SUBJECT INDEX

accABCD genes, in flavanone synthesis, 177 Aclacinomycin A, 96 Acceptors, of DesVII–Des VIII, 68 biosynthetic pathway of, 100 Acceptor specificity, in directed molecular structure of, 95 glycosyltransferase evolution, 106 Aclarubicins, 96 Acetaldehyde, in ethanol production, molecular structure of, 95 191–192 Acridone synthase (ACS), in polyketide Acetaphenone, in flavonoid synthesis, 176 synthesis, 169 Acetate kinase (ACK), in malonyl-CoA Actinomycetes, macrolide antibiotics from, 64 formation, 179, 180 Activation, of inosine 50-monophosphate Acetic acid, in combinatorial pathway design, dehydrogenase, 36–39 129 Acute myelogenous leukemia, enediynes Acetoacetyl-CoA (coenzyme A) versus, 89 in ethanol production, 192 Acyclic carotenoids, synthesis of, 165 in MVA pathway, 153, 154 Acyclic xanthophylls, biosynthesis of, 124 Acetoacetyl-CoA ligase, in MVA pathway, Acyl carrier protein (ACP) 154 in combinatorial pathway design, 129 Acetoacetyl-CoA thiolase, in MVA pathway, protein–protein interactions and, 133–134 153 Acyltransferase (AT) domain Acetyl-CoA in combinatorial pathway design, 129, in butanol production, 196 130, 132 in ethanol production, 192 protein–protein interactions and, 133 in MVA pathway, 153, 154 Adenosine monophosphate (AMP), polyketides and, 167 biosynthesis of, 2, 3 Acetyl-CoA carboxylase (ACC) Adriamycin, 95–96, 98 in flavanone synthesis, 177–179, 180 molecular structure of, 95 in malonyl-CoA formation, 179 Aerobacter aerogenes, IMPDH in, 5, 18, 26 Acetyl-CoA synthase (ACS), in malonyl-CoA Aglycones. See also Aglycons formation, 179 anthracyclines and, 98–101 N-Acetyl-glucosamine, in teicoplanin, 83 calicheamicin, 91, 92 Acetyl phosphate, in malonyl-CoA macrolide glycosyltransferases and, 66 formation, 179 of vicenistatin, 93 3-Acetylpyridine adenine dinucleotide Aglycone substrates, accepted by OleD, 74 (APAD), in Tritrichomonas foetus,21 Aglycon exchange reactions AcinetobacterCOPYRIGHTED bayli ADP1, in wax ester CalG1-catalyzed, MATERIAL 92 biosynthesis, 124–125 CalG4-catalyzed, 93

Advances in Enzymology and Related Areas of Molecular Biology, Volume 76 Edited by Eric J.Toone Copyright 2009 by John Wiley & Sons, Inc. 243 244 SUBJECT INDEX

Aglycon exchanges, erythromycins shikimates and, 173–174 and, 70 Amino acid sequences, in glycosyltransferase Aglycons. See also Aglycones design, 101–103 anthracyclines and, 98–101 Aminocoumarins, 86–88 avermectin and, 76–77 molecular structures of, 87 in natural product glycosylation, 59 Aminomalonyl-ACP extender unit, in oleandomycin and, 74–75 combinatorial pathway design, 129, 130 in vicenistatin reactions, 94–95 Ammonia, in purine nucleotide biosynthesis, 2 Aglycon specificity, methymycin and, Ammonia-limited conditions, biosynthesis 66–69 optimization under, 141–142 Agrobacterium tumefaciens Amorpha-4,11-diene monooxygenase, in in artemisinin production, 158 MVA pathway, 154 in ubiquinone production, 166–167 Amorphadiene Aklavinone biosynthetic pathway, 72 in artemisinin synthesis, 158 AknK glycosyltransferase, 96 in terpene biosynthesis, 138 mechanism of action of, 99 Amorphadiene synthase reactions catalyzed by, 97 in artemisinin synthesis, 158 AknS glycosyltransferase, 96, 98, in MVA pathway, 154 100–101 AmpD1 glycosyltransferase, calicheamicin mechanism of action of, 99 and, 93 aknT gene, 98 AMP-dependent protein kinase (ADPK), 41 AknT glycosyltransferase, 98, 100–101 Angiogenesis, flavonols in, 182 mechanism of action of, 99 D6,7-Anhydroerythromycin C, synthesis of, Alanine 172 cytochrome-P450 enzymes and, 189 Anomeric kinases, in natural product in hydroxylated flavonoid synthesis, 190 glycosylation, 59 protein dynamics and, 34 Anthocyanidin synthase (ANS) Alcohol dehydrogenase (Ec-adhE), in butanol in anthocyanin synthesis, 184–185 production, 196–197 in flavonoid pathway, 178–179 Alcohol dehydrogenase (adh), in ethanol Anthocyanins, 175–176, 183–185 production, 192 medicinal uses of, 183 Aldehydes, in epothilone synthesis, 169 from plant cell cultures, 155 Alkaloids, in combinatorial pathway design, synthesis of, 178–179 128 Anthracyclines, 95–101 a-carotene, in carotenoid biosynthesis, 161, mechanism of action of, 96–101 162 Anthurium andraeanum, in anthocyanin a-helix synthesis, 184 of glycosyltransferases, 61, 62 Antibiotics of IMPDH, 33–34 aminocoumarins as, 86–88 a-zearalenol, 94 aromatic polyketides as, 95–101 Amino acid residues, in polyketide synthesis, enediynes as, 88–93 169 glycopeptides as, 78–86 Amino acids macrolactams as, 93–95 in flavanone synthesis, 177 macrolides as, 64–78 in glycosyltransferase classification, 60 nonribosomal peptides as, 78–86 in purine nucleotide biosynthesis, 2 polyketides as, 167 SUBJECT INDEX 245

Anticancer agents/drugs artemisinin from, 157 anthracyclines as, 96 in terpene biosynthesis, 138 terpenoids as, 152 Artemisinic acid pathway, 154 Antimicrobial agents, terpenoids as, 152 Artemisinin, 134, 154 Antioxidants, ubiquinone, 166–167 enhanced production of, 157–158 Apiferol, in flavonoid pathway, 178–179 microbial synthesis of, 158 Apples from plant cell cultures, 157–158 in anthocyanin synthesis, 184 synthesis of, 157 flavonols from, 182–183 in terpene biosynthesis, 138 appY gene, in carotenoid biosynthesis, 164 yeast synthesis of, 158–159 Aquifex aelicus, peptidoglycan GTs of, 62 Aryltetrasaccharide, in calicheamicin, 89 araBAD promoter, carotenoid biosynthesis Aspartate, vancomycin Gtf’s and, 62 and, 140 Aspartate–alanine substitutions, in IMPDH, Arabidopsis thaliana 24–25 in anthocyanin synthesis, 185 Astaxanthin flavonols from, 182–183 biosynthesis of, 164 resveratrol from, 186 in carotenoid biosynthesis, 162 Arabinose, oleandomycin and, 75 ATP binding, to IMPDH subdomain, 41 araGT gene, 101 Autosomal dominant retinitis pigmentosa AraGT glycosyltransferase, 101 (adRP), 40, 41 Aranciamycin, rhamnosylation of, 101 aveBI gene, 75 ArcA regulon, in ethanol production, 193 AveBI glycosyltransferase, 75–77 Archaea calicheamicin and, 93 IMPDH from, 5, 11 reactions catalyzed by, 76 in KEGG database, 126 Avermectin, 75–77 Arginine molecular structure of, 57, 76 IMPDH ligand binding and, 299 reactions of, 76 protein dynamics and, 34–35 AviGT4 glycosyltransferase, 61 species-selective affinity and, 35 Avilamycin, AviGT4 glycosyltransferase of, Aristolocolchine, optimizing biosynthetic 61 pathway for, 139 Azepinomycin, as IMPDH inhibitor, 16 AroE catalysis, in shikimate synthesis, 174, Azithromycin, 64 175 molecular structure of, 65 aro enzymes, in shikimate synthesis, 174–175 Aromatic amino acids, shikimates and, Baccatin III, in Taxol synthesis, 159 173–174 Bacillus subtilis, MEP pathway in, 153 Aromatic flavonoid derivatives, 173–190 Bacteria. See also Microbial synthesis from cytochrome-P450, 186–190 as biofuel synthesis biocatalysts, 191 flavonoids, 175–185 in butanol production, 196 shikimates, 173–175 carotenoid biosynthesis in, 161–165 stilbenes, 185–186 carotenoids in, 160 Aromatic polyketides, 95–101 enterobactins from, 83–85 Artemisia annua in ethanol production, 191–192 artemisinin from, 157, 158, 159 IMPDH from, 5–8, 11 in terpene biosynthesis, 138 in KEGG database, 126 Artemisinic acid, 154 MEP pathway in, 153–155 246 SUBJECT INDEX

Bacteria. (Continued) b-zearalenol, 94 terpene cyclases from, 137, 138 Binding sites, of inosine 50-monophosphate ubiquinone from, 166–167 dehydrogenase, 26–29 unnatural carotenoids from, 165–166 Biocatalysis database, 127–128 vancomycin-resistant, 79 Biocatalyst-based processes, green chemistry Bacteriophage P1, in shikimate synthesis, 175 and, 152 Bacteriophage T5, in astaxanthin synthesis, Biocatalysts, microorganisms as, 191 165 BioCyc database, 127 Bacteriophage T7 Biodegradation database, 127–128 in flavanone synthesis, 177 Biofuels, 191–197 in Taxol synthesis, 160 butanol, 191, 195–197 Baker’s yeast, in carotenoid biosynthesis, 163 ethanol, 191–195 Barrel fold structure microbial synthesis of, 152 in IMPDH ligand binding, 27 utility of, 191 in IMPDH molecules, 9 Bioinformatics Bateman domains green chemistry and, 152 defined, 40 in polyketide synthesis, 168–169 of inosine 50-monophosphate in protein engineering and pathway dehydrogenase, 37, 39–42 design, 123 in various proteins, 41–42 Bioreactors, in flavonoid bioproduction, Benzalacetone, medicinal applications of, 168 175 Benzalacetone synthase (BAS), in polyketide Biosynthesis, 151–217 synthesis, 169 of anthocyanins, 184 Benzaldehyde, in flavonoid synthesis, 176 of aromatic derivatives, 173–190 Benzimidazole NAD analog (BAD), 16 of biofuels, 191–197 Berberine, from plant cell cultures, 155 of carotenoids, 160–167 b-carotene of cell walls, 62 in astaxanthin biosynthesis, 164, 165 of epothilones, 169, 170–171 in carotenoid biosynthesis, 161, 162 of ethanol, 191–195 b-carotene hydroxylase (crtZ) future of, 142–143 in astaxanthin biosynthesis, 164 of guanine, 14 in carotenoid biosynthesis, 162 of isoflavones, 180–181 b-carotene ketolase (crtW) of natural products, 197–198 in astaxanthin biosynthesis, 164 of polyketides, 167–173 in carotenoid biosynthesis, 162 of purine nucleotides, 1–4 b-estradiol, 94 of terpenoids, 152–160 b-methylene-biphosphonate (b-TAD, Biosynthetic enzymes b-CH2-TAD). See also Tiazofurin in natural product glycosylation, 59 adenine dinucleotide (TAD) searching for, 124 in IMPDH activation, 38 Biosynthetic pathways IMPDH crystal structure and, 8, 11, 12 design of, 128–138 in IMPDH ligand binding, 28 diversification of, 128–138 kinetic properties of, 5, 6 optimization of, 128, 137, 138–142 NAD analogs of IMPDH and, 16 Biosynthetic reaction sequences, combina- species-selective affinity and, 35 torial and evolutionary design of, b-sheets, of glycosyltransferases, 60, 61 121–150 SUBJECT INDEX 247

Biotin ligase (BirA) CalG2 glycosyltransferase, calicheamicin in flavanone synthesis, 177–179, 180 and, 93 in malonyl-CoA formation, 179 CalG3 glycosyltransferase, calicheamicin BLAST (Basic Local Alignment Search Tool) and, 93 algorithm, 123–124, 128 CalG4 glycosyltransferase, 93 Borrelia burgdorferi, IMPDH from, 5–9, Calicheamicin, 88–93 11–13, 33 molecular structure of, 57, 89 Bovine b-1,4-galactosyltransferase, in Calorimetric studies, of IMPDH, 32 structure-guided glycosyltransferase CAMERA (Cyberinfrastructure for design, 104 Advanced Marine Microbial Ecology Bovine P450 17a-hydroxylase, cytochrome- Research and Analysis) database, 128 P450 enzymes and, 189 Cancer. See also Acute myelogenous Breast cancer, flavones versus, 181 leukemia; Anticancer agents/drugs; Brefaldin A, 94 Breast cancer; Leukemia; Melanoma; Butanol Tumor cells as biofuel, 191, 195–197 carotenoids in treating, 161 in ethanol production, 192 IMPDH inhibitors versus, 14 physical properties of, 195 Cancer therapeutics, aminocoumarins as, 86 Butanol dehydrogenase (bdhB) Candida albicans, species-specific drug in butanol production, 196 selectivity and IMPDH of, 36 in ethanol production, 192 Carbocation migration, in terpene Butyraldehyde biosynthesis, 137 in butanol production, 196 Carbomycin, 64 in ethanol production, 192 molecular structure of, 65

Butyraldehyde dehydrogenase (adhE, Carbon dioxide (CO2), in purine nucleotide Ca-adhE) biosynthesis, 2 in butanol production, 196 Carboxylase gene, in erythromycin synthesis, in ethanol production, 192 172 Butyric acid, in butanol production, 196 Carotein. See z-carotein Butyryl-CoA Carotenes, 160–161. See also b-carotene in butanol production, 196 entries in ethanol production, 192 in carotenoid biosynthesis, 161, 162 Butyryl-CoA dehydrogenase (bcd) Carotenoid cyclases, in unnatural carotenoid in butanol production, 196 synthesis, 165 in ethanol production, 192 Carotenoid desaturases, 135–136 Carotenoid end group modifying enzymes, Cadinene synthase, in terpene biosynthesis, 136 137 Carotenoid enzymes, 124, 125 Caenorhabditis elegans, resveratrol effects Carotenoid genes, in biosynthesis in, 185 optimization, 141 Caffeic acid Carotenoid oxygenase, 124, 125 in flavonoid pathway, 178–179 Carotenoid pathways, 161–163 in resveratrol synthesis, 186 Carotenoids, 152, 160–167 calG1–4 genes, 89 classic, 161–165 CalG1 glycosyltransferase, 89–91 evolutionary biosynthesis of, 135–136 reactions catalyzed by, 90, 91, 92 medicinal uses of, 160–161 248 SUBJECT INDEX

Carotenoids (Continued) Chemical mechanisms, of inosine optimizing biosynthesis of, 140 50-monophosphate dehydrogenase, 29–31 polyketides versus, 167 Chemical synthesis as tetraterpenes, 134 of epothilones, 169 ubiquinone, 166–167 of flavonoids, 176 unnatural, 165–166 green chemistry and, 152 Carotenoid synthases, 136 of polyketides, 167–168 Catalytic triads, in glycosyltransferase Chemoenzymatic glycorandomization, in mechanism of action, 62 natural product glycosylation, 58, 59 Catechins Chemotherapeutic agents, purine nucleotide in anthocyanin synthesis, 185 targets of, 14 in flavonoid synthesis, 176 6-Chloropurine riboside 50-monophosphate Catharanthus roseus, in flavone synthesis, (6-Cl-IMP). See 6-Cl-purine riboside 182, 189–190 monophosphate (6-Cl-IMP) Cation activation, of inosine 50-mono- Chloride ion channels, avermectin and, 75 phosphate dehydrogenase, 36–39 Chloroeremomycin, 79–83 CAZY database, 60, 78 Chloroeremomycin pathway, in glycosyl- in glycosyltransferase classification, transferase mechanism of action, 62 101–102 Chlorophyll-containing organisms, CBS (cysteine b-synthase) domains, carotenoids in, 160 41–42 Chloroquine, 157 IMPDH, 39–40 Chromosomes, locating genes on, 124 C–C bond formation, in polyketide synthesis, Chrysanthemic acid, from plant cultures, 167–168 156–157 Cell wall biosynthesis, 62 Chrysanthemum cinerariaefolium, pyrethrins Cethromycin, 65 from, 156–157 molecular structure of, 65 Chrysanthemum coccinum, pyrethrins from, C-GT mechanisms, 86 157 Chain elongation, in rearranging and Chrysin, in flavonoid pathway, 178–179 modifying PKS assembly line, 132 Cinchona bark, quinic acid from, 174 Chalcone isomerase (CHI) Cinerolone, from plant cultures, 156–157 in flavanone synthesis, 177 Cinnamate 4-hydroxylase (C4H), 188, 189 in flavone synthesis, 181 in flavone synthesis, 181 in flavonoid pathway, 178–179 Cinnamoyl-CoA, in flavonoid pathway, in isoflavone synthesis, 181 178–179 Chalcones (CHL), 175 Claisen(Schmidt condensation reaction, in in flavanone synthesis, 177 flavonoid synthesis, 176 in isoflavone synthesis, 181 Clarithromycin, 64 synthesis of, 176 molecular structure of, 65 Chalcone synthase (CHS) Classic carotenoids, 161–165 in flavanone synthesis, 177 Cleaning products, terpenoids as, 152 in flavone synthesis, 181 CLM library, of calicheamicin in flavonoid pathway, 178–179 variants, 91 in polyketide synthesis, 169 Clostridia, in butanol production, 196 Chemical manufacturing, natural resources Clostridium in, 152 as biofuel synthesis biocatalyst, 191 SUBJECT INDEX 249

in butanol production, 197 crl gene, in carotenoid biosynthesis, 164 in ethanol production, 192 Crotonase (crt, Ca-crt) Clostridium acetobutylum, in butanol in butanol production, 196 production, 196 in ethanol production, 192 6-Cl-purine riboside monophosphate (6-Cl- Crotonoyl-CoA, in butanol production, 196 IMP), 9, 13, 15, 23–24, 27. See also Crotonyl-CoA reductase, in erythromycin Inosine monophosphate (IMP) synthesis, 172 IMPDH activation and, 37, 38, 39 CrtB. See Phytoene synthase (crtB) IMPDH chemical mechanism and, 30 CrtE. See Geranylgeranyldiphosphate IMPDH ligand binding and, 28 synthase (GGPPS, crtE) protein dynamics and, 32 crtEBI operon, in carotenoid biosynthesis, CMP-sialic acid, in directed 163 glycosyltransferase evolution, 105 CrtI. See Phytoene desaturase (crtI) CoA-esters, in flavanone synthesis, 177 CrtM. See Dehydrosqualene synthase (crtM) Coenzyme-Q10 (CoQ10), in carotenoid CrtM carotenoid gene, 124, 125 biosynthesis, 162, 166–167. See also CrtN. See Dehydrosqualene desaturase (crtN) Ubiquinone(s) CrtN carotenoid gene, 124, 125 Colchicine, glycosylation of, 56 CrtOx homolog, 124, 125 Coleus blumei, terpenoids from, 155 CrtW. See b-carotene ketolase (crtW) Colorants, anthocyanins as, 183 CrtWZYIBE protein, in astaxanthin Combinatorial biosynthesis, in natural biosynthesis, 164 product glycosylation, 59 CrtY. See Lycopene cyclase (crtY) Combinatorial design, of biosynthetic crtY gene, in unnatural carotenoid synthesis, reaction sequences, 121–150 166 Combinatorial pathway design, 128 CrtZ. See b-carotene hydroxylase (crtZ) Comprehensive Microbial Resource (CMR), Cryptosporidium parvum, IMPDH from, 6 124, 125 Crystal structures Conformation, of IMPDH, 26 of IMPDH, 5–8, 9 Conformational flexibility, of inosine protein dynamics and, 32 50-monophosphate dehydrogenase, 13, C-terminal domain, in glycosyltransferases, 31–35 60–62 Congenital amaurosis, 40 Cyanidin-3-O-glucoside, in anthocyanin Contigs, in KEGG database, 126–127 synthesis, 185 Cooperativity, protein dynamics and, 32 Cyaninidin, in flavonoid pathway, 178–179 Coptis japonica, terpenoids from, 155 Cyclases, in unnatural carotenoid synthesis, 4-Coumaryl-CoA ligase (4CL) 165 in flavanone synthesis, 177 Cyclic carotenoids, synthesis of, 165 in flavone synthesis, 181 Cycloguanile, 157 in flavonoid pathway, 178–179 Cyclonovobiocic acid, 86–87 in resveratrol synthesis, 186 CYP71AV1 P450 enzyme, in artemisinin Coumaric acid synthesis, 159 in flavonoid pathway, 178–179 CYP71 P450 enzymes, in terpene in resveratrol synthesis, 186 biosynthesis, 138 Coumermycin A1, 88 Cysteine molecular structure of, 87 in IMPDH activation, 37 CouM glycosyltransferase, 88 in IMPDH ligand binding, 27 250 SUBJECT INDEX

Cysteine (Continued) 3-Dehydroshikimic acid (DHS), in shikimate in IMPDH molecules, 9–11, 14, 15 synthesis, 174, 175 protein dynamics and, 32 Dehydrosqualene desaturase (crtN), in Cytochrome-P450. See also P450 entries carotenoid biosynthesis, 162, 163 in flavone synthesis, 181 Dehydrosqualene synthase (crtM), in in Taxol synthesis, 160 carotenoid biosynthesis, 162, 163 Cytochrome-P450 enzymes, aromatic 13-Dehydroxybaccatin, from Taxus cell flavonoid derivatives via, 186–190 cultures, 156 Cytochrome-P450 isoflavone synthase (IFS), Demethylsperoidene, biosynthesis of, 165 in isoflavone synthesis, 180–181 3-Deoxy-D-arabino-heptulosonic acid Cytochrome-P450 reductase (CPR) 7-phosphate (DAHP), in shikimate in artemisinin synthesis, 159 synthesis, 174 in flavone synthesis, 182 3-Deoxy-D-arabino-heptulosonic acid in flavonoid pathway, 178–179 7-phosphate synthase (aroF), in in hydroxylated flavonoid synthesis, 190 shikimate synthesis, 174, 175 in MVA pathway, 154 6-Deoxyerythronolide B (6-DEB, 6dEB) in terpene biosynthesis, 138 erythromycins from, 69–70, 171, 172 Cytotoxicity production of, 131 of anthracyclines, 96 in rearranging and modifying PKS of avermectins, 75 assembly line, 132 of enediynes, 88–89 synthesis of, 167–168 Deoxyerythronolide B synthase (DEBS), in

D2O, IMPDH chemical mechanism and, 31 erythromycin synthesis, 171–172 Daidzein, synthesis of, 180 Deoxyfucose, AknK glycosyltransferase and, Dalbavancin, 79 96–98 molecular structure of, 80 2-Deoxyfucosyl-rhodinosaminyl-aklavinone, Databases 98 future of, 143 Deoxysugars, in polyketide biosynthesis, 132 of genomic sequences, 123–126 Deoxyxylulose-5-phosphate (DXP), of metabolic pathways, 126–128 153–154, 155 Daunomycin, 95–96, 97–98 Deoxyxylulose-5-phosphate molecular structure of, 95 isomeroreductase, 153–154, 155 Daunorubicin, 95–96 Deoxyxylulose-5-phosphate pathway, 135 molecular structure of, 95 Deoxyxylulose-5-phosphate synthase (DXPS) Daunosamine, 96–98 in carotenoid biosynthesis, 163 ddsA gene, in ubiquinone biosynthesis, in MEP pathway, 153 167 in Taxol synthesis, 160 10-Deacetylpaclitaxel, from Taxus cell Deoxyxylulose-P synthase promoter, cultures, 156 carotenoid biosynthesis and, 140 Dehydratase domain, in combinatorial Desaturases, carotenoid, 135–136 pathway design, 129 Desosamine, 70, 72 Dehydration, in rearranging and modifying desVII/VIII genes, methymycin and, 66 PKS assembly line, 132 DesVII–DesVIII glycosyltransferases Dehydrogenase activity, potassium ion in, 5, 6 anthracyclines and, 98 3-Dehydroquinic acid (DHQ), in shikimate erythromycins and, 70 synthesis, 174, 175 methymycin and, 66–69 SUBJECT INDEX 251

Deuterium kinetic isotope effect (2H KIE). Donor/acceptor specificity, of

See also D2O glycosyltransferases, 101 IMPDH activation and, 38–39 Donor substrates, accepted by OleD, 74 IMPDH kinetics and, 19–20, 21, 24, 31 Double-displacement mechanism, of 3,4-Dichloroaniline, oleandomycin and, 74 glycosyltransferases, 63–64 Digitoxin, glycosylation of, 56 Downstream enzyme promoters, carotenoid Dihydro-b-carotenes, biosynthesis of, 165 biosynthesis and, 140 Dihydroflavonol 4-reductase (DFR), in Doxorubicin, 95–96, flavonoid pathway, 178–179 molecular structure of, 95 Dihydroflavonols, in flavonol synthesis, 182 Drosophila melanogaster, resveratrol effects Dihydrokaempferol in, 185 in hydroxylated flavonoid synthesis, 190 Drug resistance, in Saccharomyces synthesis of, 183 cerevisiae, 36. See also Resistance Dihydroquercetin dTDP donor substrates in hydroxylated flavonoid synthesis, 190 erythromycins and, 70 synthesis of, 183 of DesVII–DesVIII, 68 1,10-Dihydroxylycopene, biosynthesis of, 165 vicenistatin and, 93–94, 95 7,8-Dihydrozeaxanthin, biosynthesis of, 165 dTDP-rhodosamine, 98 Dimethylallyl diphosphate. See Dimethylallyl DXD motif, in glycosyltransferases, 60 pyrophosphate (DMAPP) dxs gene, carotenoid biosynthesis and, 140, Dimethylallyl pyrophosphate (DMAPP), 134 164, 165 in Taxol synthesis, 159–160 in terpenoid synthesis, 153, 154, 155 EcoCyc database, 127 4-Diphosphocytidyl-2-C-methyl-D-erythritol EXIMP complex. See also Inosine (CDP-ME), in MEP pathway, 154, 155 monophosphate (IMP) Diphospholipid donor-dependent in IMPDH kinetics, 17–19 peptidoglycan glycosyltransferases, 62 protein dynamics and, 32 Diphosphomevalonate decarboxylase, in in Tritrichomonas foetus, 20, 22, 27–28 MVA pathway, 154 Electron transfer proteins (etfAB), in butanol Directed evolution production, 196 of carotenoids, 135–136 Elloramycin, 132 of glycosyltransferases, 104–106 EXMMP complex. See also Mizoribine of terpene biosynthesis, 137–138 monophosphate (MMP) Disaccharides, in vancomycin, 56, 57 in IMPDH activation, 38 Diterpenes, 134 protein dynamics and, 33, 34 Diversification,biosyntheticpathway,128–138 species-selective affinity and, 35 DNA, anthracycline interactions with, 96 EXNAD complex, in Tritrichomonas DNA damage, from enediynes, 88–89 foetus, 22. See also Nicotinamide DNA sequences, BLAST algorithm with, adenine dinucleotide (NAD) 123–124 Endoplasmic reticulum (ER), cytochrome- DNA technologies, future of, 143 P450 enzymes and, 186–187, 188 dNDP-D-olivose, urdamycin A and, 102. See Enediynes, 88–93 also NDP (nucleoside diphosphate) Engineering. See also Genetic engineering; donors Metabolic engineering; Metabolic dNDP-L-rhodinose, urdamycin G and, 102 pathway engineering; Pathway Domains, protein dynamics and, 31 engineering; Protein engineering 252 SUBJECT INDEX

Engineering. (Continued) in medical and industrial compound of anthocyanin synthesis, 184–185 synthesis, 122, 123 of biofuels, 191 in shikimate synthesis, 174–175 of flavanone synthesis, 177 in Taxol synthesis, 159, 160 of flavonoids, 175–176 epoA gene, in epothilone biosynthesis, 170 of flavonols, 182–183 epo genes, in epothilone biosynthesis, 170 of hydroxylated flavonoid synthesis, EPOSA module, in epothilone biosynthesis, 189–190 170 of isoprenoid pathways, 134–135 EPOSP module, in epothilone biosynthesis, of natural product glycosyltransferases, 170 101–106 Epothilone A of resveratrol synthesis, 185–186 biosynthesis of, 170, 171 of unnatural carotenoids, 165–166 molecular structure of, 168 Enolates, synthesis of, 167–168 Epothilone B Enoyl reductase domain, in combinatorial biosynthesis of, 170, 171 pathway design, 129, 132 molecular structure of, 168 Enterobactins, 83–86 Epothilone C, biosynthesis of, 170, 171 glucosylation of, 85 Epothilone D, biosynthesis of, 170, 171 molecular structure of, 57, 85 Epothilones, 167, 169–171 Enterococci, vancomycin-resistant, 79 biosynthesis of, 169, 170–171 Enterococcus faecium, vancomycin chemical synthesis of, 169 derivatives versus, 82 industrial development of, 169–170 Enthalpy–entropy compensation, protein molecular structure of, 168, 170 dynamics and, 32 Epoxidases, in carotenoid biosynthesis, 161, Enzyme activity, in biosynthetic pathway 162 regulation, 143 ERG genes, in artemisinin synthesis, Enzyme-based reactions, green chemistry 158–159 and, 152 Ergosterol, 134, 135 Enzyme-dependent approaches, to natural in carotenoid biosynthesis, 163 product glycosylation, 58, 59 ERG8 gene, MVA pathway and, 153, 154 Enzyme expression levels, messenger RNA Eriodictyol (mRNA) transcript and, 140–141 in flavonoid pathway, 178–179 Enzyme function, protein dynamics synthesis of, 183 and, 31 Erwinia, carotenoid desaturases from, 136 Enzymes Erwinia herbicola, unnatural carotenoids in anthocyanin synthesis, 184 from, 165–166 in biosynthetic pathway optimization, Erwinia uredovora 138–139 in carotenoid biosynthesis, 163 in butanol production, 196–197 unnatural carotenoids from, 165–166 carotenoid end group modifying, 136 EryBV glycosyltransferase, 70, 71 cytochrome-P450, 186–190 calicheamicin and, 93 in ethanol production, 192 EryCII/III glycosyltransferases, 70–72 in flavanone synthesis, 177 eryCIII gene, 70 in flavone synthesis, 182 Erythromycin(s), 69–72, 167, 171–172 in flavonoid pathway, 178–179 molecular structure of, 168 in isoflavone synthesis, 180–181 oleandomycin and, 75 SUBJECT INDEX 253

Erythromycin A, 64 patellamide biosynthesis by, 126 biosynthesis of, 69 in PCP degradation, 142 molecular structure of, 65, 69 polyketide biosynthesis in, 130–132 synthesis of, 167–168 as production organism, 142–143 Erythromycin B, molecular structure and resveratrol from, 185–186 biosynthesis of, 69, 70 in shikimate synthesis, 174–175 Erythromycin C, molecular structure and in Taxol synthesis, 160 biosynthesis of, 69, 70 in terpene biosynthesis, 138 Erythromycin D, molecular structure and ubiquinone from, 167 biosynthesis of, 69, 70 unnatural carotenoids from, 165–166 Erythromycin G, 70 Esperamycin-A, shikimates and, 173 Erythronolides, 69–70. See also Esters, from plant cultures, 156–157 6-Deoxyerythronolide B entries Estradiol, 94, 180 Erythrose 4-phosphate (E4P), in shikimate Ethanol, as biofuel, 191–195 synthesis, 174 5-Ethylerythromycin, synthesis of, 172 Escherichia coli Ethylmalonyl-CoA extender unit anthocyanins from, 184, 185 in combinatorial pathway design, 129, 130 aromatic flavonoid derivatives from, 186, Eucarya (eukaryotes) 187, 188–189 aromatic flavonoid derivatives from, 186 in artemisinin synthesis, 158, 159 IMPDH from, 5, 11 in astaxanthin biosynthesis, 164, 165 in KEGG database, 126 as biofuel synthesis biocatalyst, 191 Eukaryotic cytochrome-P450, in isoflavone in butanol production, 196–197 synthesis, 180–181 calicheamicin from, 89 Euphorbia milli, terpenoids from, 155 in carotenoid biosynthesis, 140, 163, 164 Evolutionary design in combinatorial pathway design, 128, 129 of biosynthetic reaction sequences, in directed glycosyltransferase evolution, 121–150 104–105 of glycosyltransferases, 104–106 enterobactin and, 85 in isoprenoid biosynthesis, 134–138 epothilones from, 169 EXXMP complex. See also Xanthosine in erythromycin synthesis, 171, 172 5-monophosphate (XMP) in ethanol production, 191–192, 192–193 in IMPDH kinetics, 17–19 ethanol-tolerant strains of, 193–194, 195 in Tritrichomonas foetus,21 in flavanone synthesis, 177, 179, 180 E-XMP* hydrolysis flavones from, 181 in Escherichia coli, 22, 23–24 in flavonoid synthesis, 176 in humans, 25–26 flavonols from, 183 protein dynamics and, 34–35, 36 IMPDH subdomain in, 41 EXXMPXNAD complex. See also Nicotinamide inosine 50-monophosphate dehydrogenase adenine dinucleotide (NAD) from, 6, 9, 12, 15, 22–25, 29, 36, 38–39 in IMPDH kinetics, 18–19 isoflavones from, 181 in IMPDH ligand binding, 29 isoprenoid pathways engineered in, protein dynamics and, 34 134–135 E-XMP* thioinidate, 4 MEP pathway in, 154, 155 in IMPDH activation, 37, 39 in natural product biosynthesis, 198 IMPDH chemical mechanism and, 29, 30 optimizing biosynthesis in, 141 in IMPDH kinetics, 17–19 254 SUBJECT INDEX

E-XMP* (Continued) in flavonoid pathway, 178–179 IMPDH ligand binding and, 26, 27, 28, 29 Flavonoid 30,50-hydroxylase (F3050H) species-selective affinity and, 35 cytochrome-P450 enzymes and, 189–190 in Tritrichomonas foetus, 21–22 in flavonoid pathway, 178–179 Extender units, in combinatorial pathway Flavonoid 30-hydroxylase (F30H), design, 129, 130, 131 cytochrome-P450 enzymes and, 189–190 Flavonoid glycosyltransferases, mechanisms Farnesyl diphosphate (FPP), 135, 136 of action of, 62 in biosynthetic pathway optimization, 139 Flavonoid pathways, 178–179 in carotenoid biosynthesis, 162, 163 in combinatorial pathway design, 129 in MVA pathway, 153, 154 Flavonoids, 175–185 Farnesyl diphosphate synthase. See Farnesyl anthocyanins, 183–185 pyrophosphate synthase (FPPS) in directed glycosyltransferase evolution, Farnesyl pyrophosphate synthase (FPPS) 105–106 in artemisinin synthesis, 158 flavanones, 177–180 in carotenoid biosynthesis, 163 flavones, 181–182 in MVA pathway, 154 flavonols, 182–183 Far-ultraviolet (UV) dichroism spectrum, isoflavones, 180–181 protein dynamics and, 32 polyketides versus, 167 Fe(III). See Iron [Fe(III)] Flavonols, 175, 182–183 Fermentation synthesis of, 176, 178–179 in biosynthesis optimization, 142 Flavonol synthase (FLS) in butanol production, 197 in flavonoid pathway, 178–179 in erythromycin synthesis, 172 in flavonol synthesis, 182 in ethanol production, 191–192 Flexibility, of inosine 50-monophosphate in terpene biosynthesis, 138 dehydrogenase molecule, 13, 31–35 FK506 immunosuppressant, shikimates and, Fluorescent-activated cell sorting (FACS), 173 in directed glycosyltransferase Flanking domain, in IMPDH molecules, 9 evolution, 105 Flap structures FNR regulatory function, in ethanol in IMPDH ligand binding, 27 production, 193 in IMPDH molecule, 4, 9, 11, 12, Fold structures 13, 20 in glycosyltransferase mechanism of protein dynamics and, 31, 32, 33–34 action, 62–63 Flavanone 3b-hydroxylase (FHT) in glycosyltransferases, 60, 61–62 in flavonoid pathway, 178–179 FPP genes, in artemisinin synthesis, 158–159 in flavonol synthesis, 182 Fragaria, in anthocyanin synthesis, 185 Flavanones, 175, 177–180 Fragrances, terpenoids as, 152 in flavone synthesis, 181 Front-face mechanism, of in flavonol synthesis, 182 glycosyltransferases, 64 synthesis of, 176, 177–180 Fruits Flavones, 175, 181–182 anthocyanins in, 183 medicinal applications of, 181 flavonoids from, 175 synthesis of, 176, 178–179 improving carotenoid content of, 161 Flavone synthases (FSI, FSII) Fucose, AknK glycosyltransferase and, in flavone synthesis, 182 96–98 SUBJECT INDEX 255

Fuel, in chemical manufacturing, 152 Geranylgeranyl diphosphate (GGDP, GGPP), Fumarate reductase (frd, frdBC) 135, 136 in butanol production, 196–197 in carotenoid biosynthesis, 161, 162 in ethanol production, 192 in Taxol synthesis, 160 Fungi, carotenoids in, 160. See also Yeast Geranylgeranyldiphosphate synthase (GGPPS, crtE) Galactose, oleandomycin and, 74–75 in carotenoid biosynthesis, 140, 161, 162, b-1,4-Galactosyltransferase, in structure- 163 guided glycosyltransferase design, 104 in Taxol synthesis, 159, 160 Gasoline, butanol and, 195 in unnatural carotenoid synthesis, GenBank, 124 165–166 Gene assignments, in genomes, 123–124 Gerbera, in anthocyanin synthesis, 185 Gene cassettes, in natural product Gibberellins, 152 glycosylation, 58 Gluconobacter suboxydans, ubiquinone Gene clusters, 124 from, 167 methymycin and, 66 Glucosaminyltransferases, 83 in tylosin synthesis, 173 Glucose Gene deletions, in carotenoid biosynthesis, calicheamicin and, 89 163–164 NovM glycosyltransferase and, 88 Gene expression, in biosynthetic pathway Glucose metabolism, in shikimate synthesis, regulation, 143 174 Genes Glucosylase, carotenoid, 136 in biosynthesis optimization, 141 Glutamic acid (glutamate) in butanol production, 196 cytochrome-P450 enzymes and, 188 in epothilone biosynthesis, 170 in IMPDH activation, 37 in erythromycin synthesis, 171–172 species-selective affinity and, 35 locating on chromosomes, 124 D-Glyceraldehyde 3-phosphate (G3P) plant biosynthetic, 137 in carotenoid biosynthesis, 161, 164 Genetic engineering, green chemistry and, in isoprenoid production, 135 152. See also Engineering in MEP pathway, 153 Genetic manipulations, in improving Glycerol-limited conditions, biosynthesis carotenoid content of plants, 161 optimization under, 141–142 Genistein Glycidol, in epothilone synthesis, 169 in flavonoid pathway, 178–179 Glycine synthesis of, 180 cytochrome-P450 enzymes and, 189 Genkwanin, in flavonoid pathway, 178–179 in IMPDH activation, 37 Genome shuffling, in biosynthesis Glycine metabolism, in ethanol production, optimization, 142 193 Genomics, 123 Glycodiversification, strategies for, 56–58, 59 Genomic sequences, 123–126 Glycopeptide antibiotics, 78–86 databases of, 123–126 Glycosylation, of 6-DEB, 131–132 in medical and industrial compound Glycosyltransferases (GTs), 55–119 synthesis, 122 aminocoumarins, 86–88 Geranyl diphosphate (GPP) aromatic polyketides, 95–101 in MVA pathway, 153, 154 in carotenoid biosynthesis, 163 in Taxol synthesis, 159 chemical mechanisms of, 62–64 256 SUBJECT INDEX

Glycosyltransferases (Continued) GtfB glycosyltransferase in combinatorial pathway design, 129 calicheamicin and, 93 enediynes, 88–93 chloroeremomycin and, 79–82 engineering, 101–106 GtfC glycosyltransferase, chloroeremomycin importance of natural product, 56–58, and, 79–82 59, 107 GtfD glycosyltransferase, 61 in vitro characterization of natural product, calicheamicin and, 93 64–101 vancomycin and, 79–83 macrolactams, 93–95 GtfE glycosyltransferase, vancomycin and, macrolides, 64–78 79–82 nonribosomal peptides, 78–86 Guanacastepenes, 152 in polyketide biosynthesis, 132 Guanine biosynthesis, 14 sequence classification of, 58–60 Guanosine monophosphate (GMP), structural classification of, 60–62 biosynthesis of, 2, 3. See also GMP GMP reductase, molecular structure of, 9. See reductase also Guanosine monophosphate (GMP) GOLD database, 123 Haematococcus pluvialis, in carotenoid Grains, anthocyanins in, 183 biosynthesis, 164 Gram-negative bacteria, MEP pathway in, 153 Halogenases, in combinatorial pathway Grapes. See also Vinis vinifera design, 129 anthocyanins from, 183 Halo-purine nucleotides, IMPDH chemical resveratrol from, 185 mechanism and, 30 “Green/amber/red assay,” in oleandomycin Hamsters. See Mammals studies, 73–74 Heart disease, carotenoids in treating, 161

Green chemistry, 152 Heavy water (D2O), IMPDH chemical Growth processes, biosynthesis optimization mechanism and, 31 and, 141–142 Hedamycin, 86 Grubbs catalyst, in epothilone synthesis, 169 HedL glycosyltransferase, 86 GT-A fold structure Hemoglobin, in astaxanthin synthesis, in directed glycosyltransferase evolution, 164–165 104–105 Herbs, flavonoids from, 175 in glycosyltransferase mechanism of Heterologous hosts action, 62–63 optimizing biosynthesis in, 141 in glycosyltransferases, 60, 61, 62 polyketide production in, 131–132 in structure-guided glycosyltransferase as production organisms, 142–143 design, 103–104 in terpene biosynthesis, 137–138 GT-B fold structure Hsp90 glycosyltransferase, 86 in directed glycosyltransferase evolution, Humans 105–106 flavonoids for, 175 in glycosyltransferase mechanism of IMPDH subdomain in, 41 action, 62–63, 86 inosine 50-monophosphate dehydrogenase in glycosyltransferases, 60, 61–62, 78 from, 5–9, 25–27, 29, 37–39 in structure-guided glycosyltransferase medicinal benefits of carotenoids to, 161 design, 104 resveratrol effects in, 185 GtfA glycosyltransferase, chloroeremomycin Hybrid genomes, in combinatorial pathway and, 79–82 design, 129 SUBJECT INDEX 257

Hydride transfer, IMPDH activation and, 38 IMP analogs, of IMPDH, 15, 16. See also Hydrogen bonding Inosine monophosphate (IMP) in IMPDH ligand binding, 29 IMP binding site, of IMPDH, 26–28 vicenistatin reactions and, 94 IMP dehydrogenases, 15 Hydrolysis IMPDH inhibitors, 4. See also Inosine of E-XMP* thioimidate, 4 50-monophosphate dehydrogenase IMPDH chemical mechanism and, 30 (IMPDH) 1-Hydroxy-2-methyl-2-(E)-butenyl medicinal applications of, 14–16 4-diphosphate (HMBPP), in MEP IMPDH monomer, 4 pathway, 154, 155 Industrial compounds, synthesis of, 122 3-Hydroxy-3-methylglutaryl-coenzyme A Ingenol, 152 (HMG-CoA), in MVApathway, 153, 154 Inhibitors, of inosine 50-monophosphate 3-Hydroxy-3-methylglutaryl-coenzyme A dehydrogenase, 14–16, 17 reductase Inosine 50-monophosphate dehydrogenase in artemisinin synthesis, 158 (IMPDH), 1–53. See also IMPDH in MVA pathway, 153, 154 entries 3-Hydroxy-b-zeacarotene, biosynthesis of, active site of, 23–24 165 Bateman domain of, 37, 39–42 3-Hydroxybutyryl-CoA, in ethanol chemical mechanism of, 29–31 production, 192 crystal structure of, 5–8 3-Hydroxybutyryl-CoA dehydrogenase (hbd) effects of mutations of, 25 in butanol production, 196 from Escherichia coli, 6, 9, 12, 15, in ethanol production, 192 22–25, 29 10-Hydroxy-g-carotene, biosynthesis of, 165 human, 5–9, 25–26 Hydroxylases IMP analogs of, 15, 16 carotenoid, 136 isozymes of, 3–4 in carotenoid biosynthesis, 161, 162 kinetic mechanism of, 17–26 Hydroxylated flavonoids, synthesis of, kinetic properties of, 5, 6 189–190 ligand binding of, 26–29 1-Hydroxylycopene, biosynthesis of, 165 medicinal applications of inhibitors of, Hydroxymalonyl-ACP extender unit, in 14–16 combinatorial pathway design, molecular structure of, 9–13 129, 130 monovalent cation activation of, 36–39 1-Hydroxyneurosporine, biosynthesis of, 165 NAD analogs of, 15–16 Hypericins, from plant cell cultures, 155 natural product inhibitors of, 16 Hypericum perforatum, terpenoids from, 155 novel synthetic inhibitors of, 17 Hypoxanthine, in purine nucleotide prominent features of, 4–5, 6, 7 biosynthetic pathways, 2 protein conformational flexibility of, 13, 31–35 Idarubicin, 98 protein structures of, 5–13 idi gene purification of, 5 in astaxanthin synthesis, 165 in purine nucleotide biosynthesis, 1–4 carotenoid biosynthesis and, 140 sequence comparisons among isozymes Illicium, shikimic acid from, 174 of, 12 IMD2/4 genes, in Saccharomyces cerevisiae, species-specific drug selectivity of, 35–36 36 subdomain of, 9, 13, 37, 39–42 258 SUBJECT INDEX

Inosine (Continued) Isolemonene, artemisinin from, 157 substrate interactions of, 17–20 Isoleucine, IMPDH ligand binding and, 299 from Tritrichomonas foetus, 6–8, 9–11, 12, Isopentenyl diphosphate. See Isopentenyl 13, 16, 20–22, 27–28, 29 pyrophosphate (IPP) water activation mechanism of, 31–35 Isopentenyl diphosphate isomerase (Idi), in Inosine monophosphate (IMP). See also carotenoid biosynthesis, 163 EXIMPcomplex;IMPentries;6-Cl-purine Isopentenyl pyrophosphate (IPP), 134. See riboside monophosphate (6-Cl-IMP) also IPP entries binding of, 4, 26–28 in biosynthetic pathway optimization, 139 in Escherichia coli, 22–25 in carotenoid biosynthesis, 161, 162, 163 in humans, 25–26 in Taxol synthesis, 159–160 in IMPDH activation, 37, 38 in terpenoid synthesis, 153, 154, 155 IMPDH chemical mechanism and, 29, Isopentenyl pyrophosphate isomerase 30, 31 promoter,carotenoid biosynthesisand,140 IMPDH inhibitors and, 14, 15, 16 Isoprene units in IMPDH kinetics, 18–19 in terpenoid synthesis, 153, 154, 155 kinetic properties of, 5, 6 in ubiquinone synthesis, 166 molecular structure of, 3 Isoprenoid biosynthesis, evolutionary design protein dynamics and, 32 in, 134–138 in purine nucleotide biosynthetic Isoprenoids, 134, 152. See also Terpenoids pathways, 2, 3 Isoprenoid wax esters, microbial synthesis of, in Tritrichomonas foetus, 20–22 124–125 Insecticides, pyrethrins as, 156–157 Isorawsonol, as IMPDH inhibitor, 16 Institute for Genomic Research, The (TIGR), Isozymes, IMPDH, 3–4, 5–13 124, 125 ispB gene, in astaxanthin synthesis, 165 Inverting enzymes, in glycosyltransferase ispD gene, carotenoid biosynthesis classification, 60 and, 140 Inverting glycosyltransferases, mechanism of ispDispF gene, in astaxanthin synthesis, 165 action of, 62–63 ispF gene, carotenoid biosynthesis and, 140 Invitro evolution, of carotenoid functions, 135 ispH gene, in MEP pathway, 154, 155 IPP–DMAPP isomerase, in MVA pathway, Ivermectins, 75–76 154. See also Dimethylallyl pyrophos- molecular structure of, 76 phate (DMAPP); Isopentenyl pyrophos- phate (IPP) Jasmolone, from plant cultures, 156–157 IPP isomerase J. Craig Venter Institute, metagenomic in artemisinin synthesis, 158 database at, 128 in Taxol synthesis, 159–160 iroB gene, 85 Kaempferol IroB glycosyltransferase, 85–86 in flavonoid pathway, 178–179 Iron [Fe(III)], enterobactins and, 83–85 in hydroxylated flavonoid synthesis, 190 Isoflavones, 175, 180–181 oleandomycin and, 75 Isoflavone synthase (IFS) synthesis of, 183 in flavonoid pathway, 178–179 KEGG (Kyoto Encyclopedia of Genes and in isoflavone synthesis, 180–181 Genomes) databases, 126–127 Isoflavonoids, 180 Ketoacids, in epothilone synthesis, 169 synthesis of, 178–179 Ketolase, carotenoid, 136 SUBJECT INDEX 259

Ketolides, 64–65 Leucocyanidin, in flavonoid pathway, Ketoreductase (KR) domain, in combinatorial 178–179 pathway design, 129, 130, 132 Leucodelphinidin, in flavonoid pathway, Ketosynthase (KS) domain 178–179 in combinatorial pathway design, 129, 130, Leucopelargonidin, in flavonoid pathway, 132–133 178–179 protein–protein interactions and, 133–134 Leukemia Kinetic analysis, of vancomycin derivatives, enediynes versus, 89 79 IMPDH isozymes and, 4 Kinetic isotope effect (KIE), IMPDH kinetics Lewis acids, in glycosyltransferase and, 19–20, 21, 24, 31 mechanism of action, 63, 64 Kinetic mechanisms, of inosine LgtC glycosyltransferase, 60, 61 50-monophosphate dehydrogenase, Library, of calicheamicin variants, 91 17–20, 20–22, 22–26 Ligand binding Kinetics of inosine 50-monophosphate of IMPDH, 5, 6 dehydrogenase, 26–29 of IMPDH chemical mechanism, 30–31, protein dynamics and, 31, 32 32–35, 37, 38–39 Ligands, in KEGG database, 126–127 of IMPDH ligand binding, 26–29 Limonene, 134 of IMP, MMP, RMP, MPA, and TAD, 5, 6 Limonene hydroxylase, 187–188 of Tritrichomonas foetus IMPDH, 19 Lindleyin, medicinal applications of, 168 Klebsiella oxytoca, in ethanol production, 192 Lipophilic antioxidants, ubiquinone, KO11 Escherichia coli, in ethanol production, 166–167 192–193 Loop structures in IMPDH ligand binding, 27 lac promoter, in artemisinin synthesis, 158 in IMPDH molecules, 9–11, 12, 13, 20 Lactate dehydrogenase (ldhA), in butanol protein dynamics and, 31, 32 production, 196–197 Low dissolved-oxygen (DO) levels, in Lactobacillus, in low pH environments, astaxanthin synthesis, 165 142 Luteolin, in flavonoid pathway, 178–179 Lactococcus lactis, IMPDH Bateman domain Lycopene, carotenoid biosynthesis and, 140, in, 41–42 161, 162, 163, 164 Lactone aglycones, macrolide Lycopene cyclase (crtY) glycosyltransferases and, 66 in carotenoid biosynthesis, 161, 162, lacZ gene, 188, 189 163 Landomycin oligosaccharide, 75 in unnatural carotenoid synthesis, 166 LanGT1 glycosyltransferase, 75 Lycopene production genes, in biosynthesis LanGT4 glycosyltransferase, 75 optimization, 141 Leber congenital amaurosis, 40 Lymphocytes, IMPDH expression in, 14 Leucine, in hydroxylated flavonoid synthesis, 190 Macrocyclic lactone aglycones, macrolide Leucoanthocyanidins glycosyltransferases and, 66 in anthocyanin synthesis, 185 Macrolactams, 93–95 in flavonoid synthesis, 176 Macrolactone ring, in combinatorial pathway Leucoanthocyanin synthase (LAR), in design, 129 flavonoid pathway, 178–179 Macrolactones, in enterobactin, 85 260 SUBJECT INDEX

Macrolides, 64–78 Melanoma, flavones versus, 181 avermectin, 75–77 MEP cytidylyltransferase, in MEP pathway, classification and development of, 154, 155. See also 2-C-Methyl-D- 64–66 erythritol-4-phosphate (MEP) erythromycin, 69–72 MEP pathway, in terpenoid synthesis, methymycin, 66–69 153–155 oleandomycin, 72–75 6-Mercaptopurine, IMPDH inhibitors and, 14 OleD glycosyltransferase of, 61 Messenger RNA (mRNA), cytochrome-P450 sorangicin, 77–78 enzymes and, 189 Malaria, artemisinin versus, 157 Messenger RNA transcript, in tuning enzyme Malonic acid, in combinatorial pathway expression levels, 140–141 design, 129 Metabolic engineering, in medical and Malonyl-CoA industrial compound synthesis, 122–123 in flavanone synthesis, 177 Metabolic pathway engineering, 128–138 in flavonoid pathway, 178–179 in natural product glycosylation, 58, 59 formation of, 179 Metabolic pathways, databases of, polyketides and, 167 126–128 Malonyl-CoA extender unit, in combinatorial Metabolic traits, in biosynthesis optimization, pathway design, 129, 130, 131 141 Malus domestica, in anthocyanin synthesis, MetaCyc database, 127 184. See also Apples Metagenomic approaches, 123–128 Mammalian cells, IMPDH expression in, 14 in medical and industrial compound Mammals, IMPDH from, 5, 12, 26, 27, 37 synthesis, 122 Mannosylglycerate synthase (MGS), Metal ions, in IMPDH activation, 38–39 60, 61 Methoxyluteolin, in flavonoid pathway, Marinobacter, peptide sequence of, 125 178–179 Marinobacter aqualolei, peptide sequence of, Methoxymalonyl-ACP extender unit, in 125 combinatorial pathway design, 129, 130 Marinobacter hydrocarbonoclasticus,wax 2-C-Methyl-D-erythritol 2,4-cyclodipho- esters from, 124–125 sphate (MECDP) synthase, in MEP Mass production, of flavonoids, 175–176 pathway, 154, 155 Mass spectrometry, in oleandomycin studies, 2-C-Methyl-D-erythritol-4-phosphate (MEP), 73–74 153–154, 155 Maximum production, in medical and in- b-Methylene-biphosphonate (b-TAD, dustrial compound synthesis, 123 b-CH2-TAD). See also Tiazofurin Mechanisms of action adenine dinucleotide (TAD) in glycosyltransferase classification, 60 in IMPDH activation, 38 of glycotransferases, 62–64 IMPDH crystal structure and, 8, 11, 12 Medicago trunculata, in structure-guided in IMPDH ligand binding, 28 glycosyltransferase design, 104 kinetic properties of, 5, 6 Medical compounds, synthesis of, 122–123 NAD analogs of IMPDH and, 16 Medicinal applications, of inosine 50- species-selective affinity and, 35e monophosphate dehydrogenase, 14–16 dinucleotide (TAD) Megalomicins Methylmalonyl-CoA molecular structure of, 57 in erythromycin synthesis, 171, 172 naturally occurring, 65–66 polyketides and, 167 SUBJECT INDEX 261

Methylmalonyl-CoA extender unit, in Misfolded proteins, studies of, 188 combinatorial pathway design, 129, 130, Mizoribine 131 as IMPDH inhibitor, 14 N-Methyl-N0-nitro-N-nitrosoguanidine (NTG) molecular structure of, 7 in ubiquinone biosynthesis, 166–167 Mizoribine monophosphate (MMP). See also Methylomonas, in astaxanthin synthesis, 164 EXMMP complex 7-O-Methyltransferase (7OMT) IMP analogs of IMPDH and, 15 in flavone synthesis, 182 in IMPDH activation, 38 in flavonoid pathway, 178–179 kinetic properties of, 5, 6 Methyl transferases, in carotenoid resistance to, 36 biosynthesis, 163 Monooxygenase, carotenoid, 136 Methymycin, 66–69 Monoterpene esters, from plant cultures, molecular structure and biosynthesis of, 67 156–157 Mevalonate (MVA) kinase Monoterpenes, 134 in artemisinin synthesis, 158 Monovalent cation activation, of inosine in MVA pathway, 153, 154 50-monophosphate dehydrogenase,36–39 Mevalonate pathway, in terpenoid synthesis, Mutagenesis 153, 154 in astaxanthin biosynthesis, 164 Mevalonate pyrophosphate decarboxylase, in in biosynthesis optimization, 141, 142 artemisinin synthesis, 158 as glycosyltransferase mechanism of MGT (macrolide glycosyltransferase), 72, 73. action, 62 See also OleD glycosyltransferase in carotenoid biosynthesis, 163 Michaelis complexes, IMPDH chemical in tylosin synthesis, 173 mechanism and, 29 Mutagenesis study, of human IMPDH, 26–27 Microbial Biocatalytic Reactions and Mutasynthesis, in natural product Biodegradation (UM-BBD) Pathway glycosylation, 59 Database, 127–128 Mutations Microbial genomics, advances in, 122–123 in biosynthesis optimization, 141–142 Microbial synthesis carotenoid biosynthesis and, 140 of anthocyanins, 184 cytochrome-P450 enzymes and, 187, 188, of biofuels, 152 189 of classic carotenoids, 161–165 in directed glycosyltransferase evolution, of epothilones, 169–170 105 of flavonoids, 176–177 in ethanol production, 193–194, 194–195 of natural products, 152 IMPDH subdomain, 40–41 of polyketides, 167–173 in ubiquinone biosynthesis, 166–167 of resveratrol, 185–186 Mycarose, 70 of terpenoids, 152–153, 158–160 Mycophenolic acid (MPA) of ubiquinone, 166–167 in humans, 25 of unnatural carotenoids, 165–166 IMPDH activation and, 37–39 Micromonospora megalomicea, IMPDH inhibitors and, 14, 15–16 megalomicins from, 65–66 in IMPDH ligand binding, 28, 29 Microorganisms kinetic properties of, 5, 6 as biofuel synthesis biocatalysts, 191 molecular structure of, 7 in medical and industrial compound protein dynamics and, 32 synthesis, 122–123 species-selective affinity of, 35–36 262 SUBJECT INDEX

Mylotarg, 89 NDP donor specificity, in directed Myrcene, 134 glycosyltransferase evolution, 106 Myricetin Negative cooperativity, protein dynamics and, in flavonoid pathway, 178–179 32 in hydroxylated flavonoid synthesis, 190 Neisseria meningitidis, glycosyltransferases Myxococcus xanthus, in epothilone of, 60 biosynthesis, 171 Neomethymycin, molecular structure and biosynthesis of, 67 N-acetyl-glucosamine, in teicoplanin, 83 Neuraminidase inhibitors, shikimates and, NAD analogs. See also Nicotinamide adenine 173 dinucleotide (NAD) Nicotiana tabacum, resveratrol from, 186 of human IMPDH, 25–26 Nicotinamide adenine dinucleotide (NAD) of IMPDH, 15–16 in Escherichia coli, 22, 23–24 NAD binding site, of IMPDH, 28–29 in humans, 25–26 NADH cofactor, in butanol production, 196. in IMPDH activation, 38 See also Reduced nicotinamide adenine IMPDH binding of, 28–29 dinucleotide (NADH) IMPDH chemical mechanism and, 30, 31 NADPH–cytochrome-P450 reductase, in IMPDH inhibitors and, 14, 15–16 terpene biosynthesis, 138 in IMPDH kinetics, 17–19 Narbomycin, molecular structure and IMPDH ligand binding and, 27 biosynthesis of, 67 molecular structure of, 3 Naringenin protein dynamics and, 32, 33–34 in flavonoid pathway, 178–179 in purine nucleotide biosynthetic in hydroxylated flavonoid synthesis, 190 pathways, 2, 3 synthesis of, 183 species-selective affinity and, 35 National Center for Biotechnology in Tritrichomonas foetus, 20, 21, 22 Information (NCBI), bioinformatics Nicotinamide adenine dinucleotide databases at, 123–124 phosphate (NADPH), cytochrome-P450 Natural product biosynthesis, future of, enzymes and, 186, 187 197–198 Nicotinamide ring, in IMPDH ligand binding, Natural product glycosylation, development 28 of, 56–58, 59 Niddamycin, synthesis of, 172 Natural product glycosyltransferases (GTs), Nitrosoguanidine, in tylosin synthesis, 173 55–119 N-methyl-N0-nitro-N-nitrosoguanidine engineering of, 101–106 (NTG), in ubiquinone biosynthesis, importance of, 56–58, 107 166–167 in vitro characterization of, 64–101 Noncovalent complexes, IMPDH chemical structural chemistry of, 58–64 mechanism and, 29 Natural product inhibitors, of IMPDH, 16 Nonribosomal peptides, 78–86 Natural products, microbial synthesis of, 152 Nonribosomal peptide synthases (NRPSs), Natural resources, in chemical manufacturing, 126 152 in combinatorial pathway design, 128, 129 NDP (nucleoside diphosphate) donors. nov gene cluster, 86 See also dNDP entries Noviose, 86, 88 in natural product glycosylation, 59 NovM glycosyltransferase, 86–88 in vicenistatin reactions, 95 Novobiocin, 86–88 SUBJECT INDEX 263

molecular structure of, 57 P1 phage, in shikimate synthesis, 175 NRP pathway, in combinatorial pathway P67T mutation, in directed design, 128–129 glycosyltransferase evolution, 105 N-terminal domain, in glycosyltransferases, P450 17a-hydroxylase, cytochrome-P450 60, 61 enzymes and, 189. See also Nuclear magnetic resonance (NMR) Cytochrome-P450 entries methods, in IMPDH conformation P450 enzymes studies, 26, 28 in artemisinin synthesis, 159 Nucleotidyltransferases, in natural product in Taxol synthesis, 160 glycosylation, 59 in terpene biosynthesis, 137–138 Nutraceutical supplements, flavonoids as, 175 P450 epoxidase, in epothilone biosynthesis, NysD1 glycosyltransferase, calicheamicin 170 and, 93 P450 proteins, 187 P450 reductases, aromatic flavonoid ole1 gene, 72 derivatives via, 186, 187 Oleandomycin, 72–75 Paclitaxel, from Taxus cell cultures, 156 in directed glycosyltransferase evolution, pACYC184 plasmid, in ubiquinone 105 biosynthesis, 167 molecular structure and glycosylation of, 73 Panthetheinylation, in erythromycin Oleandrose, 70, 71, 75, 76 synthesis, 171 Oleandrosides, 70, 71 Paracoccus denitrificans, ubiquinone from, OleD glycosyltransferase, 61, 72–75 166 OleD mutations, in directed Paracoccus haeundaensis, in astaxanthin glycosyltransferase evolution, 105–106 biosynthesis, 164 oleG1 gene, 72 Patellamide A, 126 oleG2 gene, 72 Patellamide C, 126 OleI glycosyltransferase, 72–75 Pathway design, bioinformatics in, 123 OleR glucosidase, 72 Pathway engineering, 128–138 Olivose, urdamycin A and, 102 in natural product glycosylation, 58, 59 Open reading frames (ORFs), 123–124 Pathway Prediction System (PPS), 127–128 Operons, 124 Pathways in artemisinin synthesis, 158 databases of, 126–128 Optimization, of biosynthetic pathways, 128, in medical and industrial compound 137, 138–142 synthesis, 122, 123 Orf3* glycosyltransferase, teicoplanin and, pcc gene, in erythromycin synthesis, 172 83 Pelargonidin, in flavonoid pathway, 178–179 Organelle genomes, in KEGG database, Pentachlorophenol (PCP), degradation of, 126–127 142 Oritavancin, 79 Peptide sequences, BLAST algorithm with, molecular structure of, 80 123–124 Oxidation reactions, in terpene biosynthesis, Peptidoglycan glycosyltransferases, 62 138 Perilla frutescens, terpenoids from, 155 Oxygenases, in combinatorial pathway Petroleum-based synthesis, of medical and design, 129 industrial compounds, 122 Oxygen availability, in astaxanthin synthesis, Petroselinum crispum, in flavanone synthesis, 164–165 177 264 SUBJECT INDEX

Petunia, in anthocyanin synthesis, 184 Phytoene, in carotenoid biosynthesis, 161, Pharmaceuticals 162 polyketides as, 167 Phytoene desaturase (crtI), in carotenoid terpenoids as, 152 biosynthesis, 161, 162, 163 Pharmacokinetics, glycosyltransferases Phytoene synthase (crtB) in, 56 in carotenoid biosynthesis, 161, 162, 163 Pharmacology, glycosyltransferases in, 56 in unnatural carotenoid synthesis, 165 Phenol, optimizing biosynthesis of, 141 Phytoestrogens, 180. See also Isoflavones Phenotypic screening, in ethanol production, Phytohormones, in improving carotenoid 193–195 content of plants, 161 Phenylalanine Piceatannol, in resveratrol synthesis, 186 IMPDH ligand binding and, 299 PikC hydroxylase, methymycin and, 67 in flavanone synthesis, 177 Pikromycin, molecular structure and in flavonoid pathway, 178–179 biosynthesis of, 67 in polyketide synthesis, 169 Pikromycin PKS gene cluster, 173 protein dynamics and, 34 Pinocembrin, in flavonoid pathway, 178–179 Phenylalanine ammonia lyase (PAL) PKS assembly line. See also Polyketide in anthocyanin synthesis, 184 synthases (PKSs) in flavonoid pathway, 178–179 protein–protein interactions and, 133–134 Phenylalanine/tyrosine ammonia lyase (PAL/ rearranging and modifying, 132–133 TAL), in flavanone synthesis, 177 in synthetic biology, 143 Phenylpropanoic acids, in flavanone PKS biosynthetic gene cluster, in synthesis, 177 combinatorial pathway design, 129–134 pH gradient, in biosynthesis optimization, PKS gene cluster, 173 142 PKS megasynthases, 131 Phosphoenolpyruvate (PEP), in shikimate pK values, of IMPDH chemical mechanism, synthesis, 174 31, 34–35 Phosphoenolpyruvate synthase, in Plant cell cultures astaxanthin synthesis, 164 anthocyanins from, 183–184 Phosphomevalonate kinase in flavonoid synthesis, 176–177 in artemisinin synthesis, 158 terpenoids from, 155, 156–158 in MVA pathway, 154 Plant extraction, terpenoid production via, Phosphopantetheinyl transferase, in 152–153 erythromycin synthesis, 171 Plant P450, in flavone synthesis, 181 5-Phosphoribosyl-1-pyrophosphate (PRPP), Plant PKSs, in polyketide synthesis, 168–169 in purine nucleotide biosynthetic Plants pathways, 2 anthocyanins from, 183–184 Phosphotransacetylase (PTA), in cytochrome-P450 enzymes from, 188 malonyl-CoA formation, 179, 180 flavones from, 182 Photorhabditis luminescens, in flavanone flavonoids from, 175–176 synthesis, 177–179 improving carotenoid content of, 161 pH–rate studies, of IMPDH chemical isoflavones in, 180 mechanism, 30–31 MEP pathway in, 153–155 Phytochemicals, anthocyanins as, 183 polyketides from, 168–169 Phytochrome-activating light, in anthocyanin resveratrol from, 185–186 synthesis, 184 terpene cyclases from, 136–137 SUBJECT INDEX 265

Plasmids of terpenoids, 153, 154, 155 in artemisinin synthesis, 158 Precursor supply, in biosynthetic pathway in tylosin synthesis, 173 regulation, 143 in ubiquinone biosynthesis, 167 Pregnenolone, 94 Plasmodium, artemisinin versus, 157 Prenyl chains, in terpene biosynthesis, “Plug-and-play” gene cassettes, in natural 136–137 product glycosylation, 58 Primary metabolites, terpenoids as, 152, Polyketide biosynthesis 154–155 in Escherichia coli, 130–132 Prochloron didemni, patellamide in heterologous hosts, 131–132 biosynthesis by, 126 Polyketide chain, in combinatorial pathway Proficiency, in directed glycosyltransferase design, 129, 130 evolution, 105 Polyketides, 167–173 Promiscuity, in directed glycosyltransferase biosynthesis of, 129–134 evolution, 105 in combinatorial pathway design, 129 Promiscuous glycosyltransferases epothilones, 167, 169–171 in natural product glycosylation, 59 erythromycins, 167, 171–172 among vancomycin derivatives, 82–83 molecular structures of, 168 Propionyl-CoA pharmaceutical applications of, 167 in erythromycin synthesis, 171, 172 from plants, 168–169 polyketides and, 167 total chemical synthesis of, 167–168 Propionyl-CoA carbonylase, 131 tylosins, 172–173 in erythromycin synthesis, 172 Polyketide synthases (PKSs). See also PKS Propionyl-CoA ligase, 131 entries Protein conformation, of inosine in combinatorial pathway design, 128, 50-monophosphate dehydrogenase, 13, 132–133 31–35 in epothilone synthesis, 169–170 Protein Data Bank (PDB), 10–11, 12 in erythromycin synthesis, 171, 172 Protein dynamics, enzyme function and, 31 in flavanone synthesis, 177 Protein engineering polyketides and, 167, 168–169 advances in, 122–123 protein–protein interactions and bioinformatics in, 123 biosynthesis of, 133–134 Protein expression, in hydroxylated flavonoid in tylosin synthesis, 173 synthesis, 190 Polymerase chain reactions (PCRs) Protein–IMP interactions, 27 in directed glycosyltransferase evolution, 105 Protein–protein interactions, in PKS in ethanol production, 193, 194 biosynthesis, 133–134 in terpene biosynthesis, 137 Proteins Potassium ion (Kþ) Bateman domains in, 41–42 in dehydrogenase activity, 5, 6 in biosynthetic pathway optimization, IMPDH and, 12 139 in IMPDH activation, 36–39 CBS domains in, 39–40 in IMPDH kinetics, 18, 19, 22 IMPDH, 5–7, 9 Precursor-directed biosynthesis, in natural in KEGG database, 126–127 product glycosylation, 59 studies of misfolded, 188 Precursors Protein structures, of inosine 50- in carotenoid biosynthesis, 161 monophosphate dehydrogenase, 5–13 266 SUBJECT INDEX

Proteolysis data, protein dynamics and, 32 Rational protein engineering, of terpene Protoplast fusion, in biosynthesis biosynthesis, 137–138 optimization, 142 Rational sequence-guided design, of Provitamin D2, in carotenoid biosynthesis, glycosyltransferases, 101–103, 163 103–104 prpE gene, in erythromycin synthesis, Rebeccamycin, molecular structure of, 57 171–172 Recombinant DNA (rDNA), in ubiquinone prpRBCD operon, in erythromycin synthesis, biosynthesis, 167 171 Recombinant DNA technologies Pseudomonas putida in medical and industrial compound optimizing biosynthesis in, 141–142 synthesis, 122 polyketide biosynthesis in, 131 in natural product biosynthesis, 197–198 pta gene, in butanol production, 197 Recombinant Escherichia coli,in pUC19 plasmid, in ubiquinone biosynthesis, combinatorial pathway design, 128 167 Recombinant RNA methyltransferase, in Pulegone, artemisinin from, 157 polyketide biosynthesis, 131 Purine nucleotides Recombinant terpene biosynthesis, biosynthesis of, 1–4 optimization and diversification of, as chemotherapeutic agent targets, 14 137–138 Pyrethric acid, from plant cultures, Reduced nicotinamide adenine dinucleotide 156–157 (NADH) Pyrethrins, from plant cultures, 156–157 in Escherichia coli, 22, 24 Pyrethrolone, from plant cultures, in humans, 26 156–157 in IMPDH kinetics, 19 2-Pyrone synthase (2-PS), in polyketide in IMPDH ligand binding, 28 synthesis, 169 molecular structure of, 3 Pyruvate. See also Pyruvic acid protein dynamics and, 32–34 in carotenoid biosynthesis, 161, 164 in purine nucleotide biosynthetic in MEP pathway, 153 pathways, 2–4 Pyruvate decarboxylase (pcd), in ethanol in Tritrichomonas foetus, 20, 21–22 production, 192 Reduction reactions, in terpene biosynthesis, Pyruvate kinase, molecular structure of, 9 138 Pyruvic acid, in ethanol production, 192. Red wine See also Pyruvate anthocyanins in, 183 resveratrol in, 185 Quercetin, 104 Regional Display Viewer, 124 in flavonoid pathway, 178–179 Regioselective glycosylation, 58 in hydroxylated flavonoid synthesis, 190 Relavancin, 79 synthesis of, 183 molecular structure of, 80 Quinic acid, 173–174, 175 Replication processes, biosynthesis Quinones, 135 optimization and, 141–142 Resiniferatoxin, 152 Radiochromatography, cytochrome-P450 Resistance enzymes and, 189 to antimalarial agents, 157 Rate-limiting carotenoid genes, in in Saccharomyces cerevisiae,36 biosynthesis optimization, 141 to vancomycin, 79 SUBJECT INDEX 267

Resveratrol in flavonoid synthesis, 176 in flavonoid pathway, 178–179 isoflavones from, 181 synthesis of, 176, 185–186 isoprenoid pathways engineered in, Retaining double-displacement mechanism, 134–135 of glycosyltransferases, 63–64 in natural product biosynthesis, 198

Retaining SN-1-like mechanism, of resveratrol from, 185, 186 glycosyltransferases, 63, 64 species-specific drug selectivity and Retinitis pigmentosa, 40, 41 IMPDH of, 36 Retinoids, in improving carotenoid content of in Taxol synthesis, 160 plants, 161 in terpenoid synthesis, 158 Retinopathy, 40 Saccharopolyspora erythrea, erythromycin Rhamnose from, 171, 172 calicheamicin and, 89 SaGT4a glycosyltransferase, 103 NovM glycosyltransferase and, 88 Salmochelin, 85 Rhamnosylation, of aranciamycin, 101 Salmonella enterica, enterobactin and, Rhodinose, urdamycin G and, 102 85 Rhodobacter, unnatural carotenoids from, SARP family, in tylosin synthesis, 173 165 Secondary metabolites, terpenoids as, 152, Rhodobacter sphaeroides, ubiquinone from, 154–155 166 Selection, in biosynthesis optimization, 141, Ribavirin 142 IMPDH crystal structure and, 8 Selenazole adenine dinucleotide (SAD) as IMPDH inhibitor, 14 in Escherichia coli,23 molecular structure of, 7 in IMPDH activation, 38 Ribavirin monophosphate (RMP) IMPDH crystal structure and, 8, 9 in IMPDH ligand binding, 27 in IMPDH ligand binding, 28, 29 kinetic properties of, 5, 6 NAD analogs of IMPDH and, 15–16 Ribosome binding sequences, in tuning Sequence-guided design, of enzyme expression levels, 140–141 glycosyltransferases, 101–103 Rifampicin, sorangicin and, 77 Serine, enterobactins and, 85 RNA polymerase, 188 Sesquiterpenes, 134 RNase cleavage sites, in tuning enzyme sfp gene, in erythromycin synthesis, 171 expression levels, 140–141 Shikimate kinase (aroKL), in shikimate Rosmarinic acid, from plant cell cultures, 155 synthesis, 174 Rossman-like domains, in Shikimates, 173–175 glycosyltransferases, 60 Shikimic acid (shikimate), 173–174, 175 RP10 retinitis pigmentosa, 40 Shikonin, from plant cell cultures, 155 rpoD gene, in ethanol production, 193 Sialic acid, in directed glycosyltransferase rpoS gene, in carotenoid biosynthesis, 164 evolution, 105 rssB gene, in carotenoid biosynthesis, 163 Sialyltransferases (STs), in directed glycosyltransferase evolution, Saccharomyces cerevisiae 104–105 anthocyanins from, 184 Sigma 70 factor, in ethanol production, in carotenoid biosynthesis, 163 193, 195

in ethanol production, 191 SN-1-like mechanism, of in flavanone synthesis, 177 glycosyltransferases, 63, 64 268 SUBJECT INDEX

Social concerns, in chemical manufacturing, in polyketide synthesis, 169 152 in resveratrol synthesis, 186 Sodium dodecyl sulfate–polyacrylamide gel Strain improvement, in biosynthesis electrophoresis (SDS-PAGE), 187–188 optimization, 141, 142 Sodium ion (Naþ), in IMPDH activation, 37 Streptococcus pyogenes Solanum aculeatissiumum, IMPDH from, 6–9, 10–11, 12, 13, glycosyltransferases from, 103 37, 38 Sorangicin, 77–78 IMPDH subdomain in, 39–40 molecular structure and analogs of, 77 Streptomyces Sorangium cellulosum aminocoumarins from, 86 in epothilone biosynthesis, 170, 171 in erythromycin synthesis, 171 sorangicin from, 77 in tylosin synthesis, 173 sorF gene, 77 Streptomyces antibioticus, oleandomycin SorF glycosyltransferase, 77–78 from, 72 Species-specific drug selectivity, of inosine Streptomyces avermectinius, avermectin 50-monophosphate dehydrogenase, from, 75 35–36 Streptomyces coelicolor Sphingobium chlorophenolicum, in PCP in epothilone biosynthesis, 170–171 degradation, 142 in erythromycin synthesis, 171 Sphingomonas, in astaxanthin biosynthesis, Streptomyces echinatus, anthracyclines from, 164 101 SPT15 mutant,inethanol production, 194–195 Streptomyces fradiae, tylosin from, 173 Squalene synthase, in MVA pathway, 154 Streptomyces halstedii, vicenistatin from, 93 Standardization, of synthetic biology, 143 Streptomyces spheroides, novobiocin from, Staphylocccus aureus 86 carotenoid desaturase and synthase Streptomyces venezuelae from, 136 methymycin from, 66 aminocoumarins from, 86 tylosin from, 173 genome of, 124, 125 Structure-guided design, of peptidoglycan GTs of, 62 glycosyltransferases, 103–104 vancomycin derivatives versus, 82 StSGT glycosyltransferases, 103 vancomycin-resistant, 79 Subdomains Starter domain, in combinatorial pathway of inosine 50-monophosphate design, 130, 131, 132 dehydrogenase, 9, 13, 37, 39–42 Stereoselective aldol reactions, in polyketide protein dynamics and, 31 synthesis, 167–168 Substrate interactions, of inosine 50- Stereoselective C–C bond formation, in monophosphate dehydrogenase, polyketide synthesis, 167–168 17–20 Stereoselective glycosylation, 58 Substrate recognition, in rearranging and Sterol biosynthetic genes, in artemisinin modifying PKS assembly line, 133 synthesis, 158–159 Sugar biosynthesis, in natural product Sterols, 152 glycosylation, 59 Stilbenes, 185–186 Sugar donors, in natural product synthesis of, 176, 178–179 glycosylation, 58, 59 Stilbene synthase (STS) Sugar exchange reactions, CalG1-catalyzed, in flavonoid pathway, 178–179 90, 91 SUBJECT INDEX 269

Sugar moieties, in glycopeptide antibiotics, Taxane derivatives, from Taxus cell cultures, 78, 80 156 Sugar nucleotide libraries, in natural product Taxane hydroxylases, in Taxol synthesis, 159 glycosylation, 58 Taxoids, from Taxus cell cultures, 156 Sugars Taxol, 134, 138 anthracycline interactions with, 96 microbial synthesis of, 158–160 in biosynthetic pathway optimization, from Taxus cell cultures, 156 138–139 Taxol pathway engineering, in terpene glycosyltransferases and, 56–58, 59 biosynthesis, 138 in vicenistatin reactions, 94–95 Taxus Sugar substrate specificity, methymycin and, in terpene biosynthesis, 138 66–69 terpenoids from cell cultures of, 156 Sulfadoxin, 157 Taxus brevifolia Synthases, carotenoid, 136 Taxol from, 159–160 Synthesis. See also Biosynthesis; Chemical terpenoids from cell cultures of, 156 synthesis; Microbial synthesis; Sugar Taxus chinensis, terpenoids from cell cultures biosynthesis of, 156 of flavones, 181–182 Taxuyunnanine C, from Taxus cell cultures, of isoflavones, 180–181 156 of stilbenes, 185–186 TDP-vicenisamine, 94 of terpenoids, 152–155 Teicoplanin, 83 via cytochrome-P450 enzymes, biosynthesis of, 84 186–190 as glycopeptide antibiotic, 78–79 Synthetic biology molecular structure of, 78, 84 future of, 142–143 tei gene cluster, 83 standardization of, 143 Telithromycin, 65 Synthetic inhibitors, of inosine 50- molecular structure of, 65 monophosphate dehydrogenase, 17 Terpene biosynthesis, optimization and Systems biology, 143 diversification of, 137–138 Terpene cyclases, 136–137 T5 promoter, in astaxanthin synthesis, 165 in terpene biosynthesis, 137, 138 T7 phage promoter Terpenes, 134 in flavanone synthesis, 177 evolutionary biosynthesis of, 136–138 in Taxol synthesis, 160 Terpenoids, 152–160. See also Isoprenoids TAF25 mutant, in ethanol production, applications of, 152 194–195 described, 152–155 Tagetes erecta, pyrethrins from, 157 microbial synthesis of, 152–153, 158–160 TATA-binding protein, in ethanol production, from plant cell cultures, 155, 156–158 194 Tetracenomycin, 132 Taxadiene Tetramers, of IMPDH proteins, 5–7 microbial synthesis of, 159–160 Tetraterpenes, 134 from Taxus cell cultures, 156 tGtfA glycosyltransferase, 83 Taxadiene hydroxylases, in Taxol synthesis, in teicoplanin biosynthesis, 84 159 tGtfB glycosyltransferase, 83 Taxadiene synthase (TS), in Taxol synthesis, in teicoplanin biosynthesis, 84 159 Thalicrum minor, terpenoids from, 155 270 SUBJECT INDEX

The Institute for Genomic Research (TIGR), Tryptophan fluorescence, 20 124, 125 Tubulin polymerization, glycosylation Thioesterase (TE) domain, in combinatorial and, 56 pathway design, 130, 131 Tumor cells, IMPDH expression in, 14 Thiolase (thi) Tuning enzyme expression levels, messenger in butanol production, 196 RNA (mRNA) transcript in, 140–141 in ethanol production, 192 Two-phase partitioning bioreactor (TPPB), in Thio-NAD, in humans, 26 artemisinin synthesis, 158 Tiazofurin, 5 Tylosins, 172–173 as IMPDH inhibitor, 14, 15–16 molecular structure of, 168 molecular structure of, 7 oleandomycin and, 75 species-selective affinity and, 35 TylP protein, in tylosin synthesis, 173 Tiazofurin adenine dinucleotide (TAD). See TylR protein, in tylosin synthesis, 173 also b-methylene-biphosphonate TylS protein, in tylosin synthesis, 173 (b-TAD, b-CH3-TAD) TylU protein, in tylosin synthesis, 173 in Escherichia coli,22 Type I polyketide synthases, in combinatorial IMPDH inhibitors and, 14 pathway design, 128, 130, 132–133 in IMPDH ligand binding, 28, 29 Tyrosine kinetic properties of, 5, 6 in flavanone synthesis, 177 species-selective affinity and, 35 in flavonoid pathway, 178–179 Topoisomerase II inhibitors, anthracyclines IMPDH ligand binding and, 299 as, 96 protein dynamics and, 34 Torulene, in unnatural carotenoid synthesis, 166 Tyrosine ammonia lyase (TAL), in flavonoid Toxicity stresses, in biosynthesis pathway, 178–179 optimization, 142 Tyrosine phenol lyase, in optimizing phenol Toxic solvents, green chemistry and, 152 biosynthesis, 141 Transferred-NOE NMR methods, in IMPDH conformation studies, 26, 28 Ubiquinone(s), 135, 166–167. See also Tricarboxylic acid (TCA) cycle, in butanol Coenzyme-Q10 (CoQ10) production, 196 in carotenoid biosynthesis, 162 Trichomonas foetus. SeeTritrichomonasfoetus medicinal value of, 166 Triose phosphate isomerase (TIM), molecular UDP (uridine diphosphate)-galactose, structure of, 9 glycosyltransferases and, 103 Triterpenes, 134 UDP-glucose, glycosyltransferases and, 103 Tritrichomonas foetus UDP-glucose(flavonoid 3-O- IMPDH inhibitors and, 14 glucosyltransferase (3GT) IMPDH kinetics in, 19 in anthocyanin synthesis, 184 IMPDH subdomain in, 40, 41 in flavonoid pathway, 178–179 inosine 50-monophosphate dehydrogenase UDPGT signature motif, glycosyltransferases from, 6, 7, 8, 9–11, 12, 13, 16, 20–22, and, 103 27–28, 29, 33–35, 37, 38 UDP-N-acetyl-glucosaminyltransferases, 83 species-specific drug selectivity and Ultraviolet (UV) dichroism spectrum, protein IMPDH of, 35 dynamics and, 32 Tryptophan Ultraviolet irradiation IMPDH ligand binding and, 29 in anthocyanin synthesis, 184 in IMPDH molecules, 11 in tylosin synthesis, 173 SUBJECT INDEX 271

United States Vicenisamine, 93 ethanol biofuel production in, 191 Vicenistatin, 93–95 natural product biosynthesis in, VinC glycosyltransferase, 93–94 197–198 reactions catalyzed by, 93, 94 pyrethrin production/marketing in, Vinis vinifera, resveratrol from, 186. See also 156–157 Grapes Universal carotenoid pathway, 161–163 Viruses, flavones versus, 181 Universal precursors, of terpenoids, 153, 154, Vitis, terpenoids from, 155 155 VvGT1 glycosyltransferase, in directed University of Minnesota, biocatalysis/ glycosyltransferase evolution, 105–106 biodegradation database at, 127–128 VX-497, as IMPDH inhibitor, 17 Unnatural aglycone substrates, accepted by OleD, 74 Water activation, of inosine 50- Unnatural carotenoids, synthesis of, 165–166 monophosphate dehydrogenase, 31–35 Unnatural polyketides, synthesis of, 172 Wax esters, microbial synthesis of, 124–125 upc2-1 gene, in artemisinin synthesis, 158 Wax ester synthase/diacyl glycerol Urdamycin, 86 acyltransferase (WS/DGAT), 124–125 Urdamycin A, 102 Urdamycin G, 102 Xanthophylls, 160–161 UrdGT1b glycosyltransferase, 102–103 biosynthesis of, 124 UrdGT1c glycosyltransferase, 102–103 Xanthosine 5-monophosphate (XMP). UrdGT2 glycosyltransferase, 86 See also EXXMP entries UrdGT glycosyltransferases, 103 in Escherichia coli,22 Uridine diphosphate (UDP). See UDP entries in humans, 25–26 in IMPDH activation, 37 VanA glycosyltransferase, 79 IMPDH chemical mechanism and, 29, 30 VanB glycosyltransferase, 79 IMPDH inhibitors and, 14, 15 Vancomycin, 79–83 in IMPDH kinetics, 18–19 calicheamicin and, 91 IMPDH ligand binding and, 26, 28 disaccharide moiety of, 56 molecular structure of, 3 as glycopeptide antibiotic, 78–79 protein dynamics and, 32, 33 GtfD glycosyltransferase of, 61–62 in purine nucleotide biosynthetic molecular structure of, 57, 78 pathways, 2, 3 Vancomycin aglycon, 79, 81, 82 release of, 4 Vancomycin pseudoaglycon, 79, 81 in Tritrichomonas foetus,21 Vancomycin-resistant enterococci (VRE), 79 Xylose Vancomycin-resistant Staphylococcus aureus NovM glycosyltransferase and, 88 (VRSA), 79 oleandomycin and, 75 Vancosamines, 81–82 Xylosylation, oleandomycin and, 75 molecular structures of, 81 Vancosaminyl-D-glucose disaccharide, of Y289L mutation, in structure-guided vancomycin, 79 glycosyltransferase design, 104 Vegetables Yeast anthocyanins in, 183 in anthocyanin synthesis, 185 flavonoids from, 175 aromatic flavonoid derivatives from, 186 improving carotenoid content of, 161 in artemisinin synthesis, 158–159 272 SUBJECT INDEX

Yeast (Continued) terpene cyclases from, 137, 138 in carotenoid biosynthesis, 163 YifP protein, in carotenoid biosynthesis, 163 ethanol-tolerant strains of, 194–195 YjiD protein, in carotenoid biosynthesis, flavones from, 182 163 in flavonoid synthesis, 176–177 Zearalenols, 94 in isoflavone synthesis, 181 z-carotein, in carotenoid biosynthesis, 161, isoprenoid pathways engineered in, 135 162 MVA pathway in, 153 Zingiberine, 134 polyketide biosynthesis in, 130–131 Zymomonas mobilis, in ethanol production, as production organism, 142–143 191–192