Biosynthesis and molecular genetics of fungal secondary metabolites

Fungal Biology Juan-Francisco Martín Carlos García-Estrada Susanne Zeilinger Editors Biosynthesis and Molecular Genetics of Fungal Secondary Metabolites Tai Lieu Chat Luong Fungal Biology Series Editors: Vijai Kumar Gupta, PhD Molecular Glycobiotechnology Group, Department of Biochemistry, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland Maria G Tuohy, PhD Molecular Glycobiotechnology Group, Department of Biochemistry, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland For further volumes: http://www.springer.com/series/11224 Juan-Francisco Martín • Carlos García-Estrada Susanne Zeilinger Editors Biosynthesis and Molecular Genetics of Fungal Secondary Metabolites Editors Juan-Francisco Martín, Ph.D Department of Molecular Biology University of León León, Spain Susanne Zeilinger Institute of Chemical Engineering Vienna University of Technology Vienna, Austria Carlos García-Estrada, D.V.M., Ph.D Parque Científico de Ln Instituto de Biotecnología de Ln (INBIOTEC) Ln, Spain ISSN 2198-7777 ISSN 2198-7785 (electronic) ISBN 978-1-4939-1190-5    ISBN 978-1-4939-1191-2 (eBook) DOI 10.1007/978-1-4939-1191-2 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2014946216 © Springer Science+Business Media New York 2014 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer Permissions for use may be obtained through RightsLink at the Copyright Clearance Center Violations are liable to prosecution under the respective Copyright Law The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made The publisher makes no warranty, express or implied, with respect to the material contained herein Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface The Wonderful World of Fungal Secondary Metabolites There are thousands of fungal species in nature but only a handful of them, most of them ascomycetes, have been studied in detail Studies on the model fungi Neurospora crassa, Aspergillus nidulans, Aspergillus niger, Penicillium chrysogenum, and others, in comparison with the yeast Saccharomyces cerevisiae, have provided the basic core of scientific knowledge on the vegetative metabolism and morphological differentiation of filamentous fungi However, the biochemistry and molecular genetics of fungal secondary metabolites are less known due to their large diversity Some fungal products are extremely beneficial to combat tumors or bacterial and fungal infections, and others contribute to control cholesterol metabolism to improve human health A large number of fungal metabolites, the mycotoxins, are highly toxic for humans and for the livestock They also affect soil-dwelling worms or other organisms and, therefore, have a profound ecological interest Finally other fungal metabolites provide the vivid colors (e.g., β[beta]-carotene, astaxanthin) of some fungi During the last decades, there has been an intense effort to elucidate the biosynthesis pathways of fungal secondary metabolites to characterize the genes that encode the biosynthetic enzymes and the regulatory mechanisms that control their expres sion One interesting finding is that genes encoding fungal secondary metabolites are clustered together, as occurs also with the bacterial genes for secondary metabolites This is in contrast to fungal primary metabolism genes, which are frequently scattered in the genome However, in contrast to the bacterial gene clusters, most of the fungal secondary metabolite genes are expressed as monocistronic transcripts from individual promoters This raises the question of possible unbalanced levels of the different mRNAs of the genes in a pathway and the need of temporal and spatial coordination of their expression Furthermore, expression of the secondary metabo lites in fungi is correlated with differentiation and with the formation of either sexual or asexual spores, including cleistothecia and other types of differentiated cells v vi Preface Fungal secondary metabolites are complex chemical molecules that are formed by a few basic mechanisms with multiple late modifications of their chemical structures The basic mechanisms include enzymes such as non-ribosomal peptide synthetases (NRPSs), polyketide synthases (PKSs), terpene synthases and cyclases, and less known “condensing” enzymes that use as substrates a variety of activated precursors In this book we bring together 15 review articles by expert scientists on the best known secondary metabolites that serve as model of the different biosynthetic types of fungal secondary metabolites Each chapter presents an updated review of the medical, agricultural, food and feed applications, and the ecological relevance of each compound Furthermore, we provide descriptions of the present status of knowledge on the molecular genetics and biosynthesis of each of these compounds All together the expertise of the authors of those chapters provides an impressive overview of the actual knowledge of the world of fungal secondary metabolites Ln, Spain Juan-Francisco Martín Contents   1  Valuable Secondary Metabolites from Fungi 1 Arnold L Demain  2  Penicillins 17 Carlos García-Estrada and Juan-Francisco Martín  3  Cephalosporins 43 Sandra Bloemendal and Ulrich Kück   4  Cyclosporines: Biosynthesis and Beyond Tony Velkov and Alfons Lawen 65   5  Aflatoxin Biosynthesis: Regulation and Subcellular Localization 89 John E Linz, Josephine M Wee, and Ludmila V Roze   6  Roquefortine C and Related Prenylated Indole Alkaloids 111 Juan-Francisco Martín, Paloma Liras, and Carlos García-Estrada   7  Ochratoxin A and Related Mycotoxins 129 Massimo Reverberi, Anna Adele Fabbri, and Corrado Fanelli  8  Carotenoids 149 Javier Ávalos, Violeta Díaz-Sánchez, Jorge García-Martínez, Marta Castrillo, Macarena Ruger-Herreros, and M Carmen Limón   9  Astaxanthin and Related Xanthophylls 187 Jennifer Alcaino, Marcelo Baeza, and Victor Cifuentes 10  Gibberellins and the Red Pigments Bikaverin and Fusarubin 209 Lena Studt and Bettina Tudzynski 11  Fusarins and Fusaric Acid in Fusaria 239 Eva-Maria Niehaus, Violeta Díaz-Sánchez, Katharina Walburga von Bargen, Karin Kleigrewe, Hans-Ulrich Humpf, M Carmen Limón, and Bettina Tudzynski vii viii Contents 12  Lovastatin, Compactin, and Related Anticholesterolemic Agents 263 David Dietrich and John C Vederas 13 Meroterpenoids 289 Yudai Matsuda and Ikuro Abe 14  Ergot Alkaloids 303 Paul Tudzynski and Lisa Neubauer 15  Fungal NRPS-Dependent Siderophores: From Function to Prediction 317 Jens Laurids Sørensen, Michael Knudsen, Frederik Teilfeldt Hansen, Claus Olesen, Patricia Romans Fuertes, T Verne Lee, Teis Esben Sondergaard, Christian Nørgaard Storm Pedersen, Ditlev Egeskov Brodersen, and Henriette Giese Index 341 Contributors Ikuro Abe, Ph.D.  Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan Jennifer Alcaino, Sc.D.  Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santaigo, Chile Javier Ávalos, Ph.D.  Department of Genetics, Faculty of Biology, University of Seville, Sevilla, Spain Katharina Walburga von Bargen, Dr rer nat.  University Münster, Institute of Food Chemistry, Münster, Germany Sandra Bloemendal, Ph.D.  Christian Doppler Laboratory for Fungal Biotechnology, Lehrstuhl für Allgemeine und Molekulare Botanik, Ruhr-Universität Bochum, Bochum, Germany Ditlev Egeskov Brodersen, Ph.D.  Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark Marcelo Baeza, Ph.D.  Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile Marta Castrillo  Department of Genetics, Faculty of Biology, University of Seville, Sevilla, Spain Victor Cifuentes, Sc.D.  Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile Arnold L. Demain, Ph.D., M.S., B.S.  Research Institute for Scientists Emeriti (R.I.S.E.), Drew University, Madison, NJ, USA Violeta Díaz-Sánchez, Ph.D.  Department of Genetics, Faculty of Biology, University of Seville, Sevilla, Spain David Dietrich, B.Sc., Ph.D.  Department of Chemistry, University of Alberta, Edmonton, AB, Canada ix 336 J.L Sørensen et al 56 Oves-Costales D, Kadi N, Challis GL The long-overlooked enzymology of a nonribosomal peptide synthetase-independent pathway for virulence-conferring siderophore biosynthesis Chem Commun (Camb) 2009;43:6530–41 57 Haas H Molecular genetics of fungal siderophore biosynthesis and uptake: the role of siderophores in iron uptake and storage Appl Microbiol Biotechnol 2003;62:316–30 58 Winkelmann 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Markov models Bioinformatics 1998;14:755–63 127 Khayatt BI, Overmars L, Siezen RJ, Francke C Classification of the adenylation and acyltransferase activity of NRPS and PKS systems using ensembles of substrate specific hidden Markov models PLoS One 2013;8(4):e62136 128 Mootz HD, Schwarzer D, Marahiel MA Ways of assembling complex natural products on modular nonribosomal peptide synthetases Chembiochem 2002;3:490–504 129 Caboche S, Pupin M, Leclere V, Fontaine A, Jacques P, Kucherov G NORINE: a database of nonribosomal peptides Nucleic Acids Res 2008;36:D326–31 130 Doekel S, Marahiel MA Dipeptide formation on engineered hybrid peptide synthetases Chem Biol 2000;7:373–84 Index A Acetylaszonalenin aszonalenin, 115 biosynthesis, 123–124 cyclodipeptides, 119 gene cluster, 120 N fischeri, 111 orthologous cluster, 123 and roquefortine C, 113 tryptophan, 115 Acetyl coenzyme A (Acetyl-CoA) A chrysogenum, 46–47 fungal polyketides, 116 mycotoxin, 115 orsellinic acid, 220 ACP See Acyl-carrier protein (ACP) Acremonium chrysogenum arthrospore formation, 50–51 cellular differentiation, 49 molecular genetics, 52–56 morphology, 49, 50 polyphyletic taxon, 49 putative septation protein AcSepH, 51 sexual recombination, 49 Acyl-carrier protein (ACP), 221, 223, 269, 275, 277 Adenylyl cyclase (AC), 167–168, 228, 230 Aflatoxin biosynthesis biochemistry and pathway intermediates toxicity, 91–92 crop contamination, 89–90 fungal biology, 91 secondary metabolic regulation, 95–103 stress response, 103–104 vesicles and endosomes, 92–95 VPS34 and ATFB, 104–105 Aflatrem in A flavus, 227 biosynthetic gene clusters, 297 paxilline and terpendole K, 296 Alanine racemase 13 C-glucose, 74 D-alanine, 76 Krebs cycle, 74 precursor-directed synthesis, 75 protein-protein interaction, 75 subcellular fractionation, 75 Aldehyde carboxylic acid, 223 neurosporaxanthin, 163 oxidation and 13C-hydroxylation, 224 Antibiotics beta-lactams, ceftobiprole, cephalosporin, 47 classification, 17 ergot alkaloids, fermentation, modern chemotherapy, 17 penicillin biosynthetic genes, 31 screening programs, Anticancer drugs angiogenesis, camptothecin, 6, erbitux, taxadiene synthase, taxol (paclitaxel), 5, Anticholesterolemic agents compactin (see Compactin) lovastatin (see Lovastatin) Antioxidants astaxanthin, 190 J.-F Martín et al (eds.), Biosynthesis and Molecular Genetics of Fungal Secondary Metabolites, Fungal Biology, DOI 10.1007/978-1-4939-1191-2, © Springer Science+Business Media New York 2014 341 342 Antioxidants (cont.) canthaxanthin, 191 CipC function, 140 statins, toxigenic fungi, 142 xanthophylls, 188 Arthrospores CPCR1, 58 hyphal fragmentation, 51 intracellular organelles and lipidcontaining vacuoles, 49 methionine addition/glucose depletion, 49–50 molecular tools, 59 morphological effect, methionine, 51 reverse trans-sulfuration pathway, 51 yeast-like cells, 49 Aspergilli A clavatus, 120 A fumigatus, A giganteu, 151 A nidulans, 58, 93 A terreus, metabolite gene clusters, OTA pathway (see Ochratoxin A (OTA)) and Penicillium spp., 103, 131 Aspergillus nidulans A fumigatus, 124 carbon catabolite regulation, 28 CSL, 30 penicillin biosynthesis, 20 sterigmatocystin, 227 Aspergillus niger and A carbonarius, 129–130, 133 bikaverin, 211 OTA, 136 Thaumatococcus danielli, 10 Aspergillus terreus acetylaszonalenin orthologous cluster, 123 CP450 oxidoreductase, 279 genome database, 293 lovastatin production (see Lovastatin) LovC, 275, 276 mutants, 268 and N fischeri, 120 and P citrinum, 282 Astaxanthin See also Xanthophylls aquaculture, 190 biosynthesis, 171 layer hens, health and fertility, 190 X dendrorhous (see Xanthophyllomyces dendrorhous) AtfB, transcription factor aflatoxin gene promoters, 100 binuclear zinc cluster transcription factor, 100 Index ChIP Seq, 102 CoIP, 103 EMSA, 101 gene knockdown, A parasiticus, 102–103 nucleotide sequence analysis, 102 RNA sequence (RNA Seq), 101–102 transcriptional activity, 104 Austinol biosynthetic pathway, 293 fungal meroterpenoids, 292 P450, AusI and AusG, 294 post-cyclization modification reactions, 295 AvaA gene disruption, A nidulans, 93 transcript accumulation, 93 B Bakanae (foolish seedling) disease, 209, 210 β(Beta)-carotene biosynthetic pathway, 151 chemical activation, 156–157 description, 151–152 downstream metabolism, 159–160 enzymatic steps, 152–153 industrial production, 157–159 light induction, 153–155 mutational deregulation, 155–156 sexual activation, 157–159 β(Beta)-lactam antibiotics bactericidal agents, 20 bicyclic system, 19 biosynthesis, 34 classification, 43 penicillins and cephalosporins, 17 structure, 20 Bikaverin biological activity, 211 F fujikuroi carS, 169 gene cluster, 215–216 nitrogen regulation, 253–254 Bimolecular fluorescence complementation (BiFC), 55, 59 Biosynthesis acetylaszonalenin, 123–124 acetyl coenzyme A, 47 aflatoxin (see Aflatoxin) β-carotene (see β(Beta)-carotene) cephalosporin C (see Cephalosporin C) chromosomal organization, genes, 45, 46 cyclosporine (see Cyclosporine) deacetoxycephalosporin C (DAOC), 46 deacetylcephalosporin C (DAC), 46 epimerization reaction, 46 Index ergots (see Ergot alkaloids) FA, 253, 255 fumitremorgin, 124 fusarin C, 251, 252, 255 IPNS, 45 lovastatin and compactin, 265–268 neurosporaxanthin (see Neurosporaxanthin) penicillins (see Penicillins) siderophore (see Siderophores) SM (see Secondary metabolites (SM)) xanthophylls, 170–171, 193–196 Bmt polyketide synthase (PKS) 13 C-labeled acetate and glucose, 76 elongation cycle, 76 PKS gene, 76 Botrytis cinerea, 215, 319 bZIP transcription factors aflatoxin, 100–101 A niger, 141 AreA, 229 AtfB (see AtfB, transcription factor) MeaB, 225 stress signal, 96 C Carotene See also β(Beta)-carotene B trispora, 157 chromatography, 188 colorless precursor phytoene, 154 immobilized mycelia, 168 light, 154 non-oxygenated carotenoids, 188 photoinduction, 155 sclerotia-forming fungi, 172 sterols, 156 Carotenoids albino mutants, 171, 172 annual production, 187 astaxanthin, 197 Candida utilis, 199 carrot roots, 187 chemical structures, 187 chromophoric system, 187 description, 149 fat-soluble compounds, 149 HMG–CoA, 149, 150 mevalonate terpenoid pathway, 149, 150 microbial sources, 188 molecular structure, 187 phytoene synthase, 150 protective properties, 171 putative rhodopsin-encoding genes, 171 xanthophyll biosynthesis, 193 CarS, 155, 157–160, 168, 169 343 Cephalosporin C A chrysogenum (see Acremonium chrysogenum) antibacterial effect, 43 biosynthesis pathway, 45–47 derivatives, 47–49 gene expression, hirudin, 57 global transcriptional regulators, 57 hirudin synthesis, 56–57 isopenicillin N (IPN), 44 β-lactam antibiotic biosynthesis, 43–44 morphological effect, methionine, 51–52 regulatory proteins, 58 RNAi techniques, 59 secondary metabolism and morphology, 58 sequence analysis, 57 strain optimization, 59 thrombin inhibitor hirudin, 56 velvet protein AcVEA, 59 yeast-like pseudohyphal growth, 58 Cephalosporin derivatives cefaclor, 47, 48 cefadroxil, 47, 48 cefazolin, 47, 48 cefepime, 47, 48 cefixime, 47, 48 cefotaxime, 47, 48 cefpodoxime, 47, 48 ceftobiprole, 49 cefuroxime, 47, 48 cephalexin, 47, 48 medical applications, 49 semisynthetic, 47 Cholesterol hypocholesterolemic agents, 3–5 indicator, CVD, 263 mevalonic acid pathway, 264 pharmaceutical management, 263 Clavine alkaloids Aspergillus fumigatus, 305 C fusiformis strain, 308 EAS pathway, 309 paspalic/lysergic acid, 312 Compactin biosynthesis, 281–282 fungal PKSs, 268 vs lovastatin (see Lovastatin) and LovC, 275 in P brevicomaptum, 263 Streptomyces carbophilus, Corn-steep liquor (CSL) composition, 30 cornstarch manufacturing process, 30 penicillin biosynthetic gene cluster, 30 CSL See Corn-steep liquor (CSL) 344 Cyclodipeptide synthetase (CDPS) adenylation domains, 119 ascomycetes, 115, 116 catalyzation, 115 domain structure, 115 indole alkaloid, 117 N fischeri, 117 phylogenetic tree, 117, 118 Rds and NFIA_074300, 118, 119 roquefortine C/meleagrin cluster, 117 tryptophan-activating A2 domain, 123 Cyclosporine A (CsA) chemical structure, 66 clinical applications, 66 pharmacological properties, 66 sequential Edman degradation, 66 Cyclosporines alanine racemase, 74–76 Bmt polyketide synthase, 76 CsA (see Cyclosporine A) CySyn, 67–70 enzyme systems, 67 in toto synthetic strategies, 79 in vitro directed biosynthesis, 77–79 in vivo directed biosynthesis, 77 N-methylation, 70–74 recombinant synthetic strategies, 79–80 Cyclosporine synthetase (CySyn) biosynthetic pathway, 70 functional domains, 69 linear peptidyl-S-enzyme intermediate stages, 68 SDS-PAGE analysis, 67 sedimentation velocity ultracentrifugation, 68 D 6-O-Demethylnectriachrysone, 223–224 Diels–Alder reaction cyclization products, 267 DML production, 274 enzyme-catalyzed, 282 lovastatin and compactin, 266 spinosyn A, 283 stereochemistry, 268 Diketopiperazine ring, 111, 115, 120, 323 3,5-Dimethylorsellinic acid (DMOA)-derived meroterpenoids andrastin A and anditomin, 295 Aspergillus nidulans, 292 ausN deletion, 292 biosynthetic pathway, austinol and terretonin, 293 carbon skeleton rearrangement, 294 Index C-3 hydroxyl group, 295 “hypothetical protein”, 294 methylation, 294 post-cyclization modification reactions, 294, 295 reconstitution study, A oryzae, 293 Dothideomycetes, 215 E Endophytes C purpurea, 304 Epichloe and Neotyphodium species, 308 extracellular siderophores, 319 F maire, Neotyphodium lolii, 309 panaccione, 309 as pathogens, 303 Endosomes cell biology, 92–93 stress response enzymes, 94–95 synthesis, storage and export, aflatoxin, 93 Enhanced yellow fluorescent protein (EYFP), 56 Enzyme inhibitors, Ergopeptines apoptosis-inducing effect, 307 C purpurea, 304, 306 ergonovine, 305 ergovaline, 311 saturated D ring, 307 sclerotia-like cells, 312 terminal pathway, 308 Ergot alkaloids bioactive indole-derivatives, 303 biosynthesis and molecular genetics, 307–310 biotechnology, 311–312 Claviceps purpurea, 303, 304 disease symptoms, 303–304 economic impact, 310–311 mycotoxins, 304 pharmacological and therapeutical applications, 305–307 Trichocomaceae, 303–304 Exocytosis aflatoxin export, 94 peroxisomes, secretory vesicles, 27 EYFP See Enhanced yellow fluorescent protein (EYFP) F Feedback regulation, 153, 155, 160, 218, 308 Filamentous fungi biosynthetic genes, 20 345 Index chemical and physical mutagenesis, 31 metabolite gene clusters, Neurospora and Aspergillus, 100 pH-dependent gene expression, 57 siderophores (see Siderophores) Fungal meroterpenoids biosynthetic gene clusters, 289 description, 289 DMOA (see 3,5-Dimethylorsellinic acid (DMOA)-derived meroterpenoids) indole-diterpenes, 296–299 pyripyropene A, 290–293 Fungal polyketide, 216, 268, 282–283 Fungal regulation aeration conditions, 30 amino acids, 29–30 A nidulans CCAAT-binding factor (AnCF), 31 carbon catabolite, 28 CSL, 30 nitrogen source, 29 PcRFX1, 31 pH, 28–29 phosphate, 29 polyamines, 30 Fungi intracellular iron levels, 318 iron uptake, 318 phytoene β(beta)-carotene synthase (PBS), 195 SM (see Secondary metabolites) siderophores, 325 soil-dwelling organisms, 91 Fusaria F fujikuroi, 209, 227 and 13-hydroxynorjavanicin, 224 Fusaric acid biological activity, 243–245 biosynthetic pathways, 253 detection and structural analysis, 250–251 distribution, gene cluster, 246, 248 food and feed contamination, 248 Gibberella fujikuroi species, 240 structures, 240–242 Fusarin C biological activity, 242–243 biosynthetic pathways, 251–252 detection and structural analysis, 249–250 distribution, gene cluster, 246–248 Fusarium species, 239–241 isolation, 240 polyketide metabolites, 239 Fusarium fujikuroi aldehyde dehydrogenase, 163 carboxyfusarin C, 250 F proliferatum, 247 fusarubins, 211 FUSS homologs, 247 FvVe1 homologue, 254 gene cluster, 248 gibberellins/bikaverin, 169 neurosporaxanthin, 161 pigments and mycotoxins, 209 SM gene clusters, 253 Fusarium graminearum aurofusarin, 215 and F verticillioides, 215 mycoestrogen, 243 zearelanone, Fusarubins biological activity, 211–212 gene cluster, 216 G Gene clusters acetylaszonalenin, N fischeri and A terreus, 120 bikaverin, 215–216 FA, 248 in filamentous fungi, fungal genome sequences, 245 fungal-specific velvet complex, 254 FUS and FUB gene expression, 256 fusarin C, 246–248 fusarubin, 216 gibberellic acid, 212–215 histone modifications, 255 lovastatin, 275, 276, 278, 280 meleagrin/roquefortine, 122 mycotoxin, 141 nitrogen regulation, 253–254 paspaline-derived indole-diterpenes, 297 penicillin, biosynthetic, 30–32 roquefortine C, 119 SM, ter cluster, 298 Geranylgeranyl diphosphate (GGDP), 219 Gibberellic acids (GAs) See Gibberellins Gibberellins biological activity, 210–211 cyclosporin A/mycotoxins, F fujikuroi, 164 fusarins, 254 gene cluster, 212–215 isoprenoid pathway, 218–220 346 Glandicolines inflammatory responses, 140 methyltransferase, 117 roquefortine C, 111, 112 Glutamine synthetase (GS), 225, 254 Growth hormones, 193, 211 GS See Glutamine synthetase (GS) H HMG-CoA See Hydroxymethylglutaryl coenzyme A (HMG-CoA) Hydrophobic penicillins, 23–24 3-Hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) mevalonate biosynthesis, 263 pharmaceutical cholesterol management, 263 Hydroxymethylglutaryl coenzyme A (HMG-CoA), 149, 150 Hypocholesterolemics lovastatin, chemical structure, simvastatin, statins, Zocor® (simvastatin), I Immunosuppressants autoimmune diseases, cyclosporin, drugs/radiation, microbial compounds, mycophenolic acid, signal transduction, Indole-diterpenes biosynthetic diversity, 297, 298 Chaunopycnis alba, 298 paspaline and non-paspaline-derived, 296 paxilline, 297 PaxM and PaxB, 297 Penicillium paxilli, 296 terQ-expressing strain, 299 tremorgenic mammalian mycotoxins, 296 Industrial production, β-carotene, 157–159 Infection ergot, 310–311 HBV, hepatitis B and C virus, 90 microbes, 320 Iron animal hosts, 318 endophytic relationships, 319 extracellular and intracellular, 319–320 ferritin-like molecules, 318–319 heterothallic fungus, 319 Index iron secretion mechanism, 318 microbial siderophores, 320 pathogenic organisms, 317 starvation, 55 Isopenicillin N (IPN) antimicrobial properties, 22 cytosol, 26 epimerization reaction, 46 filamentous fungi, 23 gene fusion expression, 29, 30 β-lactam antibiotics, 44 side chain replacement, 24 synthase activity, 28 L Light induction β(beta)-carotene, 153–155 neurosporaxanthin, 165–167 Lisea fujikuroi, 210 Lolitrems biosynthetic gene clusters, 297 terpendoles, 299 transformation, 299 Lovastatin vs compactin, 281–282 Diels–Alder reaction, 265–268 gene cluster, 268–270 labeling studies, 265, 266 LovA, 278–279 LovB–LovC PKS System, 270–275 LovD, 276–278 LovF, 275–276 LovG, 279–281 methyl butyrate, 265 synthetic hexaketide precursor, 267 Lycopersin, 211 Lysergic acid biosynthesis, 305 C paspal and C fusiformis, 312 stereoisomer, 305 M Meleagrin glandicolines A, 113 and neoxaline, 121–122 Penicillium glandicola, 121 roquefortine C, 112 Methicillin-resistant Staphylococcus aureus (MRSA), 49 Methionine amino-terminal processing, morphological effect, Cephalosporin C, 51–52 347 Index 8-O-Methylanhydrofusarubin, 224 Microbial natural products (NPs) antibiotics, immunosuppressants, pharmacological agents, 3–10 Molecular genetics, A chrysogenum expression vectors, 55 filamentous fungi, 52 FLP/FRT recombination system, 54 functional resistance, 53–54 gene replacement strategies, 53 NHEJ-deficient strain, 54 PCR fragments, 53 random mutagenesis, 52 recombinant fungal strains, 54 resistance markers, 54 RNAi vector systems, 55, 56 RNA silencing, 55 split-marker system, 54 Molecular tools arthrospores, 59 cephalosporin C biosynthesis, 59 MRSA See Methicillin-resistant Staphylococcus aureus (MRSA) Mucorales, 151–153, 156, 159, 160 Mutant al-1 and al-3 mRNA levels, 169 albino, 172 carB and carRA, 153 carD, 164 β-carotene, 155 carotenoid overaccumulator, 169 carRA, 154 carRP, 152 carS, 160, 169 crgA, 156 deep-pigmented, 169 Neurospora and Fusarium, 163 P blakesleeanus, 156 phosphorylation, 154 phytoene dehydrogenase, 161 wc-1, 166 ylo-1, 164 Mutation β-carotene, 155–156 carS, 158, 160 P blakesleeanus, 152 Mycotoxins aflatoxin, 91 applications, chemical structure, 245 food and feed contamination, 248 fusarin C, 242, 249 Fusarium, 244 nitrogen regulation, 253, 254 nitrogen reserve nutrients, 113 and OTA (see Ochratoxin A (OTA)) Penicillium, 111 roquefortine C (see Roquefortine C) N Neoxaline and meleagrin, 121–122 roquefortine C (see Roquefortine C) Neurosporaxanthin biosynthesis carT and cao-2 enzymatic activities, 163 description, 160–161 developmental regulation, 167–168 F fujikuroi, 164–165 light induction, 165–167 overproduction, 169–170 oxidative cleavage, 164 temperature and nitrogen, 168 torulene-accumulating mutants, 163 torulene production, enzymatic steps, 161–163 ylo-1 mutant, 164 Neurotransmitters ergoline system, 305 receptors, 305 serum melatonin, 244 N-methyltransferase AdoMet-dependent, 70 amide bonds, 70 14 C-labeled AdoMet, 71 crystallographic studies, 72 depsipeptide antibiotics, 74 enzyme-bound intermediates, 74 in vitro biosynthetic reactions, 71 macrocyclization, 73 molecular modeling and NMR analysis, 72 mutagenesis studies, 72 peptide tyrocidine A, 73 radio-sequencing detected Glu10654 and Pro10655, 71 sequence identity, 70 streptogramin B antibiotics, 73 structural modifications, 80–81 Nocardia lactamdurans, 44, 219 Nonribosomal peptide synthetase (NRPS) chimeras, 79 construction recombinant synthases, 77 C purpurea, 309 crystallographic studies, 72 C-terminus, 115 cyclosporine synthetase, 67 CySyn, 67 348 Nonribosomal peptide synthetase (NRPS) (cont.) hybrid, 80 LovB, 283 molecular weight, 67 monomodular enzyme, 309 N-methyltransferase, 117 and PKS, 251 prediction (see Prediction, NRPS products) protein templates, 81 recombinant engineering, 81 secondary metabolism, 138 siderophores (see Siderophores) single polypeptide chain, 67 Nonribosomal peptide synthetases (NRPSs) A carbonarius, 130 and pks, 138 NRPS See Nonribosomal peptide synthetase (NRPS) O Ochratoxin Aspergillus and Penicillium species, 129 OTA (see Ochratoxin A (OTA)) OTB, 130–132, 136 Ochratoxin A (OTA) biosynthesis pathway, 130, 137–139 genomic approaches, 130 light effects, 136 molecular factors, 139–141 pH effect, 136–137 putative genes, biosynthesis, 130, 131 water activity and temperature effect, 130, 132–135 Orsellinic acid, 220–222 Oxidative stress aflatoxin biosynthesis, 101 in bacteria and fungi, 100 external environment, 98 paraffin addition, 172 resistance, 319 Oxylipins biosynthesis, 140 linoleic-acid-derived, 99 metabolism, 140 P Paxilline biosynthetic diversity, 298 gene deletion and transfer, 296 Penicillia, 136, 137 Index Penicillins aeration conditions, 30 amino acids regulation, 29–30 6-aminopenicillanic acid (6-APA), 19 ancillary proteins, 24–25 benzylpenicillin structure, 19 biosynthetic pathway, 20, 21 carbon catabolite regulation, 28 CSL, 30 discovery, 17–19 global regulators, 31 hydrophobic, 20 industrial technology, 18 nitrogen source regulation, 29 P chrysogenum (see Penicillium chrysogenum) phosphate regulation, 29 pH regulation, 28–29 polyamines, 30 production process, 18 and secretion, transport processes, 25–27 side chain replacement, 23–24 structure and mechanism of action, 19–20 therapeutic properties, 18 transport processes, 25–27 tripeptide biosynthesis, 21–22 X-ray crystallography, 18 Penicillium See also Penicillins OTA production (see Ochratoxin A (OTA)) P chrysogenum, 18 P glaucum, plant bulbs, 121 P roqueforti, 1, 112 Penicillium chrysogenum chemical and physical mutagenesis, 31 global metabolic reorganizations, 33 penicillin gene cluster amplification, 31–32 peroxisomes, 32–33 phenylacetic acid, 32 Penicillium citrinum compactin, 263 and Monascus pilosus, 280 Trichocomaceae, 282 Perithecial pigment, 215 Peroxisomes autophagic degradation, 27 cephalosporin C production pathway, 46 exocytosis mechanism, 27 IAT, 23 microbodies, 32–33 mycotoxins, 125 Pharmacological agents anticancer drugs, 5–7 enzyme inhibitors, 349 Index hypocholesterolemic agents, 3–5 immunosuppressant drugs, 7–8 mycotoxins applications, pigments, 9–10 sweeteners, 10 Phenylacetic acid and amino acids, 25–26 benzylpenicillin side chain precursor, 32 catabolic reduction, 32 point mutations, 32 PTS1 signal, 24 Photoinduction carRA and carB, 154 neurosporaxanthin, 165, 166 P blakesleeanus, 153 slot blot analyses, 154 Phytopathogens, 209, 243 Pigments adenylyl cyclase, 228 astaxanthin (see Astaxanthin) canthaxanthin, 191 carotenoids, 149 dihydrofusarubin, 223 fucoxanthin, 191 lutein, 192 monascorubrin and rubropunctatin, 9–10 N crassa, 165 neoxanthin, 192 secondary metabolites, 9–10 violaxanthin, 192–193 xanthophylls (see Xanthophylls) zeaxanthin, 193 Plant pathogen, 209, 243 Polyketides bikaverin, 211 13 C-labeled acetate and glucose, 76 fusarins, 239 pigment biosynthesis, 220 pyripyropene A, 290 Polyketide synthases (PKS) A carbonarius and A ochraceus, 138 biosynthesis, 210 Bmt, 76 FA, 253 fusarin C, 247, 251 multi-modular enzymes, OTA production, 130 Prediction, NRPS products adenylation domains, 331 antiSMASH and SMURF server, 331 hybrid peptide synthetases, 333 in silico methods, 331 NRPSpredictor2, 332 posttranslational modifications, 332 Prenylated indole alkaloids acetylaszonalenin, 123–124 anthranilic acid moiety, 115 CDPS, 115–119 chemical structures, roquefortine C, 113, 114 diketopiperazine ring, 115 dimodular peptide synthetase, 124 fungal diketopiperazines, 113, 114 MFS transporter, 122 orthologous cluster, N fischeri, 122–123 roquefortine prenyltransferase Rpt, 119–121 tryptophan, 115 Pyripyropene A Aspergillus oryzae, 291 biosynthetic pathway, 290 Penicillium coprobium PF1169, 291 Pyr3 and Pyr9, 291–292 terpenoid moiety, 291 tricyclic C15-terpenoid, 290 R Regulation aflatoxin biosynthesis (see Aflatoxin biosynthesis) amino acids, 29–30 biosynthetic process, 19 carbon catabolite, 28 β-carotene, 153 cephalosporin C (see Cephalosporin C) cluster gene expression (see Gene clusters) fungal-specific velvet complex, 254 immune response, neurosporaxanthin, 165–170 nitrogen, 224–227 penicillin biosynthesis, 28–31 polyamines and CSL, 30 SM (see Secondary metabolites) siderophore (see Siderophores) velvet complex, 227 Roquefortine C chemical structures, 113, 114 Claviceps species, 111 14 C-roquefortine C, 113 DKP alkaloid family, 112 ergot alkaloids, 111 indole alkaloids (see Prenylated indole alkaloids) meleagrin and neoxaline, 111, 112 reverse prenylation, 112 toxicity and medical interest, 112 350 S Secondary metabolism AcVEA, 59 aflatoxin biosynthesis, 95–103 and asexual development, 100 AtfB, 101–103 biochemical pathways, 129 cephalosporin C biosynthesis genes, 57 and conidiospore, 99 and differentiation, 227 environmental factors, 132 fungal-specific velvet complex, 254 gene cluster expression, 132 global regulator, 93 mycotoxins, 129 NPs, NRPS, 138 oxidative stress, 140 P chrysogenum, 34 regulatory proteins, 58 subcellular localization, 94–95 velvet complex, 227 and virulence, 140 Secondary metabolites (SM) A chrysogenum, 47 antibiotics production, bikaverin biosynthesis, 220–222 biosynthetic genes, cephalosporin C, 57 diterpenes, 216–217 fungal polyketides, 216 Fusarium heterosporum, 283 fusarubin biosynthesis, 222–224 histone modifications, 229 isoprenoid pathway, 218–220 microbial natural products, 2–10 mutagenesis and/or genetic engineering, mycotoxins, 129 nitrogen regulation, 224–227 NPs, polyketides, 220, 268 recombinant DNA technologies, regulatory mechanism evolution, screening programs, separation and isolation techniques, signaling components, 228 velvet complex, 227 Sexual activation, β-carotene, 157–159 Siderophores biosynthesis, 325–326 domain architecture, 327–328 environmental signals, 320–321 enzymes, biosynthesis, 329–331 ferrichrome transporter, 321 Index fusarinines and coprogens, 323 HAS, 324–325 hydroxamate-type, 321 iron (see Iron) L-ornithine, 321, 322 NRPSs evolution, 328–329 oxidation-reduction reactions, 317 rhizoferrin, 324 staphyloferrin, 324 SM See Secondary metabolites (SM) Solanione, 211 Sphaceloma manihoticola, 215, 218, 220 Statins in clinical use, hypolipidemic drugs, lovastatin (see Lovastatin) pravastatin, prescription medication, 263 Subcellular localization aflatoxin biosynthesis (see Aflatoxin biosynthesis) secondary metabolism, 94–95 Vps34, 104 Sweetening agents, 10 T Terpendoles Chaunopycnis alba, 298 and lolitrems, 297, 298 TerP and TerQ, 299 terQ-expressing strain, 299 Terretonin biosynthetic study, 293 cyclization reactions, 293 post-cyclization modification reactions, 295 Torulene production, 161–163, 170–171 Transport processes, penicillin amino acids and phenylacetic acid, 25–26 hydrophobic penicillins, 27 intermediates, 26–27 V Vesicles aflatoxin (see Endosomes) confocal laser scanning microscopy, 94 passive diffusion and active transport, 27 Vps16 proteins and AvaA transcript accumulation, 93 sortin3, 93 Vps34 homolog expanded branch model, 104–105 homolog (Class III PI3 Kinase), 94 Index X Xanthophyllomyces dendrorhous astaxanthin synthase, 198 β(beta)-carotene hydroxylases, 197 carotenogenesis precursors, 199 carotenoid production, 198 cytochrome P450s (P450s), 197 genetic modification, 199 ketolases, 196 metabolic engineering, 199 MVA pathway, 200 nutritional factors, 198 physical factors, 198 random mutagenesis methods, 199 Xanthophylls antioxidant properties, 188 astaxanthin, 190 β(Beta)-Cryptoxanthin, 190 351 biological roles, 188 biosynthesis, 193–196 canthaxanthin, 191 capsanthin, 191 C10-geranyl pyrophosphate (GPP), 193–194 chemical structures, 170–171 chemical synthesis, 188, 189 fucoxanthin, 191 fungal production, 170 isoprenoids, 193 lutein, 192 lycopene cyclization, 195 neoxanthin, 192 phytoene synthase enzyme, 195 post-phytoene carotenoid molecules, 196 violaxanthin, 192–193 X dendrorhous, 196–198 zeaxanthin, 193