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Genome mining of sulfonated lanthipeptides reveals unique cyclic peptide sulfotransferases
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作者 Meng Wang Wen-Wei Li +7 位作者 Zhe Cao Jianong Sun Jiang Xiong Si-Qin Tao Tinghong Lv Kun Gao Shangwen Luo Shi-Hui Dong 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2024年第6期2773-2785,共13页
Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads,it is rare and underexplored ... Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads,it is rare and underexplored in ribosomally synthesized and post-translationally modified peptides(RiPPs).Biosynthesis of RiPPs typically entails modification of hydrophilic residues,which substantially increases their chemical stability and bioactivity,albeit at the expense of reducing water solubility.To explore sulfonated RiPPs that may have improved solubility,we conducted co-occurrence analysis of RiPP class-defining enzymes and sulfotransferase(ST),and discovered two distinctive biosynthetic gene clusters(BGCs)encoding both lanthipeptide synthetase(LanM)and ST.Upon expressing these BGCs,we characterized the structures of novel sulfonated lanthipeptides and determined the catalytic details of LanM and ST.We demonstrate that SslST-catalyzed sulfonation is leader-independent but relies on the presence of A ring formed by LanM.Both LanM and ST are promiscuous towards residues in the A ring,but ST displays strict regioselectivity toward Tyr5.The recognition of cyclic peptide by ST was further discussed.Bioactivity evaluation underscores the significance of the ST-catalyzed sulfonation.This study sets up the starting point to engineering the novel lanthipeptide STs as biocatalysts for hydrophobic lanthipeptides improvement. 展开更多
关键词 Lanthipeptides SULFOTRANSFERASES SULFONATION BIOSYNTHESIS genome mining
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Nitric oxide synthase-guided genome mining identifies a cytochrome P450 enzyme for olefin nitration in bacterial specialized metabolism
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作者 Hu Li Wei Li +3 位作者 Kaihui Song Yu Liu Guiyun Zhao Yi-Ling Du 《Synthetic and Systems Biotechnology》 SCIE CSCD 2024年第1期127-133,共7页
The biological signaling molecule nitric oxide(NO)has recently emerged as a metabolic precursor for the creation of microbial natural products with diversified structures and biological activities.Within the biosynthe... The biological signaling molecule nitric oxide(NO)has recently emerged as a metabolic precursor for the creation of microbial natural products with diversified structures and biological activities.Within the biosynthetic gene clusters(BGCs)of these compounds,genes associated with NO production pathways have been pinpointed.In this study,we employ a nitric oxide synthase(NOS)-guided genome mining strategy for the targeted discovery of NO-derived bacterial natural products and NO-utilizing biocatalysts.We show that a conserved NOS-containing BGC,distributed across several actinobacterial genomes,is responsible for the biosynthesis of lajollamycin,a unique nitro-tetraene-containing antibiotic whose biosynthetic mechanism remains elusive.Through a combination of in vivo and in vitro studies,we unveil the first cytochrome P450 enzyme capable of catalyzing olefin nitration in natural product biosynthesis.These results not only expand the current knowledge about biosynthetic nitration processes but also offer an efficient way for targeted identification of NO-utilizing metabolic pathways and novel nitrating biocatalysts. 展开更多
关键词 Nitric oxide genome mining BIOSYNTHESIS NITRATION CYTOCHROME P450
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Genome mining of multi-substituted alkylresorcinols from a hybrid highly reducing-and typeⅢ-polyketide pathway
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作者 Huaran Zhang Yuting Huang +2 位作者 Yingjie Tang Dekun Kong Yi Zou 《Chinese Chemical Letters》 SCIE CAS CSCD 2024年第7期345-349,共5页
Fungal alkylresorcinols are a class of polyketides,which are commonly synthesized by the hybridization of highly reducing polyketide synthase(hrPKS)with non-reducing polyketide synthase(nrPKS).In this study,we identif... Fungal alkylresorcinols are a class of polyketides,which are commonly synthesized by the hybridization of highly reducing polyketide synthase(hrPKS)with non-reducing polyketide synthase(nrPKS).In this study,we identified and demonstrated a new assembly model for synthesizing alkylresorcinol(scirpilin A,1),which was accomplished by collaboration of a hrPKS(FscA)and a typeⅢPKS(FscB).Furthermore,three post-tailoring enzymes(FscC,FscD,and FscE)act iteratively on 1 skeleton,including successive 14e-oxidation of inert carbons,di-halogenation,and di-methylation,to form highly oxidized and multisubstituted alkylresorcinols.Our work presents an unusual synthesis manner of alkylresorcinols,sheds light on the collaborative mechanism between hrPKS and typeⅢPKS and provides three valuable enzymatic catalysts for the tailoring of alkylresorcinol family natural products in future. 展开更多
关键词 genome mining Alkylresorcinol hrPKS TypeⅢPKS Iterative catalysis
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Targeted genome mining for microbial antitumor agents acting through DNA intercalation
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作者 Zhijie Zhao Guiyun Zhao +7 位作者 Yi Chai Wei Li Kaihui Song Wenbin Zhao Hairong Li Miaolian Wu Zhan Zhou Yi-Ling Du 《Synthetic and Systems Biotechnology》 SCIE CSCD 2023年第3期520-526,共7页
Microbial natural products have been one of the most important sources for drug development.In the current postgenomic era,sequence-driven approaches for natural product discovery are becoming increasingly popular.Her... Microbial natural products have been one of the most important sources for drug development.In the current postgenomic era,sequence-driven approaches for natural product discovery are becoming increasingly popular.Here,we develop an effective genome mining strategy for the targeted discovery of microbial metabolites with antitumor activities.Our method employs uvrA-like genes as genetic markers,which have been identified in the biosynthetic gene clusters(BGCs)of several chemotherapeutic drugs of microbial origin and confer self-resistance to the corresponding producers.Through systematic genomic analysis of gifted actinobacteria genera,identification of uvrA-like gene-containing BGCs,and targeted isolation of products from a BGC prioritized for metabolic analysis,we identified a new tetracycline-type DNA intercalator timmycins.Our results thus provide a new genome mining strategy for the efficient discovery of antitumor agents acting through DNA intercalation. 展开更多
关键词 genome mining Microbial natural product DNA intercalator UvrA-like protein Biosynthetic gene clusters TETRACYCLINE
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Recombineering enables genome mining of novel siderophores in a non-model Burkholderiales strain
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作者 Xingyan Wang Haibo Zhou +4 位作者 Xiangmei Ren Hanna Chen Lin Zhong Xianping Bai Xiaoying Bian 《Engineering Microbiology》 2023年第3期30-36,共7页
Iron is essential for bacterial survival,and most bacteria capture iron by producing siderophores.Burkholde-riales bacteria produce various types of bioactive secondary metabolites,such as ornibactin and malleobactin ... Iron is essential for bacterial survival,and most bacteria capture iron by producing siderophores.Burkholde-riales bacteria produce various types of bioactive secondary metabolites,such as ornibactin and malleobactin siderophores.In this study,the genome analysis of Burkholderiales genomes showed a putative novel siderophore gene cluster crb,which is highly similar to the ornibactin and malleobactin gene clusters but does not have pvdF,a gene encoding a formyltransferase for N-δ-hydroxy-ornithine formylation.Establishing the bacteriophage recom-binase Redγ-Redδβ7029 mediated genome editing system in a non-model Burkholderiales strain Paraburkholderia caribensis CICC 10960 allowed the rapid identification of the products of crb gene cluster,caribactins A-F(1-6).Caribactins contain a special amino acid residue N-δ-hydroxy-N-δ-acetylornithine(haOrn),which differs from the counterpart N-δ-hydroxy-N-δ-formylornithine(hOrn)in ornibactin and malleobactin,owing to the absence of pvdF.Gene inactivation showed that the acetylation of hOrn is catalyzed by CrbK,whose homologs proba-bly not be involved in the biosynthesis of ornibactin and malleobactin,showing possible evolutionary clues of these siderophore biosynthetic pathways from different genera.Caribactins promote biofilm production and en-hance swarming and swimming abilities,suggesting that they may play crucial roles in biofilm formation.This study also revealed that recombineering has the capability to mine novel secondary metabolites from non-model Burkholderiales species. 展开更多
关键词 Burkholderiales Recombineering Siderophore genome mining Caribactins
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Challenges and advances in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs) 被引量:4
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作者 Zheng Zhong Beibei He +1 位作者 Jie Li Yong-Xin Li 《Synthetic and Systems Biotechnology》 SCIE 2020年第3期155-172,共18页
Ribosomally synthesized and post-translationally modified peptides(RiPPs)are a class of cyclic or linear peptidic natural products with remarkable structural and functional diversity.Recent advances in genomics and sy... Ribosomally synthesized and post-translationally modified peptides(RiPPs)are a class of cyclic or linear peptidic natural products with remarkable structural and functional diversity.Recent advances in genomics and synthetic biology,are facilitating us to discover a large number of new ribosomal natural products,including lanthipeptides,lasso peptides,sactipeptides,thiopeptides,microviridins,cyanobactins,linear thiazole/oxazole-containing peptides and so on.In this review,we summarize bioinformatic strategies that have been developed to identify and prioritize biosynthetic gene clusters(BGCs)encoding RiPPs,and the genome mining-guided discovery of novel RiPPs.We also prospectively provide a vision of what genomics-guided discovery of RiPPs may look like in the future,especially the discovery of RiPPs from dominant but uncultivated microbes,which will be promoted by the combinational use of synthetic biology and metagenome mining strategies. 展开更多
关键词 Natural products Ribosomally synthesized and posttranslationally modified peptides RiPPs genome mining Metagenome mining Synthetic biology
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Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products 被引量:5
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作者 Qian Wei Jian Bai +7 位作者 Daojiang Yan Xiuqi Bao Wenting Li Bingyu Liu Dan Zhang Xiangbing Qi Dequan Yu Youcai Hu 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2021年第2期572-587,共16页
Endophytic fungi are promising producers of bioactive small molecules.Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters,exhibited its strong abi... Endophytic fungi are promising producers of bioactive small molecules.Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters,exhibited its strong ability to produce numbers of secondary metabolites.However,this strain mainly produce rubratoxins alone with high yield in varied culture conditions,suggested most gene clusters are silent.Efforts for mining the cryptic gene clusters in P.dangeardii,including epigenetic regulation and one-strain-many-compounds(OSMAC)approach were failed probably due to the high yield of rubratoxins.A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases(PKSs),and led to the trace compounds detectable.As a result,a total of 23 new compounds including azaphilone monomers,dimers,turimers with unprecedented polycyclic bridged heterocycle and spiral structures,as well as siderophores were identified.Some compounds showed significant cytotoxicities,anti-inflammatory or antioxidant activities.The attractive dual PKS s gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor.Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi. 展开更多
关键词 Endophytic fungi Penicillium dangeardii genome mining Silent gene cluster Azaphilones TRIMERS Metabolic shunting
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Genome mining of fungal globin-like enzymes for catalyzing the synthesis of linear terpenes
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作者 LIU Li CHEN Xiwei ZOU Yi 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2022年第10期795-800,共6页
Genome mining for the search and discovery of two new globin-like enzymes,TriB from Fusarium poae and TutaA from Schizophyllum commne,are involved in the synthesis of two linear terpenes tricinonoic acid(1)and 2-buten... Genome mining for the search and discovery of two new globin-like enzymes,TriB from Fusarium poae and TutaA from Schizophyllum commne,are involved in the synthesis of two linear terpenes tricinonoic acid(1)and 2-butenedioic acid(3).Both in vivo heterologous biosynthesis and in vitro biochemical assays showed that these two enzymes catalyzed the C-C double bond cleavage of a cyclic sesquiterpene precursor(-)-germacrene D(7)and a linear diterpene backbone schizostain(2),respectively.Our work presents an unusual formation mechanism of linear terpenes from fungi and expands the functional skills of globin-like enzymes in the synthesis of terpene compounds. 展开更多
关键词 genome mining Globin-like enzyme Linear terpene C-C double bond cleavage FUNGI
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Genome mining reveals the biosynthetic potential of the marinederived strain Streptomyces marokkonensis M10
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作者 Liangyu Chen Ying-Mi Lai +1 位作者 Yu-Liang Yang Xinqing Zhao 《Synthetic and Systems Biotechnology》 SCIE 2016年第1期56-65,共10页
Marine streptomycetes are rich sources of natural products with novel structures and interesting biological activities,and genome mining of marine streptomycetes facilitates rapid discovery of their useful products.In... Marine streptomycetes are rich sources of natural products with novel structures and interesting biological activities,and genome mining of marine streptomycetes facilitates rapid discovery of their useful products.In this study,a marine-derived Streptomyces sp.M10 was revealed to share a 99.02%16S rDNA sequence identity with that of Streptomyces marokkonensis Ap1T,and was thus named S.marokkonensis M10.To further evaluate its biosynthetic potential,the 7,207,169 bps of S.marokkonensis M10 genome was sequenced.Genomic sequence analysis for potential secondary metaboliteassociated gene clusters led to the identification of at least three polyketide synthases(PKSs),six non-ribosomal peptide synthases(NRPSs),one hybrid NRPS-PKS,two lantibiotic and five terpene biosynthetic gene clusters.One type I PKS gene cluster was revealed to share high nucleotide similarity with the candicidin/FR008 gene cluster,indicating the capacity of this microorganism to produce polyene macrolides.This assumption was further verified by isolation of two polyene family compounds PF1 and PF2,which have the characteristic UV adsorption at 269,278,290 nm(PF1)and 363,386 and 408 nm(PF2),respectively.S.marokkonensis M10 is therefore a new source of polyene metabolites.Further studies on S.marokkonensis M10 will provide more insights into natural product biosynthesis potential of related streptomycetes.This is also the first report to describe the genome sequence of S.marokkonensis-related strain. 展开更多
关键词 Streptomyces marokkonensis genome mining Secondary metabolites Polyketide synthase Polyene macrolides
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Mining of a streptothricin gene cluster from Streptomyces sp.TP-A0356 genome via heterologous expression 被引量:4
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作者 LI JinE GUO ZhengYan +4 位作者 HUANG Wei MENG XiangXi AI GuoMin TANG GongLi CHEN YiHua 《Science China(Life Sciences)》 SCIE CAS 2013年第7期619-627,1-4,共9页
Streptothricins (STs) are used commercially to treat bacterial and fungal diseases in agriculture. Mining of the sequenced microbial genomes uncovered two cryptic ST clusters from Streptomyces sp. C and Streptomyces s... Streptothricins (STs) are used commercially to treat bacterial and fungal diseases in agriculture. Mining of the sequenced microbial genomes uncovered two cryptic ST clusters from Streptomyces sp. C and Streptomyces sp. TP-A0356. The ST cluster from S. sp. TP-A0356 was verified by successful heterologous expression in Streptomyces coelicolor M145. Two new ST analogs were produced together with streptothricin F and streptothricin D in the heterologous host. The ST cluster was further confirmed by inactivation of gene stnO, which was proposed encoding an aminomutase supplying -lysines for the poly-β-Lys chain formation. A putative biosynthetic pathway for STs is proposed based on bioinformatics analyses of the ST genes and experimental evidence. 展开更多
关键词 genome mining streptothricin STREPTOMYCES heterologous expression BIOSYNTHESIS
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Genus-specific secondary metabolome in Allokutzneria and Kibdelosporangium
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作者 Man-Jing Ma Wen-Chao Yu +8 位作者 Huai-Ying Sun Bing-Cheng Dong Gang-Ao Hu Zhen-Yi Zhou Yi Hua Buddha Bahadur Basnet Yan-Lei Yu Hong Wang Bin Wei 《Synthetic and Systems Biotechnology》 SCIE CSCD 2024年第3期381-390,共10页
Rare actinomycete genera are highly recognized as a promising source of structurally diverse and bioactive natural products.Among these genera,Allokutzneria and Kibdelosporangium are two phylogenetically closely relat... Rare actinomycete genera are highly recognized as a promising source of structurally diverse and bioactive natural products.Among these genera,Allokutzneria and Kibdelosporangium are two phylogenetically closely related and have been reported to encode some valuable biosynthetic enzymes and secondary metabolites.However,there is currently no relevant systematic research available to outline the linkage of genomic and metabolomics for specific secondary metabolites in these two promising genera.In this study,we first investi-gated the genus-specific secondary metabolic potential in Allokutzneria and Kibdelosporangium by comparing the diversity and novelty of their secondary metabolite biosynthetic gene clusters(BGCs).The specific secondary metabolites produced by two representative strains of these genera were comprehensively investigated using untargeted metabolomics techniques.The findings unveiled that the majority(95.4%)of the gene cluster families(GCFs)encoded by Allokutzneria and Kibdelosporangium were genus-specific,including NRPS GCFs encoding siderophores.The untargeted metabolomics analysis revealed that the metabolic profiles of two representative strains exhibit extensive specificity,with the culture medium having a big impact on the metabolic profiles.Besides,an MS-cluster featuring a series of hydroxamate-type siderophores was identified from Allokutzneria albata JCM 9917,with two of them,including a novel one(N-deoxy arthrobactin A),being experimentally validated.The present study offers valuable insights for the targeted discovery of genus-specific natural products from microorganisms. 展开更多
关键词 Genus-specific secondary metabolism Allokutzneria Kibdelosporangium genome mining Untargeted metabolomics SIDEROPHORE
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Generate a bioactive natural product library by mining bacterial cytochrome P450 patterns 被引量:2
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作者 Xiangyang Liu 《Synthetic and Systems Biotechnology》 SCIE 2016年第2期95-108,共14页
The increased number of annotated bacterial genomes provides a vast resource for genome mining.Several bacterial natural products with epoxide groups have been identified as pre-mRNA spliceosome inhibitors and antitum... The increased number of annotated bacterial genomes provides a vast resource for genome mining.Several bacterial natural products with epoxide groups have been identified as pre-mRNA spliceosome inhibitors and antitumor compounds through genome mining.These epoxide-containing natural products feature a common biosynthetic characteristic that cytochrome P450s(CYPs)and its patterns such as epoxidases are employed in the tailoring reactions.The tailoring enzyme patterns are essential to both biological activities and structural diversity of natural products,and can be used for enzyme pattern-based genome mining.Recent development of direct cloning,heterologous expression,manipulation of the biosynthetic pathways and the CRISPR-CAS9 system have provided molecular biology tools to turn on or pull out nascent biosynthetic gene clusters to generate a microbial natural product library.This review focuses on a library of epoxide-containing natural products and their associated CYPs,with the intention to provide strategies on diversifying the structures of CYP-catalyzed bioactive natural products.It is conceivable that a library of diversified bioactive natural products will be created by pattern-based genome mining,direct cloning and heterologous expression as well as the genomic manipulation. 展开更多
关键词 genome mining Microbial P450 Natural product library Synthetic biology
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Genomic data mining for functional annotation of human long noncoding RNAs 被引量:2
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作者 Brian L.GUDENAS Jun WANG +3 位作者 Shu-zhen KUANG An-qi WEI Steven B.COGILL Liang-jiang WANG 《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 SCIE CAS CSCD 2019年第6期476-487,共12页
Life may have begun in an RNA world,which is supported by increasing evidence of the vital role that RNAs perform in biological systems.In the human genome,most genes actually do not encode proteins;they are noncoding... Life may have begun in an RNA world,which is supported by increasing evidence of the vital role that RNAs perform in biological systems.In the human genome,most genes actually do not encode proteins;they are noncoding RNA genes.The largest class of noncoding genes is known as long noncoding RNAs(lncRNAs),which are transcripts greater in length than 200 nucleotides,but with no protein-coding capacity.While some lncRNAs have been demonstrated to be key regulators of gene expression and 3D genome organization,most lncRNAs are still uncharacterized.We thus propose several data mining and machine learning approaches for the functional annotation of human lncRNAs by leveraging the vast amount of data from genetic and genomic studies.Recent results from our studies and those of other groups indicate that genomic data mining can give insights into lncRNA functions and provide valuable information for experimental studies of candidate lncRNAs associated with human disease. 展开更多
关键词 Long noncoding RNA Functional annotation Genomic data mining Machine learning
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Identification and heterologous expression of the globomycin biosynthetic gene cluster
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作者 Daniel Oves-Costales Tetiana Gren +8 位作者 Eva Baggesgaard Sterndorff Jesús Martín Francisco Javier Ortiz-Lopez Tue S.Jørgensen Xinglin Jiang Fernando Roman-Hurtado Fernando Reyes Olga Genilloud Tilmann Weber 《Synthetic and Systems Biotechnology》 SCIE CSCD 2023年第2期206-212,共7页
Globomycin is a cyclic lipodepsipeptide originally isolated from several Streptomyces species which displays strong and selective antibacterial activity against Gram-negative pathogens.Its mode of action is based on t... Globomycin is a cyclic lipodepsipeptide originally isolated from several Streptomyces species which displays strong and selective antibacterial activity against Gram-negative pathogens.Its mode of action is based on the competitive inhibition of the lipoprotein signal peptidase II(LspA),which is absent in eukaryotes and considered an attractive target for the development of new antibiotics.Despite its interesting biological properties,the gene cluster encoding its biosynthesis has not yet been identified.In this study we employed a genome-mining approach in the globomycin-producing Streptomyces sp.CA-278952 to identify a candidate gene cluster responsible for its biosynthesis.A null mutant was constructed using CRISPR base editing where production was abolished,strongly suggesting its involvement in the biosynthesis.The putative gene cluster was then cloned and heterologously expressed in Streptomyces albus J1074 and Streptomyces coelicolor M1146,therefore unambigu-ously linking globomycin and its biosynthetic gene cluster.Our work paves the way for the biosynthesis of new globomycin derivatives with improved pharmacological properties. 展开更多
关键词 Globomycin Signal peptidase II Cyclic lipodepsipeptide genome mining CRISPR-cBEST Heterologous expression
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Nobachelins,new siderophores from Nocardiopsis baichengensis protecting Caenorhabditis elegans from Pseudomonas aeruginosa infection
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作者 Haowen Zhao Yuhao Ren +4 位作者 Feng Xie Huanqin Dai Hongwei Liu Chengzhang Fu Rolf Müller 《Synthetic and Systems Biotechnology》 SCIE CSCD 2023年第4期640-646,共7页
The biosynthetic potential of actinobacteria to produce novel natural products is still regarded as immense.In this paper,we correlated a cryptic biosynthetic gene cluster to chemical molecules by genome mining and ch... The biosynthetic potential of actinobacteria to produce novel natural products is still regarded as immense.In this paper,we correlated a cryptic biosynthetic gene cluster to chemical molecules by genome mining and chemical analyses,leading to the discovery of a new group of catecholate-hydroxamate siderophores,nobachelins,from Nocardiopsis baichengensis DSM 44845.Nobachelin biosynthesis genes are conserved in several bacteria from the family Nocardiopsidaceae.Structurally,nobachelins feature fatty-acylated hydroxy-ornithine and a rare chlorinated catecholate group.Intriguingly,nobachelins rescued Caenorhabditis elegans from Pseudomonas aeruginosa-mediated killing. 展开更多
关键词 NOCARDIOPSIS genome mining SIDEROPHORE Pseudomonas aeruginosa INFECTION
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Fungal arginine-containing cyclodipeptide synthases are finally revealed
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作者 Hang Li 《Engineering Microbiology》 2023年第2期83-85,共3页
Biosynthetic pathways without any identifiable core enzymes may encode unknown(biosynthetic route)-unknown(molecular structure)natural products.However,bioinformatics-guided mining for such unknown-unknown metabolites... Biosynthetic pathways without any identifiable core enzymes may encode unknown(biosynthetic route)-unknown(molecular structure)natural products.However,bioinformatics-guided mining for such unknown-unknown metabolites is challenging.Recently,an unknown-unknown biosynthetic route has been deciphered in fungi.It was found that a class of enzymes previously annotated as hypothetical proteins catalyze the biosynthesis of arginine-containing cyclodipeptides(CDPs).This advances the understanding of the biosynthesis of CDPs and highlights the vast potential of unknown-unknown natural products encoded by microbial genomes. 展开更多
关键词 Arginine-containing cyclodipeptide BIOSYNTHESIS Cyclodipeptide synthase Fungi genome mining
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Recent advances in the direct cloning of large natural product biosynthetic gene clusters
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作者 Jiaying Wan Nan Ma Hua Yuan 《Engineering Microbiology》 2023年第3期58-64,共7页
Large-scale genome-mining analyses have revealed that microbes potentially harbor a huge reservoir of unchar-acterized natural product(NP)biosynthetic gene clusters(BGCs),and this has spurred a renaissance of novel dr... Large-scale genome-mining analyses have revealed that microbes potentially harbor a huge reservoir of unchar-acterized natural product(NP)biosynthetic gene clusters(BGCs),and this has spurred a renaissance of novel drug discovery.However,the majority of these BGCs are often poorly or not at all expressed in their native hosts under laboratory conditions,and thus are regarded as silent/orphan BGCs.Currently,connecting silent BGCs to their corresponding NPs quickly and on a large scale is particularly challenging because of the lack of universal strategies and enabling technologies.Generally,the heterologous host-based genome mining strategy is believed to be a suitable alternative to the native host-based approach for prioritization of the vast and ever-increasing number of uncharacterized BGCs.In the last ten years,a variety of methods have been reported for the direct cloning of BGCs of interest,which is the first and rate-limiting step in the heterologous expression strategy.Es-sentially,each method requires that the following three issues be resolved:1)how to prepare genomic DNA;2)how to digest the bilateral boundaries for release of the target BGC;and 3)how to assemble the BGC and the capture vector.Here,we summarize recent reports regarding how to directly capture a BGC of interest and briefly discuss the advantages and disadvantages of each method,with an emphasis on the notion that direct cloning is very beneficial for accelerating genome mining research and large-scale drug discovery. 展开更多
关键词 Natural product Silent BGCs genome mining Direct cloning Heterologous expression
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Discovery of angucyclinone polyketides from marine actinomycetes with a genomic DNA-based PCR assay targeting type Ⅱ polyketide synthase 被引量:3
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作者 杨小燕 金晶 +5 位作者 周梦洁 许青霞 刘发旺 张英涛 马明 杨东辉 《Journal of Chinese Pharmaceutical Sciences》 CAS CSCD 2017年第3期173-179,共7页
Angucyclinones are aromatic polyketides produced by type Ⅱ polyketide synthases(PKS) and are mainly found in terrestrial actinomycetes. To discover more angucyclinones from marine actinomycetes, a genomic DNA-based... Angucyclinones are aromatic polyketides produced by type Ⅱ polyketide synthases(PKS) and are mainly found in terrestrial actinomycetes. To discover more angucyclinones from marine actinomycetes, a genomic DNA-based PCR assay targeting type Ⅱ polyketide synthases was performed. Among the 167 marine actinomycetes strains screened, twelve strains were identified as the "positive" strains possessing type Ⅱ PKS-encoding genes based on the sequencing of PCR products. One of the 12 "positive" strains, Streptomyces sp. PKU-MA00218 was selected for the large-scale fermentation based on the HPLC and TLC analysis. Four angucyclinones, 6-deoxy-8-O-methylrabelomycin(1), 8-O-methylrabelomycin(2), 8-O-methyltetrangulol(3), C-ring cleavage product of angucyclinone C(4), were isolated and their structures were elucidated based on spectroscopic analyses. The isolation of angucyclinones 1–4 highlights the power of genome mining technologies based on biosynthetic knowledge in natural products discovery. 展开更多
关键词 Angucyclinone Aromatic polyketides genome mining Marine actinomycetes Type polyketide synthases
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Discovery of thiazostatin siderphores from Streptomyces sp. HMU0027 with a genomic DNA-based PCR assay targeting nonribosomal peptide synthetase 被引量:2
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作者 刘发旺 周梦洁 +4 位作者 金晶 杨小燕 张英涛 马明 杨东辉 《Journal of Chinese Pharmaceutical Sciences》 CAS CSCD 2017年第10期737-746,共10页
Nonribosomal peptides (NRPs) represent a large family of natural products with great diversities of chemical structures and biological activities. The peptide backbones of NRPs are synthesized by nonribosomal peptid... Nonribosomal peptides (NRPs) represent a large family of natural products with great diversities of chemical structures and biological activities. The peptide backbones of NRPs are synthesized by nonribosomal peptide synthetases (NRPSs) that minimally consist of one adenylation (A) domain, one peptidyl carrier protein (PCP) and one condensation (C) domain. In this study, we carded out a PCR screening and identified 21 "positive" strains from 100 actinomycete strains with the degenerate primers designed from the conserved sequences of A domains of NRPSs. One of the 21 "positive" strains, Streptomyces sp. HMU0027, was selected for large-scale fermentation (9 L) based on HPLC analysis, and subsequent isolation and structural elucidation afforded seven NRPS-synthesized thiazostatin siderophore analogues (1-7). Compound 1 was a new compound containing an unusual linkage between a phenolate siderophore and a sugar moiety. These results laid the foundation for further biosynthetic research of these thiazostatin analogues and highlighted the power of genome mining technologies based on biosynthetic knowledge in NRP discovery. 展开更多
关键词 genome mining Nonribosomal peptide synthetase SIDEROPHORE Strain prioritization Thiazostation
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Epigenetic modification in histone deacetylase deletion strain of Calcarisporium arbuscula leads to diverse diterpenoids 被引量:5
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作者 Jian Bai Rong Mu +6 位作者 Man Dou Daojiang Yan Bingyu Liu Qian Wei Jun Wan Yi Tang Youcai Hu 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2018年第4期687-697,共11页
Epigenetic modifications have been proved to be a powerful way to activate silent gene clusters and lead to diverse secondary metabolites in fungi. Previously, inactivation of a histone H3 deacetylase in Calcarisporiu... Epigenetic modifications have been proved to be a powerful way to activate silent gene clusters and lead to diverse secondary metabolites in fungi. Previously, inactivation of a histone H3 deacetylase in Calcarisporium arbuscula had led to pleiotropic activation and overexpression of more than 75% of the biosynthetic genes and isolation of ten compounds. Further investigation of the crude extract of C. arbuscula Δhda A strain resulted in the isolation of twelve new diterpenoids including three cassanes(1-3), one cleistanthane(4), six pimaranes(5-10), and two isopimaranes(11 and 12) along with two know cleistanthane analogues. Their structures were elucidated by extensive NMR spectroscopic data analysis. Compounds 2 and 4 showed potent inhibitory effects on the expression of MMP1 and MMP2(matrix metalloproteinases family) in human breast cancer(MCF-7) cells. 展开更多
关键词 Calcarisporium arbuscula Calcarisporic acids Pimarane DITERPENOID Matrix metalloproteinases inhibitor Epigenetic genome mining
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