Investigation on how nature produces natural compounds with chemical and biological diversity at the genetic level offers inspiration for the discovery of new natural products and even their biological targets.The pol...Investigation on how nature produces natural compounds with chemical and biological diversity at the genetic level offers inspiration for the discovery of new natural products and even their biological targets.The polyketide rumbrin(1)is a lipid peroxide production and calcium accumulation inhibitor,which contains a chlorinated pyrrole moiety that is a rare chemical feature in fungal natural products.Here,we identify the biosynthetic gene cluster(BGC)rum of 1 and its isomer 12E-rumbrin(2)from Auxarthron umbrinum DSM3193,and elucidate their biosynthetic pathway based on heterolo-gous expression,chemical complementation,and isotopic labeling.We show that rumbrins are assembled by a highly reducing polyketide synthase(HRPKS)that uniquely incorporates a proline-derived pyrrolyl-CoA starer unit,and followed by methylation and chlorination.Sequent precursor directed biosynthesis was able to yield a group of rumbrin analogues.Remarkably,inspired by the presence of a human immunodeficiency virus(HIV)-Nef associated gene in the rum cluster,we predicted and pharmacologically demonstrated rumbrins as potent inhibitors of HIV at the nanomolar level.This work enriches the recognition of unconventional starter units of fungal PKSs and provides a new strategy for genome mining-guided drug discovery.展开更多
A plenty of cytochrome P450s have been annotated in the Daldinia eschosholzii genome.Inspired by the fact that some P450s have been reported to catalyze the carbon-nitrogen(C-N)bond formation,we were curious about whe...A plenty of cytochrome P450s have been annotated in the Daldinia eschosholzii genome.Inspired by the fact that some P450s have been reported to catalyze the carbon-nitrogen(C-N)bond formation,we were curious about whether hybrids through C-N bond formation could be generated in the indole-3-carbinol(I3C)exposed culture of D.eschscholzii.As expected,two skeletally undescribed polyketide-indole hybrids,designated as indolpolyketone A and B(1 and 2),were isolated and assigned to be constructed through C-N bond formation.Their structures were elucidated by 1D and 2D NMR spectra.The absolute configurations of 1 and 2 were determined by comparing the recorded and calculated electronic circular dichroism(ECD)spectra.Furthermore,the plausible biosynthetic pathways for 1 and 2 were proposed.Compounds 1 and 2 exhibited significant antiviral activity against H1N1 with IC_(50) values of 45.2 and 31.4μM,respectively.In brief,compounds 1 and 2 were reported here for the first time and were the first example of polyketide-indole hybrids pieced together through C-N bond formation in the I3C-exposed culture of D.eschscholzii.Therefore,this study expands the knowledge about the chemical production of D.eschscholzii through precursor-directed biosynthesis(PDB).展开更多
基金supported financially by the National Key Research and Development Program of China(2018YFA0901900)the CAMS Innovation Fund for Medical Sciences (CIFMS, No. 2021-I2M-1-029, China)
文摘Investigation on how nature produces natural compounds with chemical and biological diversity at the genetic level offers inspiration for the discovery of new natural products and even their biological targets.The polyketide rumbrin(1)is a lipid peroxide production and calcium accumulation inhibitor,which contains a chlorinated pyrrole moiety that is a rare chemical feature in fungal natural products.Here,we identify the biosynthetic gene cluster(BGC)rum of 1 and its isomer 12E-rumbrin(2)from Auxarthron umbrinum DSM3193,and elucidate their biosynthetic pathway based on heterolo-gous expression,chemical complementation,and isotopic labeling.We show that rumbrins are assembled by a highly reducing polyketide synthase(HRPKS)that uniquely incorporates a proline-derived pyrrolyl-CoA starer unit,and followed by methylation and chlorination.Sequent precursor directed biosynthesis was able to yield a group of rumbrin analogues.Remarkably,inspired by the presence of a human immunodeficiency virus(HIV)-Nef associated gene in the rum cluster,we predicted and pharmacologically demonstrated rumbrins as potent inhibitors of HIV at the nanomolar level.This work enriches the recognition of unconventional starter units of fungal PKSs and provides a new strategy for genome mining-guided drug discovery.
基金This work was co-financed by grants from the National Natural Science Foundation of China(NSFC)(82073721 and 81991524)National Key R&D Program of China(2018YFC1706205).
文摘A plenty of cytochrome P450s have been annotated in the Daldinia eschosholzii genome.Inspired by the fact that some P450s have been reported to catalyze the carbon-nitrogen(C-N)bond formation,we were curious about whether hybrids through C-N bond formation could be generated in the indole-3-carbinol(I3C)exposed culture of D.eschscholzii.As expected,two skeletally undescribed polyketide-indole hybrids,designated as indolpolyketone A and B(1 and 2),were isolated and assigned to be constructed through C-N bond formation.Their structures were elucidated by 1D and 2D NMR spectra.The absolute configurations of 1 and 2 were determined by comparing the recorded and calculated electronic circular dichroism(ECD)spectra.Furthermore,the plausible biosynthetic pathways for 1 and 2 were proposed.Compounds 1 and 2 exhibited significant antiviral activity against H1N1 with IC_(50) values of 45.2 and 31.4μM,respectively.In brief,compounds 1 and 2 were reported here for the first time and were the first example of polyketide-indole hybrids pieced together through C-N bond formation in the I3C-exposed culture of D.eschscholzii.Therefore,this study expands the knowledge about the chemical production of D.eschscholzii through precursor-directed biosynthesis(PDB).
