04.7 Conclusions	5502
References	5503
7.05 The Use of Subsystems to Encode Biosynthesis of Vitamins and Cofactors	5508
7.05.1 The Goal	5508
7.05.2 More Precisely, What Is a Subsystem?	5510
7.05.3 How Are Subsystems Built?	5517
7.05.4 What Is Revealed by the Construction of Subsystems?	5521
7.05.5 The Project to Annotate 1000 Genomes	5522
7.05.6 Summary	5522
Acknowledgments	5523
Abbreviations	5523
References	5523
7.06 Biosynthesis of Biotin	5528
7.06.1 Introduction	5528
7.06.2 The Biosynthetic Pathway	5528
References	5545
7.07 Lipoic Acid Biosynthesis and Enzymology	5548
7.07.1 Introduction	5548
7.07.2 The Biological Functions of Lipoamide	5550
7.07.3 Pathways for Construction of the Lipoyl Cofactor	5557
7.07.4 Characterization of Enzymes Involved in Lipoic Acid Biosynthesis and Metabolism	5560
Acknowledgment	5573
Glossary	5573
References	5575
7.08 Genomics and Enzymology of NAD Biosynthesis	5580
7.08.1 Introduction	5580
7.08.2 Biochemical Transformations and Enzymes	5581
7.08.3 Genomic Reconstruction of NAD Biosynthetic Pathways	5608
Acknowledgments	5617
Abbreviations	5617
References	5618
7.09 Pyridoxal Phosphate Biosynthesis	5626
7.09.1 Introduction	5626
7.09.2 Enzymology of PLP Biosynthesis via the DXP-Dependent Route	5627
7.09.3 Enzymology of PLP Biosynthesis via the R5P-Dependent Route	5632
7.09.4 Transport, Salvage, and Interconversion of Various Forms of Vitamin B6	5634
7.09.5 Conclusions	5635
Glossary	5635
Abbreviations	5635
References	5636
7.10 Pyridoxal 5Prime-Phosphate-Dependent Enzymes: Catalysis, Conformation, and Genomics	5640
7.10.1 Introduction	5641
7.10.2 Reactivity of Amino Acids at Alpha-Position	5647
7.10.3 Reactivity of Amino Acids at Beta-Position	5662
7.10.4 Reactivity of Amino Acids at Gamma-Position	5673
7.10.5 Radical Reactions in PLP-Enzymes	5679
7.10.6 Reactivity with Inhibitors	5682
7.10.7 Role of Conformational Changes in Substrate and Reaction Specificity and Allosteric Regulation	5694
7.10.8 Genomics, Evolution, Structure, and Reactivity/Specificity	5696
Acknowledgment	5703
Glossary	5703
Abbreviations	5703
References	5704
7.11 Coenzyme A Biosynthesis and Enzymology	5718
7.11.1 Introduction	5719
7.11.2 Coenzyme A and the Elucidation of Its Biosynthetic Pathway: A Historical Perspective	5720
7.11.3 CoA Biosynthesis	5722
7.11.4 CoA Utilization, Degradation, and Recycling	5741
7.11.5 CoA-Dependent Enzymes	5749
7.11.6 Chemical Biology Tools Based on CoA Enzymology	5763
7.11.7 Drug Development Efforts Targeting CoA Enzymology	5769
7.11.8 Conclusion	5770
References	5770
7.12 Menaquinone/Ubiquinone Biosynthesis and Enzymology	5778
7.12.1 Introduction	5778
7.12.2 Menaquinone Biosynthesis	5781
7.12.3 Phylloquinone Biosynthesis	5792
7.12.4 Ubiquinone Biosynthesis	5793
7.12.5 Organization of Q Biosynthetic Enzymes into a Complex	5803
7.12.6 Comparison of Q Biosynthesis in Yeast and Escherichia coli	5803
7.12.7 Biosynthesis of Isoprenoid Side Chain of MK and Q	5806
Acknowledgments	5806
Abbreviations	5806
References	5807
7.13 Biosynthesis of Heme and Vitamin B12	5812
7.13.1 Tetrapyrroles – The Pigments of Life	5813
7.13.2 Tetrapyrrole Biosynthetic Pathways	5813
7.13.3 Formation of 5-Aminolevulinic Acid	5815
7.13.4 Conversion of 5-Aminolevulinic Acid into Uroporphyrinogen III	5820
7.13.5 Tetrapyrrole Biosynthesis Branch Point – Uroporphyrinogen III	5826
7.13.6 Conversion of Uroporphyrinogen III into Protoheme	5826
7.13.7 The Biosynthesis of Adenosylcobalamin (Vitamin B12)	5832
7.13.8 A Note on Nomenclature	5832
7.13.9 Overview of Cobalamin Biosynthesis	5836
7.13.10 Uroporphyrinogen III to Precorrin-2	5836
7.13.11 The Aerobic Pathway	5841
7.13.12 The Anaerobic Pathway – From Precorrin-2 to Adenosylcobyric Acid	5848
7.13.13 Biosynthesis of Cobinamide (Phosphate)	5853
7.13.14 Nucleotide Loop Assembly	5856
References	5860
7.14 Cobalamin Coenzymes in Enzymology	5868
7.14.1 Introduction	5869
7.14.2 Early Theories of B12 Function	5870
7.14.3 Cobalamin Chemistry	5873
7.14.4 Adenosylcobalamin in Enzymatic Catalysis	5876
7.14.5 Methylcobalamin in Enzymatic Catalysis	5905
7.14.6 Conclusion	5907
Acknowledgment	5908
Abbreviations	5908
Nomenclature	5909
References	5909
7.15 Thiamin Biosynthesis	5914
7.15.1 Introduction	5914
7.15.2 Thiamin Biosynthesis in Bacillus subtilis	5914
7.15.3 Thiamin Phosphate Synthase	5915
7.15.4 Biosynthesis of the Thiazole Moiety of Thiamin in Bacteria	5916
7.15.5 Protein Thiocarboxylates as Sulfide Carriers in Thiamin Biosynthesis	5917
7.15.6 Formation of the Glycine Imine	5918
7.15.7 Formation of the Pyrimidine Moiety of Thiamin	5918
7.15.8 Kinases Involved in Thiamin Biosynthesis	5920
7.15.9 Thiamin Salvage	5920
7.15.10 Chemoenzymatic Synthesis of Thiamin Pyrophosphate	5921
7.15.11 Thiamin Biosynthesis in Saccharomyces cerevisiae	5922
7.15.12 Formation of the Thiamin Thiazole in Yeast	5922
7.15.13 Formation of the Thiamin Pyrimidine in Yeast	5923
7.15.14 Conclusions	5923
References	5924
7.16 Thiamin Enzymology	5928
7.16.1 Introduction	5929
7.16.2 Detection of Thiamin Diphosphate-Related Intermediates and Their Kinetic Fates, and the Information Gained from Such Data	5929
7.16.3 Determination of Rate-Limiting Steps and Microscopic Rate Constants on ThDP Enzymes	5946
7.16.4 Function and Dynamics of Mobile Loops on YPDC and E1ec	5947
7.16.5 Structure–Function Studies in ThDP-Initiated Multienzyme Complex Reactions at the E1 (ThDP-Dependent) Component	5954
7.16.6 Probing ThDP Enzyme Mechanisms with Coenzyme Analogs	5957
7.16.7 Active Center Communication in ThDP Enzymes	5957
7.16.8 Continuing Fascination with Thiamin Enzymes as Paradigm for Enzymatic Solvent Effects	5960
7.16.9 Perspective for Future Studies	5961
Acknowledgments	5962
Abbreviations	5962
References	5962
7.17 The Biosynthesis of Folate and Pterins and Their Enzymology	5966
7.17.1 Introduction	5967
7.17.2 The Biosynthesis of Folate	5969
7.17.3 Tetrahydrobiopterin Metabolism and Function	5983
7.17.4 Molybdopterin and Molybdenum Cofactor Biosynthesis	5995
Acknowledgments	6006
Abbreviations	6006
References	6008
7.18 Cofactor Catabolism	6016
7.18.1 Introduction	6016
7.18.2 Vitamin B6 Catabolism	6016
7.18.3 Heme Catabolism	6019
7.18.4 Vitamin B3 Catabolism	6024
7.18.5 Vitamin B2 Catabolism	6026
7.18.6 Vitamin B1 Catabolism	6026
7.18.7 Vitamin B9, Folate Catabolism	6026
7.18.8 Vitamin B7, Biotin Catabolism	6029
7.18.9 Lipoate Catabolism	6030
7.18.10 Other Cofactors	6030
7.18.11 Conclusion	6030
Acknowledgment	6032
Glossary	6036
Abbreviations	6036
References	6037
7.19 Protein-Derived Cofactors	6042
7.19.1 Introduction	6042
7.19.2 Pyruvoyl Cofactor – A Product of Peptide Cleavage	6044
7.19.3 4-Methylideneimidazole-5-One – A Product of Peptide Cyclization and Dehydration	6047
7.19.4 Protein-Derived Quinone Cofactors	6049
7.19.5 Functional Covalently Cross-Linked Amino Acid Residues in Metalloproteins	6062
7.19.6 Green Fluorescent Protein and Protein-Derived Fluorophores	6068
7.19.7 Pyrroloquinoline Quinone, a Protein-Derived Exogenous Cofactor	6070
7.19.8 Lantibiotics, Protein-Derived Antibiotic Peptides	6073
7.19.9 Conclusions and Perspectives	6074
Abbreviations	6074
References	6075
7.20 Biosynthesis of the Methanogenic Coenzymes	6078
7.20.1 Introduction	6078
7.20.2 Biosynthesis of Methanofuran	6079
7.20.3 Biosynthesis of Methanopterin	6083
7.20.4 Biosynthesis of Coenzyme F420 and Riboflavin Precursors	6091
7.20.5 Biosynthesis of Riboflavin, FMN, and FAD	6097
7.20.6 Biosynthesis of Coenzyme M and Coenzyme B	6102
7.20.7 Biosynthesis of Corrinoids and Coenzyme F430	6107
7.20.8 Concluding Remarks	6112
References	6112
e9780080453811v8	6116
Cover	6116
Title Page	6119
Copyright Page	6120
Contents	6121
Contributors	6123
Preface	6127
Introduction	6129
Editors in Chief	6133
Volume Editors	6135
8.01 Overview and Introduction	6141
8.01.1 Introduction	6141
8.01.2 Chapter Summaries	6142
References	6147
8.02 Evolution and the Enzyme	6149
8.02.1 Introduction	6149
8.02.2 The Earliest Enzymes: Getting the Basic Chemistry in Place	6150
8.02.3 Exploring Fold Space	6155
8.02.4 Elaborating on the Basics	6160
8.02.5 Enzyme Evolution in the Context of the Cell	6175
8.02.6 Enzyme Evolution in the Modern Age	6180
Abbreviations	6183
References	6184
8.03 Enzyme Promiscuity – Evolutionary and Mechanistic Aspects	6187
8.03.1 Introduction	6188
8.03.2 Promiscuity – The Rule or an Exception	6188
8.03.3 The Definitions of Promiscuity	6190
8.03.4 Quantifying the Degree and Magnitude of Promiscuity	6192
8.03.5 Predicting Promiscuity	6196
8.03.6 Mechanistic Aspects of Promiscuity	6197
8.03.7 Promiscuity and the Divergence of Enzyme Superfamilies	6202
8.03.8 Evolutionary Aspects of Promiscuity	6206
Acknowledgments	6223
Abbreviations	6223
References	6224
8.04 Mechanistic and Structural Studies of Microbial Dehalogenases: How Nature Cleaves a Carbon–Halogen Bond	6229
8.04.1 Introduction	6229
8.04.2 Dehalogenation Via Covalent Catalysis	6230
8.04.3 Dehalogenation Via Noncovalent Catalysis	6240
8.04.4 Structurally Undefined Dehalogenases	6250
8.04.5 Conclusions	6256
Acknowledgments	6258
Abbreviations	6258
Nomenclature	6259
References	6259
8.05 Guanidine-Modifying Enzymes in the Pentein Superfamily	6265
8.05.1 Introduction to the Pentein Superfamily	6266
8.05.2 Noncatalytic Proteins	6267
8.05.3 Hydrolases	6268
8.05.4 Dihydrolases	6285
8.05.5 Amidinotransferases	6288
8.05.6 Conclusion	6294
Acknowledgments	6295
References	6295
8.06 Tunnels and Intermediates in the Glutamine-Dependent Amidotransferases	6301
8.06.1 Introduction	6302
8.06.2 Glutamine-Dependent Amidotransferases and Nitrogen Metabolism	6303
8.06.3 Class I Amidotransferases	6308
8.06.4 Class II Amidotransferases	6335
8.06.5 Class III Amidotransferases	6355
8.06.6 Other Aspects	6359
8.06.7 Conclusion	6361
Acknowledgment	6361
References	6361
8.07 Fatty Acid Biosynthesis and Oxidation	6371
8.07.1 Introduction	6371
8.07.2 Thiolase Enzyme Homologs	6372
8.07.3 Oxidoreductases in Fatty Acid Biosynthesis and Breakdown	6383
8.07.4 Hydratases and Dehydratases	6398
8.07.5 Summary and Future Prospects	6408
References	6410
8.08 Diels-Alderases	6417
8.08.1 Introduction	6417
8.08.2 Enzymatic Formation of Diels–Alder Adducts	6422
8.08.3 Diels–Alder Reaction Catalyzed by the Biological System	6436
8.08.4 Enzyme-Catalyzed Diels–Alder Reactions	6441
8.08.5 Natural Diels–Alder Adducts Whose Biosynthetic Gene Clusters Have Been Identified	6447
8.08.6 Conclusions	6450
References	6451
8.09 Phosphoryl and Sulfuryl Transfer	6455
8.09.1 Introduction	6455
8.09.2 Uncatalyzed Reactions of Phosphate and Sulfate Monoesters	6458
8.09.3 Key Features of Enzymatic Catalysis, and Structural Similarities between Sulfatases and Phosphatases	6461
8.09.4 Enzymes that Catalyze the Hydrolysis of Phosphate Monoesters	6462
8.09.5 Sulfatases	6477
8.09.6 Conclusions	6482
Abbreviation	6482
References	6483
8.10 Catalytic Mechanism of DNA Polymerases	6489
8.10.1 Introduction	6490
8.10.2 Polymerase Families	6490
8.10.3 Structural Requirements for Polymerase Catalysis	6492
8.10.4 General Mechanism of Nucleotide Incorporation Catalyzed by DNA Polymerases	6495
8.10.5 Computational Studies	6512
8.10.6 Final Thoughts	6517
Abbreviations	6518
Nomenclature	6518
References	6519
8.11 Mechanisms of Enzymatic Glycosyl Transfer	6525
8.11.1 Introduction	6525
8.11.2 Reaction Mechanisms of Glycoside Hydrolases	6531
8.11.3 Examples of Mechanistic Studies of Some Representative Glycosidases	6535
8.11.4 Glycosyltransferases	6548
References	6554
8.12 Synthesis of Alginate in Bacteria	6563
8.12.1 Introduction	6563
8.12.2 Alginate Structure	6563
8.12.3 Overview of Alginate Biosynthesis	6565
8.12.4 Phosphomannose Isomerase	6566
8.12.5 Phosphomannomutase	6567
8.12.6 Guanosine Diphosphate-Mannose Pyrophosphorylase	6570
8.12.7 Guanosine Diphosphate-Mannose Dehydrogenase	6570
8.12.8 Mannuronan Synthesis	6572
8.12.9 C5-Mannuronan Epimerase	6572
8.12.10 Alginate Acetylation	6576
8.12.11 Alginate Lyase	6577
8.12.12 Secretion of Alginate	6578
8.12.13 Regulation of Alginate Synthesis	6578
8.12.14 Future Directions	6578
Abbreviations	6579
References	6579
8.13 Enzymology of Bacterial Resistance	6583
8.13.1 Introduction	6583
8.13.2 Enzymatic Basis for Beta-Lactam Resistance	6584
8.13.3 Enzymatic Basis for Glycopeptide Resistance	6595
8.13.4 Enzymatic Basis for Aminoglycoside Resistance	6601
8.13.5 Enzymatic Basis for Macrolide and Ketolide Resistance	6610
8.13.6 Enzymatic Basis for Resistance to the Quinolone Antibacterials	6614
8.13.7 Conclusion	6616
Abbreviations	6616
References	6616
8.14 Copper Metalloenzymes	6629
8.14.1 Introduction	6629
8.14.2 Copper Enzyme Catalysis	6639
Acknowledgment	6679
References	6679
8.15 Mechanisms of Metal-Dependent Hydrolases in Metabolism	6687
8.15.1 Introduction	6687
8.15.2 Metal Ion Cofactors	6688
8.15.3 Mononuclear Metallohydrolases	6693
8.15.4 Binuclear Metallohydrolases	6709
8.15.5 Conclusions	6715
Abbreviations	6716
References	6717
8.16 Dioxygenase Enzymes and Oxidative Cleavage Pathways	6723
8.16.1 Bacterial Aromatic Degradation Pathways	6723
8.16.2 Mammalian Aromatic Amino Acid Degradation Pathways	6743
8.16.3 Carotenoid Oxidative Cleavage Pathways	6749
8.16.4 Other Dioxygenase Enzymes Involved in Catabolic and Biosynthetic Pathways	6754
References	6759
8.17 S-Adenosylmethionine and Iron–Sulfur Clusters in Biological Radical Reactions: The Radical SAM Superfamily	6765
8.17.1 Introduction	6766
8.17.2 Radical SAM Enzymes: A Common Mechanistic Start	6770
8.17.3 Diverse Reactions Catalyzed by Radical SAM Enzymes	6775
8.17.4 Insights from Structural Studies of Radical SAM Enzymes	6790
8.17.5 Conclusions	6797
Acknowledgements	6797
Abbreviations	6797
References	6797
8.18 Detection of Novel Enzyme Intermediates	6803
8.18.1 Introduction	6803
8.18.2 Criteria for Establishing Enzyme Intermediates	6804
8.18.3 Methodologies and Experimental Design for Optimal Intermediate Detection of Enzyme Intermediates	6805
8.18.4 Selected Examples of Enzymological Studies Involving Detection and Characterization of Novel Enzyme Intermediates	6811
8.18.5 Novel Approaches for Detecting and Characterizing Enzyme Intermediates	6821
8.18.6 Conclusions	6822
Acknowledgments	6823
Abbreviations	6824
References	6824
8.19 Bisubstrate Analog Inhibitors	6829
8.19.1 Introduction	6829
8.19.2 Design and Analysis of Bisubstrate Analog Inhibitors	6830
8.19.3 Gcn5-Related N-Acetyltransferases	6831
8.19.4 Acetyl-CoA Carboxylase	6837
8.19.5 Protein Kinases	6838
8.19.6 Catechol-O-Methyltransferase	6840
8.19.7 Farnesyltransferase	6842
8.19.8 Current Bisubstrate Analogs as Therapeutics	6844
8.19.9 Future Perspectives	6853
Abbreviations	6853
References	6854
8.20 Quantum Chemical Modeling of Enzymatic Reactions – Applications to Epoxide-Transforming Enzymes	6859
8.20.1 Introduction	6859
8.20.2 Density Functional Theory	6860
8.20.3 Modeling Enzyme Active Sites and Reactions	6862
8.20.4 Applications to Epoxide-Transforming Enzymes	6866
8.20.5 Conclusions and Outlook	6884
Abbreviations	6884
Nomenclature	6885
References	6885
e9780080453811v9	6889
Cover	6889
Title Page	6892
Copyright Page	6893
Contents	6894
Contributors	6896
Preface	6900
Introduction	6902
Editors in Chief	6906
Volume Editors	6908
9.01 Overview and Introduction	6914
9.02 High Performance Liquid Chromatographic Separation Methods	6918
9.02.1 Introduction	6918
9.02.2 Modes of Separation by HPLC in Natural Product Isolation	6921
9.02.3 From Analytical to Preparative Scale Illustrated for HP-RPC	6926
9.02.4 Multidimensional High-Performance Liquid Chromatography	6933
9.02.5 HPLC Separation of Natural Products	6939
9.02.6 Conclusions	6954
Abbreviations	6956
References	6957
9.03 Introduction to Macromolecular X-Ray Crystallography	6964
9.03.1 Introduction	6964
9.03.2 Why Crystallography?	6965
9.03.3 Protein Crystals	6965
9.03.4 Obtaining Protein Crystals	6967
9.03.5 Principles of Diffraction	6970
9.03.6 Fourier Transforms	6973
9.03.7 Diffraction as a Fourier Series	6975
9.03.8 The Diffraction Experiment in Practice	6976
9.03.9 Phasing Methods	6980
9.03.10 The Electron Density Map	6988
9.03.11 Model Building and Refinement	6992
9.03.12 Model Validation	6995
9.03.13 An Example of a Crystal Structure Determination	6997
Acknowledgments	7000
Nomenclature	7000
References	7000
9.04 Characterization by Circular Dichroism Spectroscopy	7004
9.04.1 Introduction	7005
9.04.2 OR of Chiral Compounds	7005
9.04.3 Circular Dichroism Spectra	7007
9.04.4 CD Exciton Chirality Method	7013
9.04.5 Induced CD	7029
9.04.6 Characterization of Natural Products by CD – Selected Examples	7030
9.04.7 Concluding Remarks and Outlook	7054
References	7055
9.05 Determination of Structure including Absolute Configuration of Bioactive Natural Products	7060
9.05.1 Introduction	7060
9.05.2 Absolute Configuration and Sign of Optical Rotation	7060
9.05.3 Elucidating the Structure of Pheromones of Stink Bugs	7061
9.05.4 Absolute Configuration Involving Remote Stereocenters	7062
9.05.5 Absolute Configuration Involving Stereocenters Separated by a Polymethylene Spacer	7067
9.05.6 Origin of Biological Homochirality	7071
9.05.7 Exceptions to Biological Homochirality	7072
9.05.8 Mimics of Bioactive Natural Products and Bioisosterism	7074
9.05.9 Inventions of Pesticides and Medicinals	7076
9.05.10 Conclusion	7077
Abbreviations	7078
References	7078
9.06 NMR – Small Molecules and Analysis of Complex Mixtures	7082
9.06.1 Introduction	7082
9.06.2 Routine NMR Spectroscopy for Natural Products Structure Elucidation	7085
9.06.3 Complex Mixtures	7092
9.06.4 Methods to Improve Sensitivity	7100
9.06.5 Outlook	7105
Abbreviations	7105
References	7106
9.07 Biomolecular Recognition by Oligosaccharides and Glycopeptides: The NMR Point of View	7110
9.07.1 Scalar and Residual Dipolar Coupling Constants in the Structure Determination of Carbohydrates by NMR	7111
9.07.2 Conformation of Oligosaccharides in the Free and Bound States	7127
9.07.3 Bacterial Cell Wall Peptidoglycans and Fragments: Structural Studies and Functions	7131
9.07.4 NMR of Glycopeptide (Vancomycin-Type) Antibiotics: Structure and Interaction with Cell Wall Analogue Peptides	7140
Acknowledgments	7147
Abbreviations	7147
References	7149
9.08 Determination of Three-Dimensional Structures of Nucleic Acids by NMR	7160
9.08.1 Introduction	7160
9.08.2 Sample Preparation	7160
9.08.3 Resonance Assignments	7166
9.08.4 Extracting Structural Information	7171
9.08.5 Three-Dimensional Structure Refinement	7181
Abbreviations	7184
Nomenclature	7185
References	7185
9.09 Derivation of Peptide and Protein Structure using NMR Spectroscopy	7192
9.09.1 Introduction	7193
9.09.2 Sample Considerations and Solvent Suppression	7194
9.09.3 Data Acquisition for Nonlabeled Peptides	7201
9.09.4 Data Acquisition for Isotopically Labeled Proteins	7210
9.09.5 Extraction of Structural Constraints	7219
9.09.6 Calculation of Structures from NMR Data	7226
9.09.7 Conclusions and Future Prospects	7231
Acknowledgments	7232
Abbreviations	7232
Nomenclature	7233
References	7233
9.10 Mass Spectrometry: An Essential Tool for Trace Identification and Quantification	7240
9.10.1 Introduction	7241
9.10.2 Components of a Mass Spectrometer	7242
9.10.3 Tandem Mass Spectrometry	7262
9.10.4 Experimental Use of Mass Spectrometry	7269
Acknowledgments	7295
Abbreviations	7295
Nomenclature	7296
References	7297
9.11 Applications of Modern Mass Spectrometry Techniques in Natural Products Chemistry	7302
9.11.1 Introduction	7303
9.11.2 Applications of Mass Spectrometry on NRPS Systems	7320
9.11.3 Applications of Mass Spectrometry on PKS Systems	7349
9.11.4 Prospective Applications of Current Natural Product MS Methods on NRPS and PKS Systems	7359
9.11.5 Up-and-Coming Advances in Mass Spectrometry Tools for the Investigation of Natural Products and Their Biosynthetic Pathways	7362
Acknowledgments	7363
Abbreviations	7363
Nomenclature	7365
References	7365
9.12 Mass Spectrometry: Structure Determination of Proteins and Peptides	7370
9.12.1 Introduction	7371
9.12.2 Proteomics: A Field of Protein Characterization	7372
9.12.3 Mass Spectrometry Analysis of Proteomes	7376
9.12.4 Protein Expression Profiling through Quantitative Proteomics	7380
9.12.5 De Novo Sequencing of Peptides	7383
9.12.6 Posttranslational Modifications in Proteins and Peptides	7392
9.12.7 Higher-Order Structures of Proteins and Peptides	7397
9.12.8 Monitoring Protein–Ligand Interactions	7402
9.12.9 Conclusions	7404
Abbreviations	7405
References	7406
9.13 Application of Mass Spectrometry to Rapid Analysis of Bacterial Polysaccharides	7410
9.13.1 Introduction	7410
9.13.2 In-Source Fragmentation and Analysis of Polysaccharides by Capillary Electrophoresis–Mass Spectrometry	7411
9.13.3 Materials and Methods	7419
9.13.4 Conclusions	7421
Abbreviations	7422
References	7422
9.14 Modern Methods for the Isolation of Natural Product Receptors	7426
9.14.1 Introduction	7426
9.14.2 Traditional Approaches	7429
9.14.3 Genome-Wide Approaches	7431
9.14.4 Future Prospects	7473
Glossary	7473
References	7474
9.15 Bioinformatics	7482
9.15.1 Introduction	7482
9.15.2 Measuring Biodiversity	7484
9.15.3 Selected Data Mining Techniques for Gene Expression	7486
9.15.4 Software in Bioinformatics	7495
9.15.5 Structural Bioinformatics Approaches for Signaling Processes: A Case Study	7498
9.15.6 Summary and Future Prospects	7500
Abbreviations	7501
References	7502
9.16 Natural Products Research and Metabolomics	7508
9.16.1 Introduction	7508
9.16.2 Analytical Techniques	7511
9.16.3 Modeling and Data Analysis	7527
9.16.4 Sampling and Sample Preparation	7530
9.16.5 Examples	7530
9.16.6 Conclusion	7537
Abbreviations	7537
References	7538
9.17 Small Molecules as Versatile Tools for Activity-Based Protein Profiling Experiments	7542
9.17.1 Introduction	7543
9.17.2 Principles of Activity-Based Protein Profiling	7544
9.17.3 Chemical Probes for ABPP	7552
9.17.4 Biological Applications	7577
9.17.5 Conclusions and Outlook	7581
References	7583
9.18 Metabolic Studies Using the Retrobiosynthesis Concept – Theory, Technology, and Examples	7588
9.18.1 Isotopes in Metabolic Sciences	7588
9.18.2 Isotope Propagation in Metabolic Networks	7589
9.18.3 A Quasi-Steady-State Concept of Isotope Distribution	7590
9.18.4 A Rational Perturbation/Relaxation Strategy for Assessment of Metabolic Pathways	7590
9.18.5 The Retrobiosynthesis Concept in Practical Terms	7591
9.18.6 Isotopologue Space	7592
9.18.7 Quantitative Assessment of Isotopologue Abundance	7593
9.18.8 Application of the Retrobiosynthesis Concept to Studies in Biosynthesis	7594
9.18.9 Conclusion and Outlook	7605
Glossary	7605
References	7605
9.19 Bacterial Protein Overexpression Systems and Strategies	7608
9.19.1 Introduction	7609
9.19.2 Project Design	7609
9.19.3 Escherichia Coli Expression	7612
9.19.4 Cloning	7615
9.19.5 Methods to Improve Expression and Solubility	7618
9.19.6 Affinity Protein Purification	7623
9.19.7 Conclusions	7627
Abbreviations	7627
References	7628
9.20 Directed Evolution of Enzymes	7636
9.20.1 Introduction	7636
9.20.2 Library Construction Techniques and Consequences	7642
9.20.3 Selection and Screening Techniques	7648
9.20.4 Applications of Directed Molecular Evolution	7650
9.20.5 Conclusions	7658
Abbreviations	7658
References	7658
9.21 Single Molecule Fluorescence Methods in Enzymology	7664
9.21.1 Introduction	7664
9.21.2 Fluorescent Active Site	7665
9.21.3 Fluorogenic Reaction	7668
9.21.4 Fluorescent Substrate	7671
9.21.5 Fluorescence Resonance Energy Transfer (FRET)	7673
9.21.6 Fluorescence Quenching via Energy Transfer	7675
9.21.7 Fluorescence Quenching via Electron Transfer	7677
9.21.8 Summary	7679
Acknowledgments	7679
Abbreviations	7679
References	7679
e9780080453811v10	7684
Cover	7684
Title Page	7687
Copyright Page	7688
Contents of all Volumes	7689
Contributors to all Volumes	7701
Preface	7721
Introduction	7723
Editors in Chief	7727
Volume Editors	7729
INDEX	7735

Comprehensive Natural Products II

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