Fungal aromatic compounds comprise an important and structurally diverse group of secondary metabolites.Several genome sequencing projects revealed many putative biosynthetic gene clusters of fungal aromatic compounds...Fungal aromatic compounds comprise an important and structurally diverse group of secondary metabolites.Several genome sequencing projects revealed many putative biosynthetic gene clusters of fungal aromatic compounds,but many of these genes seem to be silent under typical laboratory culture conditions.To gain access to this untapped reservoir of natural products,we utilized chemical epigenetic modifiers to induce the expression of dormant biosynthetic genes.As a result,the concomitant supplementation of the histone deacetylase inhibitors suberoylanilide hydroxamic acid(500mM)and nicotinamide(50mM)to the culture medium of a fungal pathogen,Stagonospora nodorum,resulted in the isolation of three aromatic compounds(1-3),including a novel natural butyrophenone,(+)-4'-methoxy-(2S)-methylbutyrophenone(1),and two known polyketides,alternariol(2)and(-)-(3R)-mellein methyl ether(3).展开更多
Four new fungal polyketides named koninginins N-Q(1–4),together with four known analogues(5–8),were isolated from the endophytic fungus Trichoderma koningiopsis YIM PH30002 harbored in Panax notoginseng.Their struct...Four new fungal polyketides named koninginins N-Q(1–4),together with four known analogues(5–8),were isolated from the endophytic fungus Trichoderma koningiopsis YIM PH30002 harbored in Panax notoginseng.Their structures were determined on the basis of spectral data interpretation.These compounds were evaluated for their antifungal activity,nitric oxide inhibition,and anticoagulant activity.展开更多
Five new polyketides,craterellones A-E(1-5),were isolated from cultures of basidiomycete Craterellus odoratus,together with five known compounds(6-10).Structures of 1-5 were elucidated on the basis of extensive spectr...Five new polyketides,craterellones A-E(1-5),were isolated from cultures of basidiomycete Craterellus odoratus,together with five known compounds(6-10).Structures of 1-5 were elucidated on the basis of extensive spectroscopic analysis.All compounds were evaluated for their inhibitory activities against one isozyme of 11β-hydroxysteroid dehydrogenase(11β-HSD1)and cytotoxic activities on five tumor cell lines.Compound 10 exhibited significant cytotoxicity against HL-60,SMMC-7721,A-549,MCF-7,and SW-480,with IC50 values of 0.50,0.69,0.64,1.10,0.54μM,respectively.展开更多
Eight new furan derivatives,irpexins A‒H(1‒8),two new polyketides,irpexins I and J(9 and 10),together with nine known compounds were isolated from the fermentation of Irpex lacteus.The structures and absolute configur...Eight new furan derivatives,irpexins A‒H(1‒8),two new polyketides,irpexins I and J(9 and 10),together with nine known compounds were isolated from the fermentation of Irpex lacteus.The structures and absolute configurations were elucidated on the basis of extensive spectroscopic methods and Mosher ester reaction.All compounds shows no cytotoxicity to human MCF-7 and Hela cancer cell lines at the concentration of 10μM.展开更多
Polyketides have been widely used clinically due to their significant biological activities, but the needed structural and functional diversity cannot be achieved by common chemical synthetic methods. The tool of comb...Polyketides have been widely used clinically due to their significant biological activities, but the needed structural and functional diversity cannot be achieved by common chemical synthetic methods. The tool of combinatorial biosynthesis provides the possibility to produce "unnatural" natural drugs, which has achieved initial success. This paper provides an overview for the strategies of combinatorial biosynthesis in producing the structural and functional diversity of polyketides, including the redesign of metabolic flow, polyketide synthase(PKS) engineering, and PKS post-translational modification. Although encouraging progress has been made in the last decade, challenges still exist regarding the rational combinatorial biosynthesis of polyketides. In this review, the perspectives of polyketide combinatorial biosynthesis are also discussed.展开更多
The diversity of modular polyketide synthase (PKS) genes in sediments of Ardley Island in Antarctica, was studied by restriction fragment length polymorphism (RFLP) analysis. Phylogenetic analysis of 14 amino acid (AA...The diversity of modular polyketide synthase (PKS) genes in sediments of Ardley Island in Antarctica, was studied by restriction fragment length polymorphism (RFLP) analysis. Phylogenetic analysis of 14 amino acid (AA) sequences indicates that the identified ketosynthase (KS) domains were clustered with those from diverse bacterial groups, including Cyanobacteria, γ-Proteobacteria, Actinobacteria, Firmicutes, and some unidentified microorganisms from marine sponge, bryozoan and other environmental samples. The obtained KS domains showed 43%-81% similarity at the AA level to reference sequences in GenBank. Six identified KS domains showed diverse sequences of the motif (VQTACSTS) that was used to identify the hybrid PKS/nonribosomal peptide synthetase (NRPS) enzyme complex, and formed a new branch. These results reveal a high diversity and novelty of PKS genes in antarctic sediments.展开更多
Polyketides are one of the largest groups of natural products produced by bacteria, fungi, and plants. Many of these metabolites have highly complex chemical structures and very important biological activities, includ...Polyketides are one of the largest groups of natural products produced by bacteria, fungi, and plants. Many of these metabolites have highly complex chemical structures and very important biological activities, including antibiotic, anticancer, immunosuppressant, and anti-cholesterol activities. In the past two decades, extensive investigations have been carried out to understand the molecular mechanisms for polyketide biosynthesis. These efforts have led to the development of various rational approaches toward engineered biosynthesis of new polyketides. More recently, the research efforts have shifted to the elucidation of the three-dimentional structure of the complex enzyme machineries for polyketide biosynthesis and to the exploitation of new sources for polyketide production, such as filamentous fungi and marine microorganisms. This review summarizes our general understanding of the biosynthetic mechanisms and the progress in engineered biosynthesis of polyketides.展开更多
The bacterial trialkyl-substituted aromatic polyketides are structurally featured with the unusual aromatic core in the middle of polyketide chain such as TM-123(1),veramycin A(2),NFAT-133(3)and benwamycin I(4),which ...The bacterial trialkyl-substituted aromatic polyketides are structurally featured with the unusual aromatic core in the middle of polyketide chain such as TM-123(1),veramycin A(2),NFAT-133(3)and benwamycin I(4),which were discovered from Streptomyces species and demonstrated with antidiabetic and immunosuppressant activities.Though the biosynthetic pathway of 1-3 was reported as a type I polyketide synthase(PKS),the PKS assembly line was interpreted inconsistently,and it remains a mystery how the compound 3 was generated.Herein,the PKS assembly logic of 1-4 was revised by site-mutagenetic analysis of the PKS dehydratase domains.Based on gene deletion and complementation,the putative P450 monooxygenase nftE1 and metallo-beta-lactamase(MBL)fold hydrolase nftF1 were verified as essential genes for the biosynthesis of 1-4.The absence of nftE1 led to abolishment of 1-4 and accumulation of new products(5-8).Structural elucidation reveals 5-8 as the non-aromatic analogs of 1,suggesting the NftE1-catalyzed aromatic core formation.Deletion of nftF1 resulted in disappearance of 3 and 4 with the compounds 1 and 2 unaffected.As a rare MBL-fold hydrolase from type I PKSs,NftF1 potentially generates the compound 3 through two strategies:catalyze premature chain-offloading as a trans-acting thioesterase or hydrolyze the lactone-bond of compound 1 as an esterase.展开更多
Secondary metabolites(SMs)produced by soil bacteria,for instance antimicrobials and siderophores,play a vital role in bacterial adaptation to soil and root ecosystems and can contribute to plant health.Many SMs are no...Secondary metabolites(SMs)produced by soil bacteria,for instance antimicrobials and siderophores,play a vital role in bacterial adaptation to soil and root ecosystems and can contribute to plant health.Many SMs are non-ribosomal peptides and polyketides,assembled by non-ribosomal peptides synthetase(NRPS)and polyketide synthase(PKS)and encoded by biosynthetic gene clusters(BGCs).Despite their ecological importance,little is known about the occurrence and diversity of NRPs and PKs in soil.We extracted NRPS-and PKS-encodiing BGCs from 20 publicly available soil and root-associated metagenomes and annotated them using antiSMASH-DB.We found that the overall abundance of NRPSs and PKSs is similar in both environments,however NRPSs and PKSs were significantly clustered between soil and root samples.Moreover,the majority of identified sequences were unique to either soil-or root-associated datasets and had low identity to known BGCs,suggesting their novelty.Overall,this study illuminates the huge untapped diversity of predicted SMs in soil and root microbiomes,and indicates presence of specific SMs,which may play a role in inter-and intra-bacteriial interactions in root ecosystems.展开更多
Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functio...Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functionalities.Polyketides encompass one of the largest classes of chemically diverse natural products.With thousands of known polyketides,modular polyketide synthases(PKSs)share a particularly attractive biosynthetic logic for generating chemical diversity.The engineering of modular PKSs could open access to the deliberate production of both existing and novel compounds.In this review,we discuss PKS engineering efforts applied at both the protein and cellular level for the generation of a diverse range of chemical structures,and we examine future applications of PKSs in the production of medicines,fuels and other industrially relevant chemicals.展开更多
Spinosyns are natural broad-spectrum biological insecticides with a double glycosylated polyketide structure that are produced by aerobic fermentation of the actinomycete,Saccharopolyspora spinosa.However,their large-...Spinosyns are natural broad-spectrum biological insecticides with a double glycosylated polyketide structure that are produced by aerobic fermentation of the actinomycete,Saccharopolyspora spinosa.However,their large-scale overproduction is hindered by poorly understood bottlenecks in optimizing the original strain,and poor adaptability of the heterologous strain to the production of spinosyn.In this study,we genetically engineered heterologous spinosyn-producer Streptomyces albus J1074 and optimized the fermentation to improve the production of spinosad(spinosyn A and spinosyn D)based on our previous work.We systematically investigated the result of overexpressing polyketide synthase genes(spnA,B,C,D,E)using a constitutive promoter on the spinosad titer in S.albus J1074.The supply of polyketide synthase precursors was then increased to further improve spinosad production.Finally,increasing or replacing the carbon source of the culture medium resulted in a final spinosad titer of~70 mg/L,which is the highest titer of spinosad achieved in heterologous Streptomyces species.This research provides useful strategies for efficient heterologous production of natural products.展开更多
To accelerate the shift to bio-based production and overcome complicated functional implementation of natural and artificial biosynthetic pathways to industry relevant organisms,development of new,versatile,bio-based ...To accelerate the shift to bio-based production and overcome complicated functional implementation of natural and artificial biosynthetic pathways to industry relevant organisms,development of new,versatile,bio-based production platforms is required.Here we present a novel yeast-based platform for biosynthesis of bacterial aromatic polyketides.The platform is based on a synthetic polyketide synthase system enabling a first demonstration of bacterial aromatic polyketide biosynthesis in a eukaryotic host.展开更多
Four new polyketide decalin derivatives,penicisteck acids A-D(1-4),and three new nitrogenous compounds(7-9)z together with eight previously reported compounds,were isolated from the mangrove endophytic fungus Penicill...Four new polyketide decalin derivatives,penicisteck acids A-D(1-4),and three new nitrogenous compounds(7-9)z together with eight previously reported compounds,were isolated from the mangrove endophytic fungus Penicillium steckii SCSIO 41025.展开更多
Overproduction of polyketides has been a challenge for metabolic engineering for decades.However,recent studies have demonstrated that in both native host and heterologous host,engineeringβ-oxidation pathways can lea...Overproduction of polyketides has been a challenge for metabolic engineering for decades.However,recent studies have demonstrated that in both native host and heterologous host,engineeringβ-oxidation pathways can lead to dramatic improvement of polyketide production.展开更多
Two new isomeric modified tripeptides,aspergillamides C and D(compounds 1 and 2),together with fifteen known compounds(compounds 3-17),were obtained from the marine sponge-derived fungus Aspergillus terreus SCSIO 4100...Two new isomeric modified tripeptides,aspergillamides C and D(compounds 1 and 2),together with fifteen known compounds(compounds 3-17),were obtained from the marine sponge-derived fungus Aspergillus terreus SCSIO 41008.The structures of the new compounds,including absolute configurations,were determined by extensive analyses of spectroscopic data(NMR,MS,UV,and IR)and comparisons between the calculated and experimental electronic circular dichroism(ECD)spectra.Butyrolactone I(compound 11)exhibited strong inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B(MptpB)with the IC_(50) being 5.11±0.53μmol·L^(–1),and acted as a noncompetitive inhibitor based on kinetic analysis.展开更多
Leaf and tuber extracts of Curcuma wenyujin contain a mixture of curcuminoids.However,the curcuminoid constituents and their molecular mechanisms are poorly understood,and the relevant curcumin synthases remain unclea...Leaf and tuber extracts of Curcuma wenyujin contain a mixture of curcuminoids.However,the curcuminoid constituents and their molecular mechanisms are poorly understood,and the relevant curcumin synthases remain unclear.In this study,we comprehensively compared the metabolite profiles of the leaf and tuber tissues of C.wenyujin.A total of 11 curcuminoid metabolites were identified and exhibited differentially changed contents in the leaf and tuber tissues.An integrated analysis of metabolomic and transcriptomic data revealed the proposed biosynthesis pathway of curcuminoid.Two candidate type III polyketide synthases(PKSs)were identified in the metabolically engineering yeasts,indicating that CwPKS1 and CwPKS2 maintained substrate and product specificities.Especially,CwPKS1 is the first type III PKS identified to synthesize hydrogenated derivatives of curcuminoid,dihydrocurcumin and tetrehydrocurcumin.Interestingly,the substitution of the glycine at position 219 with aspartic acid(G219D mutant)resulted in the complete inactivation of CwPKS1.Our results provide the first comparative metabolome analysis of C.wenyujin and functionally identified type III PKSs,giving valuable information for curcuminoids biosynthesis.展开更多
A chemical investigation on Sporormiella sp.led to the isolation and structural elucidation of tripodalsporormielones Ae C(1-3),a new class of polyketide possessing unprecedented cage-like skeletons with polyvdent bri...A chemical investigation on Sporormiella sp.led to the isolation and structural elucidation of tripodalsporormielones Ae C(1-3),a new class of polyketide possessing unprecedented cage-like skeletons with polyvdent bridged and fused ring systems.These polyketides with cage-like skeletons were characterized as a high non-protonated carbon-containing system,which resulted in few HMBC correlations observed and made the accurate structures hard to be obtained by NMR.Especially,some signals of non-protonated sp;carbons are weak and even unobservable in compound 1.In order to establish the structure of 1,the calculated NMR with DP4 evaluation was applied to determine the structure from the plausible structure candidates obtained from the detailed NMR analysis.Based on NMR experiments and calculated NMR,the structures of isolated compounds were established and confirmed by X-ray technology.Through chiral isolation,the optically pure enantiomers of 1 and 3 were obtained,and their absolute configurations were determined based on ECD quantum chemical calculation.Based on the isolated compounds and our previous work,1-3 would be derived from 3-methylorcinaldehyde,and their plausible biosynthetic mechanism was proposed.Furthermore,1 exhibited obvious short-term memory improvement activity on an Alzheimer’s disease fly model.展开更多
Two new polyketides, penifellutins A (1) and B (2), possessing a 22 carbon linear skeleton, were isolated from a co-culture of the deep-sea-derived fungi Penicillium crustosum PRB-2 and Penicillium fellutanum HDN14-32...Two new polyketides, penifellutins A (1) and B (2), possessing a 22 carbon linear skeleton, were isolated from a co-culture of the deep-sea-derived fungi Penicillium crustosum PRB-2 and Penicillium fellutanum HDN14-323. Meanwhile, two esterification products of 1, penifellutins C (3) and D (4), were obtained because compound 1 could be esterified spontaneously when stored in methanol. Their configurations were difficult to determine because of chiral central crowdedness, structural flexibility and instability. As such, we solved this issue by comprehensively using Mo2(OAc)4-based CD experiments, density functional theory calculation of 13C NMR, DP4 + probability analysis and many chemical reactions, including making acetonide derivative, Mosher’s method, PGME method, etc. Compounds 1 and 2 show obvious inhibitory activity on the liver hyperplasia of zebrafish larvae at a concentration of 10 μmol/L, while 3 and 4 show no activity, indicating that two carboxyls in the structure are important active sites.展开更多
基金This work was financially supported by Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology,Japan,and by programs from the National Natural Science Foundation Province of China(21202033)the Natural Science Foundation of Hebei(C2012201047)the Foundation of Hebei University(179).
文摘Fungal aromatic compounds comprise an important and structurally diverse group of secondary metabolites.Several genome sequencing projects revealed many putative biosynthetic gene clusters of fungal aromatic compounds,but many of these genes seem to be silent under typical laboratory culture conditions.To gain access to this untapped reservoir of natural products,we utilized chemical epigenetic modifiers to induce the expression of dormant biosynthetic genes.As a result,the concomitant supplementation of the histone deacetylase inhibitors suberoylanilide hydroxamic acid(500mM)and nicotinamide(50mM)to the culture medium of a fungal pathogen,Stagonospora nodorum,resulted in the isolation of three aromatic compounds(1-3),including a novel natural butyrophenone,(+)-4'-methoxy-(2S)-methylbutyrophenone(1),and two known polyketides,alternariol(2)and(-)-(3R)-mellein methyl ether(3).
基金This work was supported partly by grants from the National Natural Science Foundation of China(Nos.81360480,21262041 and 81460536).
文摘Four new fungal polyketides named koninginins N-Q(1–4),together with four known analogues(5–8),were isolated from the endophytic fungus Trichoderma koningiopsis YIM PH30002 harbored in Panax notoginseng.Their structures were determined on the basis of spectral data interpretation.These compounds were evaluated for their antifungal activity,nitric oxide inhibition,and anticoagulant activity.
基金supported by National Basic Research Program of China(973 Program,2009CB522300)the National Natural Science Foundation of China(30830113,U1132607).
文摘Five new polyketides,craterellones A-E(1-5),were isolated from cultures of basidiomycete Craterellus odoratus,together with five known compounds(6-10).Structures of 1-5 were elucidated on the basis of extensive spectroscopic analysis.All compounds were evaluated for their inhibitory activities against one isozyme of 11β-hydroxysteroid dehydrogenase(11β-HSD1)and cytotoxic activities on five tumor cell lines.Compound 10 exhibited significant cytotoxicity against HL-60,SMMC-7721,A-549,MCF-7,and SW-480,with IC50 values of 0.50,0.69,0.64,1.10,0.54μM,respectively.
基金This work was financially supported by the joint research project from the National Natural Science Foundation of China(Grant No.21961142008)Thailand Research Fund(Grant No.DBG6280008).
文摘Eight new furan derivatives,irpexins A‒H(1‒8),two new polyketides,irpexins I and J(9 and 10),together with nine known compounds were isolated from the fermentation of Irpex lacteus.The structures and absolute configurations were elucidated on the basis of extensive spectroscopic methods and Mosher ester reaction.All compounds shows no cytotoxicity to human MCF-7 and Hela cancer cell lines at the concentration of 10μM.
基金supported by the Major Research Plan of Tianjin(No.16YFXTSF00460)
文摘Polyketides have been widely used clinically due to their significant biological activities, but the needed structural and functional diversity cannot be achieved by common chemical synthetic methods. The tool of combinatorial biosynthesis provides the possibility to produce "unnatural" natural drugs, which has achieved initial success. This paper provides an overview for the strategies of combinatorial biosynthesis in producing the structural and functional diversity of polyketides, including the redesign of metabolic flow, polyketide synthase(PKS) engineering, and PKS post-translational modification. Although encouraging progress has been made in the last decade, challenges still exist regarding the rational combinatorial biosynthesis of polyketides. In this review, the perspectives of polyketide combinatorial biosynthesis are also discussed.
基金The National Natural Science Foundation of China under contract No.40406029China Ocean Mineral Resources Research & Development Association Funds under contract No.DYXM-115-02-2-04
文摘The diversity of modular polyketide synthase (PKS) genes in sediments of Ardley Island in Antarctica, was studied by restriction fragment length polymorphism (RFLP) analysis. Phylogenetic analysis of 14 amino acid (AA) sequences indicates that the identified ketosynthase (KS) domains were clustered with those from diverse bacterial groups, including Cyanobacteria, γ-Proteobacteria, Actinobacteria, Firmicutes, and some unidentified microorganisms from marine sponge, bryozoan and other environmental samples. The obtained KS domains showed 43%-81% similarity at the AA level to reference sequences in GenBank. Six identified KS domains showed diverse sequences of the motif (VQTACSTS) that was used to identify the hybrid PKS/nonribosomal peptide synthetase (NRPS) enzyme complex, and formed a new branch. These results reveal a high diversity and novelty of PKS genes in antarctic sediments.
基金Supported in part byNSF (MCB-0614916)Nebraska Research Initiatives (NRI), Redox Biology Center (RCB) Pilot Grant, andNSFC Oversea Young Scholar Award (No. 30428023)+1 种基金The research was performed in facilities renovated with support from NIH (RR015468-01)JORGENSON Joel, MARESCHAndrew, and VOGELER Chad are supported by the UCARE program at University of Nebraska-Lincoln
文摘Polyketides are one of the largest groups of natural products produced by bacteria, fungi, and plants. Many of these metabolites have highly complex chemical structures and very important biological activities, including antibiotic, anticancer, immunosuppressant, and anti-cholesterol activities. In the past two decades, extensive investigations have been carried out to understand the molecular mechanisms for polyketide biosynthesis. These efforts have led to the development of various rational approaches toward engineered biosynthesis of new polyketides. More recently, the research efforts have shifted to the elucidation of the three-dimentional structure of the complex enzyme machineries for polyketide biosynthesis and to the exploitation of new sources for polyketide production, such as filamentous fungi and marine microorganisms. This review summarizes our general understanding of the biosynthetic mechanisms and the progress in engineered biosynthesis of polyketides.
基金supported by the National Natural Science Foundation of China(No.30670221)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry of China and by the Program for New Century Excellent Talents in University(No.NCET-05-0852)supported by the National Financial Aid for Studying Abroad(No.2007103088)(J.-C.Q.)
基金the National Natural Science Foundation of China(Nos.32070070,32211530074 and 31929001)the innovative research team of high-level local universities in Shanghai.H.D.thanks Royal Society-NSFC international exchange grant(IEC\NSFC\211349).
文摘The bacterial trialkyl-substituted aromatic polyketides are structurally featured with the unusual aromatic core in the middle of polyketide chain such as TM-123(1),veramycin A(2),NFAT-133(3)and benwamycin I(4),which were discovered from Streptomyces species and demonstrated with antidiabetic and immunosuppressant activities.Though the biosynthetic pathway of 1-3 was reported as a type I polyketide synthase(PKS),the PKS assembly line was interpreted inconsistently,and it remains a mystery how the compound 3 was generated.Herein,the PKS assembly logic of 1-4 was revised by site-mutagenetic analysis of the PKS dehydratase domains.Based on gene deletion and complementation,the putative P450 monooxygenase nftE1 and metallo-beta-lactamase(MBL)fold hydrolase nftF1 were verified as essential genes for the biosynthesis of 1-4.The absence of nftE1 led to abolishment of 1-4 and accumulation of new products(5-8).Structural elucidation reveals 5-8 as the non-aromatic analogs of 1,suggesting the NftE1-catalyzed aromatic core formation.Deletion of nftF1 resulted in disappearance of 3 and 4 with the compounds 1 and 2 unaffected.As a rare MBL-fold hydrolase from type I PKSs,NftF1 potentially generates the compound 3 through two strategies:catalyze premature chain-offloading as a trans-acting thioesterase or hydrolyze the lactone-bond of compound 1 as an esterase.
文摘Secondary metabolites(SMs)produced by soil bacteria,for instance antimicrobials and siderophores,play a vital role in bacterial adaptation to soil and root ecosystems and can contribute to plant health.Many SMs are non-ribosomal peptides and polyketides,assembled by non-ribosomal peptides synthetase(NRPS)and polyketide synthase(PKS)and encoded by biosynthetic gene clusters(BGCs).Despite their ecological importance,little is known about the occurrence and diversity of NRPs and PKs in soil.We extracted NRPS-and PKS-encodiing BGCs from 20 publicly available soil and root-associated metagenomes and annotated them using antiSMASH-DB.We found that the overall abundance of NRPSs and PKSs is similar in both environments,however NRPSs and PKSs were significantly clustered between soil and root samples.Moreover,the majority of identified sequences were unique to either soil-or root-associated datasets and had low identity to known BGCs,suggesting their novelty.Overall,this study illuminates the huge untapped diversity of predicted SMs in soil and root microbiomes,and indicates presence of specific SMs,which may play a role in inter-and intra-bacteriial interactions in root ecosystems.
基金This work was funded by the Joint BioEnergy Institute(JBEI),which is funded by the U.S.Department of Energy,Office of Science,Office of Biological and Environmental Research,under Contract DE-AC02-05CH11231by the National Science Foundation under awards MCB-1442724,NSF-GRFP DGE-1106400 and CBET-1437775+1 种基金as part of the Co-Optimization of Fuels&Engines(Co-Optima)project sponsored by the U.S.Department of Energy(DOE)Office of Energy Efficiency and Renewable Energy(EERE)Bioenergy Technologies and Vehicle Technologies Offices,and by the DOE Agile-Biofoundry(https://agilebiofoundry.org)supported by the U.S.Department of Energy,Energy Efficiency and Renewable Energy,Bioenergy Technologies Office,through contract DE-AC02-05CH11231 between Lawrence Berkeley National Laboratory and the U.S.Department of Energy.The United States Government retains and the publisher,by accepting the article for publication,acknowledges that the United States Government retains a nonexclusive,paid-up,irrevocable,world-wide license to publish or reproduce the published form of this manuscript,or allowothers to do so,for United States Government purposes.Additional funding was provided by the National Science Foundation Graduate Research Fellowship under Grant No.(DGE 1106400).
文摘Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functionalities.Polyketides encompass one of the largest classes of chemically diverse natural products.With thousands of known polyketides,modular polyketide synthases(PKSs)share a particularly attractive biosynthetic logic for generating chemical diversity.The engineering of modular PKSs could open access to the deliberate production of both existing and novel compounds.In this review,we discuss PKS engineering efforts applied at both the protein and cellular level for the generation of a diverse range of chemical structures,and we examine future applications of PKSs in the production of medicines,fuels and other industrially relevant chemicals.
基金This work was supported by the National Key R&D Program of China[grant number 2018YFA0900400]the National Natural Science Foundation of China[grant number 31670090],and J1 Biotech Co.,Ltd.
文摘Spinosyns are natural broad-spectrum biological insecticides with a double glycosylated polyketide structure that are produced by aerobic fermentation of the actinomycete,Saccharopolyspora spinosa.However,their large-scale overproduction is hindered by poorly understood bottlenecks in optimizing the original strain,and poor adaptability of the heterologous strain to the production of spinosyn.In this study,we genetically engineered heterologous spinosyn-producer Streptomyces albus J1074 and optimized the fermentation to improve the production of spinosad(spinosyn A and spinosyn D)based on our previous work.We systematically investigated the result of overexpressing polyketide synthase genes(spnA,B,C,D,E)using a constitutive promoter on the spinosad titer in S.albus J1074.The supply of polyketide synthase precursors was then increased to further improve spinosad production.Finally,increasing or replacing the carbon source of the culture medium resulted in a final spinosad titer of~70 mg/L,which is the highest titer of spinosad achieved in heterologous Streptomyces species.This research provides useful strategies for efficient heterologous production of natural products.
基金This work was funded by grants from the Novo Nordisk Foundation[NNF10CC1016517],[NNF15OC0016626]and is part of the U.S.Department of Energy Joint BioEnergy Institute supported by the U.S.Department of Energy,Office of Science,Office of Biological and Environmental Research,through Contract DE-AC02-05CH11231 between Lawrence Berkeley National Laboratory and the U.S.Department of Energy.
文摘To accelerate the shift to bio-based production and overcome complicated functional implementation of natural and artificial biosynthetic pathways to industry relevant organisms,development of new,versatile,bio-based production platforms is required.Here we present a novel yeast-based platform for biosynthesis of bacterial aromatic polyketides.The platform is based on a synthetic polyketide synthase system enabling a first demonstration of bacterial aromatic polyketide biosynthesis in a eukaryotic host.
基金This work was supported by the Key-Area Research and Development Program of Guangdong Province(2O2OB1111O3OOO5)the Key Special Project for Introduced Talents Team of Southern Marine Science and Engineering Guangdong Laboratory(Guang-zhou)(GML2019ZD0406)+4 种基金the National Natural Science Foundation of China(Nos.U20A20101,22007019,81973235)the Special Fund for Bagui Scholars of Guangxi(05019055)the Natural Science Foundation of Guangxi(Nos.2020GXNSFBA159001,2020GXNSFGA297002)the Specific Research Project of Guangxi for Research Bases and Talents(AD20297003)the Open Project of CAS Key Laboratory of Tropical Marine Bio-resources and Ecology(LMB20211005).
文摘Four new polyketide decalin derivatives,penicisteck acids A-D(1-4),and three new nitrogenous compounds(7-9)z together with eight previously reported compounds,were isolated from the mangrove endophytic fungus Penicillium steckii SCSIO 41025.
基金This work was supported by award AI144967(to H.Z.)from the U.S.National Institutes of Health(NIH)and awards DE-SC0018260 and DESC0018420(to H.Z.)from the U.S.Department of Energy.
文摘Overproduction of polyketides has been a challenge for metabolic engineering for decades.However,recent studies have demonstrated that in both native host and heterologous host,engineeringβ-oxidation pathways can lead to dramatic improvement of polyketide production.
基金supported by the National Natural Science Foundation of China(Nos.41476135,21772210,and 81741154)Guangdong Special Support Projects(Leading talent for LIU Yong-Hong,and Young talent for ZHOU Xue-Feng)
文摘Two new isomeric modified tripeptides,aspergillamides C and D(compounds 1 and 2),together with fifteen known compounds(compounds 3-17),were obtained from the marine sponge-derived fungus Aspergillus terreus SCSIO 41008.The structures of the new compounds,including absolute configurations,were determined by extensive analyses of spectroscopic data(NMR,MS,UV,and IR)and comparisons between the calculated and experimental electronic circular dichroism(ECD)spectra.Butyrolactone I(compound 11)exhibited strong inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B(MptpB)with the IC_(50) being 5.11±0.53μmol·L^(–1),and acted as a noncompetitive inhibitor based on kinetic analysis.
基金supported by the National Natural Science Foundation of China(82173919,82104320)the Natural Science Foundation of Zhejiang Province(LY21C050004,LQ22H280013).
文摘Leaf and tuber extracts of Curcuma wenyujin contain a mixture of curcuminoids.However,the curcuminoid constituents and their molecular mechanisms are poorly understood,and the relevant curcumin synthases remain unclear.In this study,we comprehensively compared the metabolite profiles of the leaf and tuber tissues of C.wenyujin.A total of 11 curcuminoid metabolites were identified and exhibited differentially changed contents in the leaf and tuber tissues.An integrated analysis of metabolomic and transcriptomic data revealed the proposed biosynthesis pathway of curcuminoid.Two candidate type III polyketide synthases(PKSs)were identified in the metabolically engineering yeasts,indicating that CwPKS1 and CwPKS2 maintained substrate and product specificities.Especially,CwPKS1 is the first type III PKS identified to synthesize hydrogenated derivatives of curcuminoid,dihydrocurcumin and tetrehydrocurcumin.Interestingly,the substitution of the glycine at position 219 with aspartic acid(G219D mutant)resulted in the complete inactivation of CwPKS1.Our results provide the first comparative metabolome analysis of C.wenyujin and functionally identified type III PKSs,giving valuable information for curcuminoids biosynthesis.
基金financially supported by grants from National Key Research and Development Program of China(2018YF A0903200/2018YFA0903201)the National Natural Science Foundation of China(81925037 and 81973213)+5 种基金Chang Jiang Scholars Program(Young Scholar)from the Ministry of Education of China(Hao Gao,2017)National High-level Personnel of Special Support Program(2017RA2259,China)the 111 Project of Ministry of Education of the People’s Republic of China(B13038)the Guangdong Natural Science Funds for Distinguished Young Scholar(2017A03036027,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036,China)K.C.Wong Education Foundation(Hao Gao,2016,China)。
文摘A chemical investigation on Sporormiella sp.led to the isolation and structural elucidation of tripodalsporormielones Ae C(1-3),a new class of polyketide possessing unprecedented cage-like skeletons with polyvdent bridged and fused ring systems.These polyketides with cage-like skeletons were characterized as a high non-protonated carbon-containing system,which resulted in few HMBC correlations observed and made the accurate structures hard to be obtained by NMR.Especially,some signals of non-protonated sp;carbons are weak and even unobservable in compound 1.In order to establish the structure of 1,the calculated NMR with DP4 evaluation was applied to determine the structure from the plausible structure candidates obtained from the detailed NMR analysis.Based on NMR experiments and calculated NMR,the structures of isolated compounds were established and confirmed by X-ray technology.Through chiral isolation,the optically pure enantiomers of 1 and 3 were obtained,and their absolute configurations were determined based on ECD quantum chemical calculation.Based on the isolated compounds and our previous work,1-3 would be derived from 3-methylorcinaldehyde,and their plausible biosynthetic mechanism was proposed.Furthermore,1 exhibited obvious short-term memory improvement activity on an Alzheimer’s disease fly model.
基金supported by the National Natural Science Foundation of China(41806167,81670709)Project funded by China Postdoctoral Science Foundation(2017M622286)+2 种基金Qingdao Postdoctoral Applied Research Project Financially Supported by Qingdao Municipal Bureau of Human Resource and Social Security,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology(LMDBKF201805)High-level Talents Research Fund of Qingdao Agricultural University(Grants 665/1120034)We thank Dr.Zhiyuan Gong(National Univeristy of Singapore)for the gift of Tg(Fabp10-rtTA:TRE-eGFPKRASV12)transgenic line.
文摘Two new polyketides, penifellutins A (1) and B (2), possessing a 22 carbon linear skeleton, were isolated from a co-culture of the deep-sea-derived fungi Penicillium crustosum PRB-2 and Penicillium fellutanum HDN14-323. Meanwhile, two esterification products of 1, penifellutins C (3) and D (4), were obtained because compound 1 could be esterified spontaneously when stored in methanol. Their configurations were difficult to determine because of chiral central crowdedness, structural flexibility and instability. As such, we solved this issue by comprehensively using Mo2(OAc)4-based CD experiments, density functional theory calculation of 13C NMR, DP4 + probability analysis and many chemical reactions, including making acetonide derivative, Mosher’s method, PGME method, etc. Compounds 1 and 2 show obvious inhibitory activity on the liver hyperplasia of zebrafish larvae at a concentration of 10 μmol/L, while 3 and 4 show no activity, indicating that two carboxyls in the structure are important active sites.
