真菌次生代谢产物挖掘策略研究进展
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摘要
真菌是最具生物多样性的类群之一,也是一系列小分子活性化合物的重要来源.近年来,发现新结构、新活性的次生代谢产物超过50%来源于真菌.因此深度挖掘真菌中天然活性化合物,既是研究热点,也将为药物研发提供必要的基础,并具有重要的科学意义.基于基因组测序技术及信息生物学的发展,结合传统方法,深入了解近几年挖掘真菌次生代谢产物的策略,了解相关真菌次生代谢的生物合成及调控机制,可以为新活性、新骨架化合物的发现以及隐性次级代谢物的激活提供理论基础.最终可以精准研究或多种策略结合,对目标菌株开展深入系统地研究.
Fungi are one of the most biologically diverse groups and an important source of active compounds. In recent years, more than 50%of new structural and active secondary metabolites have been identified in fungi. Therefore, mining naturally active compounds in fungi is not only a research hotspot but also provides the necessary foundation for drug research and development. Based on the development of genome sequencing technology and information biology combined with traditional methods, an in-depth understanding of the strategies of mining secondary metabolites of fungi in recent years, elucidation of the biosynthesis and regulation of the secondary metabolism of related fungi, new active and new skeleton compound discovery, and activation of recessive secondary metabolites provide a theoretical basis. Thus, it is possible to carry out in-depth systematic research on target fungi by combining specific or multiple strategies.
Fungi are one of the most biologically diverse groups and an important source of active compounds. In recent years, more than 50%of new structural and active secondary metabolites have been identified in fungi. Therefore, mining naturally active compounds in fungi is not only a research hotspot but also provides the necessary foundation for drug research and development. Based on the development of genome sequencing technology and information biology combined with traditional methods, an in-depth understanding of the strategies of mining secondary metabolites of fungi in recent years, elucidation of the biosynthesis and regulation of the secondary metabolism of related fungi, new active and new skeleton compound discovery, and activation of recessive secondary metabolites provide a theoretical basis. Thus, it is possible to carry out in-depth systematic research on target fungi by combining specific or multiple strategies.
引文
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4 Nielsen J C,Grijseels S,Prigent S,et al.Global analysis of biosynthetic gene clusters reveals vast potential of secondary metabolite production in Penicillium species.Nat Microbiol,2017,2:17044
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6 Duan Y C,Feng J,Bai N,et al.Four novel antibacterial sesquiterpene-α-amino acid quaternary ammonium hybrids from the mycelium of mushroom Stereum hirsutum.Fitoterapia,2018,128:213-217
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8 Romano S,Jackson S A,Patry S,et al.Extending the“one strain many compounds”(OSMAC)principle to marine microorganisms.Mar Drugs,2018,16:244
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12 Blin K,Shaw S,Steinke K,et al.antiSMASH 5.0:updates to the secondary metabolite genome mining pipeline.Nucleic Acids Res,2019,79
13 Spiteller P.Chemical ecology of fungi.Nat Prod Rep,2015,32:971-993
14 Aminov R I.The role of antibiotics and antibiotic resistance in nature.Environ MicroBiol,2009,11:2970-2988
15 Sun J,Leng B,Sheng G,et al.Biosynthesis and functions of metabolites.Sci China Life Sci,2017,60:1280-1282
16 Partida-Martinez L P,Hertweck C.Pathogenic fungus harbours endosymbiotic bacteria for toxin production.Nature,2005,437:884-888
17 Kobayashi D Y,Crouch J A.Bacterial/Fungal interactions:from pathogens to mutualistic endosymbionts.Annu Rev Phytopathol,2009,47:63-82
18 Bonfante P,Anca I A.Plants,mycorrhizal fungi,and bacteria:a network of interactions.Annu Rev Microbiol,2009,63:363-383
19 Grube M,Berg G.Microbial consortia of bacteria and fungi with focus on the lichen symbiosis.Fungal Biol Rev,2009,23:72-85
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26 Stierle A A,Stierle D B,Decato D,et al.The Berkeleylactones,antibiotic macrolides from fungal coculture.J Nat Prod,2017,80:1150-1160
27 Tsitsigiannis D I,Keller N P.Oxylipins as developmental and host-fungal communication signals.Trends MicroBiol,2007,15:109-118
28 Rodriguez Estrada A E,Hegeman A,Corby Kistler H,et al.In vitro interactions between Fusarium verticillioides and Ustilago maydis through real-time PCR and metabolic profiling.Fungal Genets Biol,2011,48:874-885
29 Brakhage A A.Regulation of fungal secondary metabolism.Nat Rev Microbiol,2013,11:21-32
30 Yin W,Keller N P.Transcriptional regulatory elements in fungal secondary metabolism.J Microbiol,2011,49:329-339
31 Bok J W,Keller N P.LaeA,a Regulator of Secondary Metabolism in Aspergillus spp..Eukaryotic Cell,2004,3:527-535
32 Jain S,Keller N.Insights to fungal biology through LaeA sleuthing.Fungal Biol Rev,2013,27:51-59
33 Sarikaya-Bayram?,Palmer J M,Keller N,et al.One Juliet and four Romeos:Ve A and its methyltransferases.Front Microbiol,2015,6
34 Martín J F.Key role of LaeA and velvet complex proteins on expression ofβ-lactam and PR-toxin genes in Penicillium chrysogenum:cross-talk regulation of secondary metabolite pathways.J Ind Microbiol Biotechnol,2017,44:525-535
35 Stinnett S M,Espeso E A,Cobe?o L,et al.Aspergillus nidulans VeA subcellular localization is dependent on the importin?carrier and on light.Mol Microbiol,2007,63:242-255
36 Rauscher S,Pacher S,Hedtke M,et al.A phosphorylation code of the Aspergillus nidulans global regulator VelvetA(VeA)determines specific functions.Mol MicroBiol,2016,99:909-924
37 Kopke K,Hoff B,Bloemendal S,et al.Members of the Penicillium chrysogenum velvet complex play functionally opposing roles in the regulation of Penicillin biosynthesis and conidiation.Eukaryotic Cell,2013,12:299-310
38 Bayram O,Krappmann S,Ni M,et al.VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism.Science,2008,320:1504-1506
39 Aghcheh R K,Kubicek C P.Epigenetics as an emerging tool for improvement of fungal strains used in biotechnology.Appl Microbiol Biotechnol,2015,99:6167-6181
40 Pfannenstiel B T,Keller N P.On top of biosynthetic gene clusters:How epigenetic machinery influences secondary metabolism in fungi.Biotech Adv,2019
41 Li Y,He Y,Li X,et al.Histone methyltransferase aflrmtA gene is involved in the morphogenesis,mycotoxin biosynthesis,and pathogenicity of Aspergillus flavus.Toxicon,2017,127:112-121
42 Satterlee T,Cary J W,Calvo A M.RmtA,a putative arginine methyltransferase,regulates secondary metabolism and development in Aspergillus flavus.PLoS ONE,2016,11:e0155575
43 Lee I,Oh J H,Keats Shwab E,et al.HdaA,a class 2 histone deacetylase of Aspergillus fumigatus,affects germination and secondary metabolite production.Fungal Genets Biol,2009,46:782-790
44 Macheleidt J,Mattern D J,Fischer J,et al.Regulation and role of fungal secondary metabolites.Annu Rev Genet,2016,50:371-392
45 Woloshuk C P,Foutz K R,Brewer J F,et al.Molecular characterization of aflR,a regulatory locus for aflatoxin biosynthesis.Appl Environ Microb,1994,60:2408-2414 doi:8074521
46 Price M S,Yu J,Nierman W C,et al.The aflatoxin pathway regulator AflR induces gene transcription inside and outside of the aflatoxin biosynthetic cluster.FEMS MicroBiol Lett,2006,255:275-279
47 Bergmann S,Schümann J,Scherlach K,et al.Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans.Nat Chem Biol,2007,3:213-217
48 Trapp S C,Hohn T M,McCormick S,et al.Characterization of the gene cluster for biosynthesis of macrocyclic trichothecenes in Myrothecium roridum.Mol General Genets MGG,1998,257:421-432
49 Hohn T M,Krishna R,Proctor R H.Characterization of a transcriptional activator controlling trichothecene toxin biosynthesis.Fungal Genets Biol,1999,26:224-235
50 Simon A,Dalmais B,Morgant G,et al.Screening of a Botrytis cinerea one-hybrid library reveals a Cys2His2 transcription factor involved in the regulation of secondary metabolism gene clusters.Fungal Genets Biol,2013,52:9-19
51 Malapi-Wight M,Smith J,Campbell J,et al.Sda1,a Cys2-His2 zinc finger transcription factor,is involved in polyol metabolism and fumonisin B1 production in Fusarium verticillioides.PLoS ONE,2013,8:e67656
52 S?rensen J L,Hansen F T,Sondergaard T E,et al.Production of novel fusarielins by ectopic activation of the polyketide synthase 9 cluster in Fusarium graminearum.Environ MicroBiol,2012,14:1159-1170
53 Oakley C E,Ahuja M,Sun W W,et al.Discovery of McrA,a master regulator of Aspergillus secondary metabolism.Mol MicroBiol,2017,103:347-365
54 Kealey J T,Liu L,Santi D V,et al.Production of a polyketide natural product in nonpolyketide-producing prokaryotic and eukaryotic hosts.Proc Natl Acad Sci USA,1998,95:505-509
55 Zobel S,Kumpfmüller J,Süssmuth R D,et al.Bacillus subtilis as heterologous host for the secretory production of the non-ribosomal cyclodepsipeptide enniatin.Appl Microbiol Biotechnol,2015,99:681-691
56 Bond C,Tang Y,Li L.Saccharomyces cerevisiae as a tool for mining,studying and engineering fungal polyketide synthases.Fungal Genets Biol,2016,89:52-61
57 Zabala A O,Chooi Y H,Choi M S,et al.Fungal polyketide synthase product chain-length control by partnering thiohydrolase.ACS Chem Biol,2014,9:1576-1586
58 Xu Y,Zhou T,Zhang S,et al.Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases.Proc Natl Acad Sci USA,2014,111:12354-12359
59 Chooi Y H,Krill C,Barrow R A,et al.An In Planta-Expressed Polyketide Synthase Produces(R)-Mellein in the Wheat Pathogen Parastagonospora nodorum.Appl Environ Microbiol,2015,81:177-186
60 Harvey C J B,Tang M,Schlecht U,et al.HEx:A heterologous expression platform for the discovery of fungal natural products.Sci Adv,2018,4:eaar5459
61 Anyaogu D C,Mortensen U H.Heterologous production of fungal secondary metabolites in Aspergilli.Front Microbiol,2015,6:77
62 He Y,Wang B,Chen W,et al.Recent advances in reconstructing microbial secondary metabolites biosynthesis in Aspergillus spp..Biotech Adv,2018,36:739-783
63 Ma Z H,Li W,Yin W B.Progress in heterologous expression of fungal natural products(in Chinese).Acta Microbiol Sin,2016,56:429-440[马紫卉,李伟,尹文兵.真菌天然产物异源生产研究进展.微生物学报,2016,56:429-440]
64 Li W,Yu J,Li Z,et al.Rational design for fungal laccase production in the model host Aspergillus nidulans.Sci China Life Sci,2019,62:84-94
65 Chiang Y M,Szewczyk E,Davidson A D,et al.A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a Polyketide,Asperfuranone,in Aspergillus nidulans.J Am Chem Soc,2009,131:2965-2970
66 Yin W B,Chooi Y H,Smith A R,et al.Discovery of Cryptic Polyketide Metabolites from Dermatophytes Using Heterologous Expression in Aspergillus nidulans.ACS Synth Biol,2013,2:629-634
67 Ye Y,Minami A,Mandi A,et al.Genome mining for sesterterpenes using bifunctional terpene synthases reveals a unified intermediate of di/sesterterpenes.J Am Chem Soc,2015,137:11846-11853
68 Patridge E,Gareiss P,Kinch M S,et al.An analysis of FDA-approved drugs:natural products and their derivatives.Drug Discovery Today,2016,21:204-207
2 Yang S D,Bao H Y,Wang H,et al.The history and application of Chinese statutory fungal drugs(in Chinese).Guide of China Medicine,2018,16:195-197[杨树东,包海鹰,王辉,等.中国法定菌物药的历史沿革及应用.中国医药指南,2018,16:195-197]
3 Raja H A,Miller A N,Pearce C J,et al.Fungal identification using molecular tools:A primer for the natural products research community.J Nat Prod,2017,80:756-770
4 Nielsen J C,Grijseels S,Prigent S,et al.Global analysis of biosynthetic gene clusters reveals vast potential of secondary metabolite production in Penicillium species.Nat Microbiol,2017,2:17044
5 Bode H B,Bethe B,H?fs R,et al.Big effects from small changes:Possible ways to explore nature’s chemical diversity.ChemBioChem,2002,3:619-627
6 Duan Y C,Feng J,Bai N,et al.Four novel antibacterial sesquiterpene-α-amino acid quaternary ammonium hybrids from the mycelium of mushroom Stereum hirsutum.Fitoterapia,2018,128:213-217
7 Meng L H,Wang C Y,Mándi A,et al.Three diketopiperazine alkaloids with spirocyclic skeletons and one bisthiodiketopiperazine derivative from the mangrove-derived endophytic fungus Penicillium brocae MA-231.Org Lett,2016,18:5304-5307
8 Romano S,Jackson S A,Patry S,et al.Extending the“one strain many compounds”(OSMAC)principle to marine microorganisms.Mar Drugs,2018,16:244
9 Pettit R K.Small-molecule elicitation of microbial secondary metabolites.Microbial Biotech,2011,4:471-478
10 Williams R B,Henrikson J C,Hoover A R,et al.Epigenetic remodeling of the fungal secondary metabolome.Org Biomol Chem,2008,6:1895-1897
11 Henrikson J C,Hoover A R,Joyner P M,et al.A chemical epigenetics approach for engineering the in situbiosynthesis of a cryptic natural product from Aspergillus niger.Org Biomol Chem,2009,7:435-438
12 Blin K,Shaw S,Steinke K,et al.antiSMASH 5.0:updates to the secondary metabolite genome mining pipeline.Nucleic Acids Res,2019,79
13 Spiteller P.Chemical ecology of fungi.Nat Prod Rep,2015,32:971-993
14 Aminov R I.The role of antibiotics and antibiotic resistance in nature.Environ MicroBiol,2009,11:2970-2988
15 Sun J,Leng B,Sheng G,et al.Biosynthesis and functions of metabolites.Sci China Life Sci,2017,60:1280-1282
16 Partida-Martinez L P,Hertweck C.Pathogenic fungus harbours endosymbiotic bacteria for toxin production.Nature,2005,437:884-888
17 Kobayashi D Y,Crouch J A.Bacterial/Fungal interactions:from pathogens to mutualistic endosymbionts.Annu Rev Phytopathol,2009,47:63-82
18 Bonfante P,Anca I A.Plants,mycorrhizal fungi,and bacteria:a network of interactions.Annu Rev Microbiol,2009,63:363-383
19 Grube M,Berg G.Microbial consortia of bacteria and fungi with focus on the lichen symbiosis.Fungal Biol Rev,2009,23:72-85
20 Adnani N,Rajski S R,Bugni T S.Symbiosis-inspired approaches to antibiotic discovery.Nat Prod Rep,2017,34:784-814
21 Marmann A,Aly A H,Lin W,et al.Co-cultivation-A powerful emerging tool for enhancing the chemical diversity of microorganisms.Mar Drugs,2014,12:1043-1065
22 Ebrahim W,El-Neketi M,Lewald L I,et al.Metabolites from the Fungal Endophyte Aspergillus austroafricanus in Axenic Culture and in Fungal-Bacterial Mixed Cultures.J Nat Prod,2016,79:914-922
23 Zuck K M,Shipley S,Newman D J.Induced Production of N-Formyl Alkaloids from Aspergillus fumigatus by Co-culture with Streptomyces peucetius.J Nat Prod,2011,74:1653-1657
24 Shen X T,Mo X H,Zhu L P,et al.Unusual and highly bioactive sesterterpenes synthesized by Pleurotus ostreatus during the co-culture with Trametes robiniophila Murr.Appl Environ Microbiol,2019
25 Meng L H,Liu Y,Li X M,et al.Citrifelins A and B,Citrinin Adducts with a Tetracyclic Framework from Cocultures of Marine-Derived Isolates of Penicillium citrinum and Beauveria felina.J Nat Prod,2015,78:2301-2305
26 Stierle A A,Stierle D B,Decato D,et al.The Berkeleylactones,antibiotic macrolides from fungal coculture.J Nat Prod,2017,80:1150-1160
27 Tsitsigiannis D I,Keller N P.Oxylipins as developmental and host-fungal communication signals.Trends MicroBiol,2007,15:109-118
28 Rodriguez Estrada A E,Hegeman A,Corby Kistler H,et al.In vitro interactions between Fusarium verticillioides and Ustilago maydis through real-time PCR and metabolic profiling.Fungal Genets Biol,2011,48:874-885
29 Brakhage A A.Regulation of fungal secondary metabolism.Nat Rev Microbiol,2013,11:21-32
30 Yin W,Keller N P.Transcriptional regulatory elements in fungal secondary metabolism.J Microbiol,2011,49:329-339
31 Bok J W,Keller N P.LaeA,a Regulator of Secondary Metabolism in Aspergillus spp..Eukaryotic Cell,2004,3:527-535
32 Jain S,Keller N.Insights to fungal biology through LaeA sleuthing.Fungal Biol Rev,2013,27:51-59
33 Sarikaya-Bayram?,Palmer J M,Keller N,et al.One Juliet and four Romeos:Ve A and its methyltransferases.Front Microbiol,2015,6
34 Martín J F.Key role of LaeA and velvet complex proteins on expression ofβ-lactam and PR-toxin genes in Penicillium chrysogenum:cross-talk regulation of secondary metabolite pathways.J Ind Microbiol Biotechnol,2017,44:525-535
35 Stinnett S M,Espeso E A,Cobe?o L,et al.Aspergillus nidulans VeA subcellular localization is dependent on the importin?carrier and on light.Mol Microbiol,2007,63:242-255
36 Rauscher S,Pacher S,Hedtke M,et al.A phosphorylation code of the Aspergillus nidulans global regulator VelvetA(VeA)determines specific functions.Mol MicroBiol,2016,99:909-924
37 Kopke K,Hoff B,Bloemendal S,et al.Members of the Penicillium chrysogenum velvet complex play functionally opposing roles in the regulation of Penicillin biosynthesis and conidiation.Eukaryotic Cell,2013,12:299-310
38 Bayram O,Krappmann S,Ni M,et al.VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism.Science,2008,320:1504-1506
39 Aghcheh R K,Kubicek C P.Epigenetics as an emerging tool for improvement of fungal strains used in biotechnology.Appl Microbiol Biotechnol,2015,99:6167-6181
40 Pfannenstiel B T,Keller N P.On top of biosynthetic gene clusters:How epigenetic machinery influences secondary metabolism in fungi.Biotech Adv,2019
41 Li Y,He Y,Li X,et al.Histone methyltransferase aflrmtA gene is involved in the morphogenesis,mycotoxin biosynthesis,and pathogenicity of Aspergillus flavus.Toxicon,2017,127:112-121
42 Satterlee T,Cary J W,Calvo A M.RmtA,a putative arginine methyltransferase,regulates secondary metabolism and development in Aspergillus flavus.PLoS ONE,2016,11:e0155575
43 Lee I,Oh J H,Keats Shwab E,et al.HdaA,a class 2 histone deacetylase of Aspergillus fumigatus,affects germination and secondary metabolite production.Fungal Genets Biol,2009,46:782-790
44 Macheleidt J,Mattern D J,Fischer J,et al.Regulation and role of fungal secondary metabolites.Annu Rev Genet,2016,50:371-392
45 Woloshuk C P,Foutz K R,Brewer J F,et al.Molecular characterization of aflR,a regulatory locus for aflatoxin biosynthesis.Appl Environ Microb,1994,60:2408-2414 doi:8074521
46 Price M S,Yu J,Nierman W C,et al.The aflatoxin pathway regulator AflR induces gene transcription inside and outside of the aflatoxin biosynthetic cluster.FEMS MicroBiol Lett,2006,255:275-279
47 Bergmann S,Schümann J,Scherlach K,et al.Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans.Nat Chem Biol,2007,3:213-217
48 Trapp S C,Hohn T M,McCormick S,et al.Characterization of the gene cluster for biosynthesis of macrocyclic trichothecenes in Myrothecium roridum.Mol General Genets MGG,1998,257:421-432
49 Hohn T M,Krishna R,Proctor R H.Characterization of a transcriptional activator controlling trichothecene toxin biosynthesis.Fungal Genets Biol,1999,26:224-235
50 Simon A,Dalmais B,Morgant G,et al.Screening of a Botrytis cinerea one-hybrid library reveals a Cys2His2 transcription factor involved in the regulation of secondary metabolism gene clusters.Fungal Genets Biol,2013,52:9-19
51 Malapi-Wight M,Smith J,Campbell J,et al.Sda1,a Cys2-His2 zinc finger transcription factor,is involved in polyol metabolism and fumonisin B1 production in Fusarium verticillioides.PLoS ONE,2013,8:e67656
52 S?rensen J L,Hansen F T,Sondergaard T E,et al.Production of novel fusarielins by ectopic activation of the polyketide synthase 9 cluster in Fusarium graminearum.Environ MicroBiol,2012,14:1159-1170
53 Oakley C E,Ahuja M,Sun W W,et al.Discovery of McrA,a master regulator of Aspergillus secondary metabolism.Mol MicroBiol,2017,103:347-365
54 Kealey J T,Liu L,Santi D V,et al.Production of a polyketide natural product in nonpolyketide-producing prokaryotic and eukaryotic hosts.Proc Natl Acad Sci USA,1998,95:505-509
55 Zobel S,Kumpfmüller J,Süssmuth R D,et al.Bacillus subtilis as heterologous host for the secretory production of the non-ribosomal cyclodepsipeptide enniatin.Appl Microbiol Biotechnol,2015,99:681-691
56 Bond C,Tang Y,Li L.Saccharomyces cerevisiae as a tool for mining,studying and engineering fungal polyketide synthases.Fungal Genets Biol,2016,89:52-61
57 Zabala A O,Chooi Y H,Choi M S,et al.Fungal polyketide synthase product chain-length control by partnering thiohydrolase.ACS Chem Biol,2014,9:1576-1586
58 Xu Y,Zhou T,Zhang S,et al.Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases.Proc Natl Acad Sci USA,2014,111:12354-12359
59 Chooi Y H,Krill C,Barrow R A,et al.An In Planta-Expressed Polyketide Synthase Produces(R)-Mellein in the Wheat Pathogen Parastagonospora nodorum.Appl Environ Microbiol,2015,81:177-186
60 Harvey C J B,Tang M,Schlecht U,et al.HEx:A heterologous expression platform for the discovery of fungal natural products.Sci Adv,2018,4:eaar5459
61 Anyaogu D C,Mortensen U H.Heterologous production of fungal secondary metabolites in Aspergilli.Front Microbiol,2015,6:77
62 He Y,Wang B,Chen W,et al.Recent advances in reconstructing microbial secondary metabolites biosynthesis in Aspergillus spp..Biotech Adv,2018,36:739-783
63 Ma Z H,Li W,Yin W B.Progress in heterologous expression of fungal natural products(in Chinese).Acta Microbiol Sin,2016,56:429-440[马紫卉,李伟,尹文兵.真菌天然产物异源生产研究进展.微生物学报,2016,56:429-440]
64 Li W,Yu J,Li Z,et al.Rational design for fungal laccase production in the model host Aspergillus nidulans.Sci China Life Sci,2019,62:84-94
65 Chiang Y M,Szewczyk E,Davidson A D,et al.A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a Polyketide,Asperfuranone,in Aspergillus nidulans.J Am Chem Soc,2009,131:2965-2970
66 Yin W B,Chooi Y H,Smith A R,et al.Discovery of Cryptic Polyketide Metabolites from Dermatophytes Using Heterologous Expression in Aspergillus nidulans.ACS Synth Biol,2013,2:629-634
67 Ye Y,Minami A,Mandi A,et al.Genome mining for sesterterpenes using bifunctional terpene synthases reveals a unified intermediate of di/sesterterpenes.J Am Chem Soc,2015,137:11846-11853
68 Patridge E,Gareiss P,Kinch M S,et al.An analysis of FDA-approved drugs:natural products and their derivatives.Drug Discovery Today,2016,21:204-207