Note: Intro -- Half title -- Title -- Copyright -- Dedication -- Preface to the 2nd Edition -- Preface to the 1st Edition -- Acknowledgements -- Contents -- 1 Major Classes of Natural Product Scaffolds and Enzymatic Biosynthetic Machinery -- 1.1 Introduction -- 1.2 Primary Metabolites vs. Secondary Metabolites -- 1.3 Eight Major Classes of Natural Products -- 1.4 Nucleophiles and Electrophiles in Natural Product Biosynthesis -- 1.5 Three Enzyme Classes that Operate in Natural Product Biosynthetic Pathways -- 1.6 Genome-independent and Genome-dependent Discovery of Natural Products -- 1.7 Approach of this Volume -- References -- 2 The Chemical Logic for Major Reaction Types -- 2.1 Two Classes of Molecules that Drive Major Reaction Types in Both Primary and Secondary Metabolisms -- 2.2 Thermodynamically Activated but Kinetically Stable Metabolites that Drive Biosynthetic Equilibria -- 2.2.1 ATP and NTP Congeners -- 2.2.2 Adenosine Phosphosulfate and Phosphoadenosine Phosphosulfate -- 2.2.3 Acetyl-S-coenzyme and Related Acyl Thioesters -- 2.2.4 NADH as Hydride Transfer Agent: Two Electrons at a Time -- 2.2.5 S-Adenosylmethionine -- 2.2.6 Carbamoyl Phosphate -- 2.2.7 UDP-Glucose -- 2.2.8 Isopentenyl Pyrophosphate -- 2.2.9 Phosphoenolpyruvate (PEP) as a Trapped Carbanion Equivalent -- 2.2.10 A Diverse Range of Thermodynamically Activated, Kinetically Stable Chemical Groups Power Metabolism -- 2.2.11 Molecular Oxygen -- 2.3 Coenzyme Forms of B Vitamins as a Convergent Set of Metabolites Enabling Chemistry -- 2.4 Overview: Chemical Logic Embodied in the Two Sets of Metabolites and Coenzymes -- References -- 3 Polyketide Natural Products -- 3.1 Introduction -- 3.2 Polyketides Have Diverse Scaffolds and Therapeutic Utilities -- 3.3 Acetyl-CoA, Malonyl-CoA and Malonyl-S-Acyl Carrier Proteins as Building Blocks for Fatty Acids and Polyketides. , 3.4 The Logic and Enzymatic Machinery of Fatty Acid Synthesis is Adapted by Polyketide Synthases -- 3.4.1 Fatty Acid Synthases (FASs) -- 3.4.2 Polyketide Synthases (PKSs) -- 3.4.3 Alternate Acyl-CoA Substrates for PKS -- 3.4.4 Organization of Multiprotein Assemblages -- 3.4.5 PKS Chain Termination Modes -- 3.5 Biosynthesis of Major Polyketide Structural Classes -- 3.5.1 Oxytetracycline Biosynthesis: Aromatic Polyketides that Initiate Cyclization at C7-C12 or C9-C14 -- 3.5.2 Fungal Aromatic Polyketides: Cyclizations that Start at C4-C9 or C6-C11 -- 3.5.3 Type II Reducing PKSs Release Polyenes as Nascent Products -- 3.5.4 Polyketide Macrolactones: Type I Assembly-line Logic and Machinery -- 3.5.5 Polyketides Formed from Concerted Pericyclic Reactions -- 3.5.6 A Stepwise Cyclization of Polyketide: Ikarugamycin -- 3.5.7 Polyene Subclass of Polyketides -- 3.5.8 Polyketide to Polyether Metabolites -- 3.6 Convergence of Polyketide and Other Natural Product Pathways -- 3.7 Post-assembly-line Tailoring Enzymes -- References -- 4 Peptide Natural Products I: RiPPs -- 4.1 RiPPs vs. NRPs -- 4.2 RiPPs: Scope of Posttranslational Modifications: One- vs. Two-electron Reaction Manifolds -- 4.3 RiPP Biosynthetic Gene Organizations -- 4.4 Lanthipeptides: RiPPs Containing Crosslinking β-Thioethers -- 4.4.1 Lysine-Dha Crosslinks -- 4.4.2 Landornamide: Protein Arginases vs. Protein Deiminase -- 4.4.3 Phomopsins and Ustiloxins -- 4.5 RiPPs with Olefins and Oxazole and Thiazole Heterocycles -- 4.5.1 Goadsporin, Microcin B17, Plantazolocin -- 4.5.2 Patellamides A and C -- 4.5.3 Pyridines, Thiazoles, Oxazoles -- 4.6 Lasso Peptides: Nature's Rotaxanes -- 4.7 One-electron Reaction Manifolds in RiPP Generation from S-Adenosylmethionine Fragmentations -- 4.7.1 Sactipeptides -- 4.7.2 Homolytic Coupling of Lys-Trp in Streptide. , 4.7.3 Six-member Aliphatic Ethers from Threonine-Glutamate Crosslinking -- 4.7.4 Polytheonamides -- 4.7.5 RiPP α-Ketoamides from Splicing Out a Tyramine Moiety -- 4.7.6 Bottromycin: Multiple PTMs -- 4.8 Other RiPP Categories -- 4.8.1 Cittilins and Protein Cyclophanes -- 4.8.2 Microviridin -- 4.8.3 Amanitin and Phalloidin -- 4.8.4 Self-N-methylation of Peptide Bonds in Borosin RiPPs -- 4.9 RiPPs from Plants -- 4.10 Summary -- 4.10.1 Multiple Macrocyclization Strategies -- 4.10.2 Rigidification by Morphing Peptide Backbone into Heterocycles -- 4.10.3 Embedding Heterocycles in Macrocycles -- 4.10.4 Rotaxane Topology Implementation -- 4.10.5 Auguries of Novel Peptide Chemical Biology from the Radical SAM Universe -- References -- 5 Peptide Natural Products II: Nonribosomal Peptides -- 5.1 NRPS Assembly-line Strategies -- 5.2 Genome Mining and Bioinformatic Analyses -- 5.3 Constituents of NRPS Assembly Lines and the Logic of Nonribosomal Peptide Chain Growth -- 5.3.1 Nonproteinogenic Amino Acid Building Blocks -- 5.3.2 Phosphopantetheinyl Arms for Tethering Growing Peptidyl Thioester Chains -- 5.3.3 NRPS Domains and Modules -- 5.4 Representative NRPS Assembly Lines -- 5.4.1 The ACV Synthetase Assembly Line -- 5.4.2 The Enterobactin Synthetase Assembly Line -- 5.4.3 Obafluorin an Amino β-lactone from a Two-module NRPS -- 5.4.4 Azabicyclene Scaffolds from Pseudomonas aeruginosa -- 5.4.5 Vancomycin and Teicoplanin Glycopeptide Antibiotics -- 5.4.6 Echinocandins: Antifungal Cyclic Hexapeptides -- 5.4.7 Syringomycins and Syringopeptins: The Outer Limit of NRPs -- 5.4.8 Structural Biology of NRPS Domains and Modules -- 5.5 Hybrid Nonribosomal Peptide-polyketide Assembly Lines -- 5.5.1 Statine, Isostatine and Vinyl-arginine Revisited -- 5.5.2 α-Cyclopiazonic Acid: a Dieckmann Condensation in Mid-pathway. , 5.5.3 Bleomycin and Yersiniabactin: Hybrid Assembly Lines that are Mostly NRPS -- 5.5.4 Epothilone D and Rapamycin: Hybrid NRP-PK Scaffolds where the PK Units Dominate -- 5.5.5 Colibactin: a Genotoxic Human Gut Hybrid Scaffold with a Reactive Cyclopropane -- 5.6 Tailoring Enzymes and Morphed Scaffolds: RiPPs vs. NRPs vs. NRP-PK Hybrids -- References -- 6 Isoprenoids/Terpenes -- 6.1 Isoprene-based Scaffolds Comprise the Most Abundant Class of Natural Products -- 6.2 Δ2- and Δ3-Isopentenyl Diphosphates are the Biological Isoprenyl Building Blocks for Head-to-tail Alkylative Chain Elongations -- 6.3 Long-chain Prenyl Scaffolds -- 6.4 Two Routes to the IPP Isomers: Classical and Nonclassical Pathways -- 6.5 Self-condensation of Two Δ2-IPPs to the Chrysanthemyl Cyclopropyl Framework -- 6.6 Cation-driven Scaffold Rearrangements and Quenching -- 6.6.1 Monoterpenes: Geranyl-PP to α-terpinyl Cation and Its Partitioning to Products -- 6.6.2 Sesquiterpenes: Six Regiospecific Cyclizations from C15 Farnesyl-PP -- 6.6.3 How Good Are Terpene Synthases at Directing Flux of the Sequential Series of Cations in Their Active Sites? -- 6.6.4 Abscisic Acid -- 6.7 Diterpene Cyclization and Scaffold Complexity Generation -- 6.7.1 Geranylgeranyl-PP to ent-kaurene -- 6.7.2 Geranylgeranyl-PP to Taxadiene -- 6.7.3 Pleuromutilin -- 6.7.4 Momilactone B and Forskolin -- 6.8 Head-to-head vs. Head-to-tail Alkylative Couplings: C30 and C40 Hydrocarbons -- 6.9 Squalene-2,3-oxide and Cyclized Triterpenes -- 6.9.1 Formation of Squalene-2,3-oxide -- 6.9.2 Squalene Cyclases: Squalene to Hopene Framework -- 6.9.3 Oxidosqualene to Lanosterol, Cycloartenol, β-amyrin -- 6.9.4 Structural Biology Insights -- 6.9.5 Promiscuity of Oxidosqualene Cyclases: How Good Are the Oxidocyclases at Directing Flux Down One Reaction Manifold? -- 6.9.6 Lanosterol to Cholesterol and Beyond: A Bevy of Oxygenases. , 6.9.7 Regiospecific Furanosteroids -- 6.10 Phytoene to Carotenes and Vitamin A -- 6.11 Reaction of Isoprenes with Other Natural Product Classes -- 6.11.1 Meroterpenoids -- 6.11.2 Hyperforin is a Tetraprenylated Polyketide -- 6.11.3 Tetrahydrocannabinol -- 6.11.4 Paxilline -- 6.11.5 Merosterolic Acid -- 6.11.6 Xenovulene -- 6.12 Geranyl-PP to Secologanin: Entryway to Strictosidine and a Thousand Alkaloids -- References -- 7 Alkaloids I -- 7.1 Introduction -- 7.2 Amino Acid Building Blocks -- 7.3 Common Enzymatic Reactions in Alkaloid Biosynthetic Pathways -- 7.3.1 Reactions Involving Amino Acid Building Blocks -- 7.3.2 Ornithine as Building Block for Cocaine and Retronecine -- 7.3.3 Lysine to Pelletierine and Pseudopelletierine and Sparteine -- 7.3.4 Lysine to the 6,5-Indolizidine Bicyclic Framework -- 7.4 Three Aromatic Amino Acids as Alkaloid Building Blocks -- 7.4.1 Phenylalanine to Hyoscyamine to Scopolamine: Radical Rearrangement -- 7.4.2 Tyrosine is the Entry Point for Several Complex Alkaloid Scaffolds -- 7.4.3 Tyrosine to S-reticuline to Berberine -- 7.4.4 Tyrosine to R-reticuline to Morphine -- 7.5 Phenylalanine and Tyrosine Scaffolds Morphed to the 6-7-7 Tricyclic Framework of Colchicine -- 7.6 Tryptophan as a Building Block to Alkaloids -- 7.6.1 Tryptophan to Harmine: β-Carbolines -- 7.6.2 Tryptophan to Strictosidine and Beyond: Ajmalicine, Camptothecin, Quinine -- 7.6.3 Tryptophan to Lysergic Acid and Ergotamine -- 7.7 Tryptophan to Indolocarbazole Alkaloids -- 7.7.1 Rebeccamycin and Staurosporine -- 7.7.2 Prenylated Carbazole Metabolites -- 7.8 Tryptophan Oxidative Dimerization to Terrequinone -- 7.9 Additional Alkaloids: Steroidal Alkaloids -- 7.10 Summary -- References -- 8 Purine- and Pyrimidine-derived Natural Products -- 8.1 Introduction -- 8.2 Pairing of Specific Purines and Pyrimidines in RNA and DNA. , 8.3 Remnants of an RNA World?.