典型文献
Biosynthesis of rumbrins and inspiration for discovery of HIV inhibitors
文献摘要：
Investigation on how nature produces natural compounds with chemical and biological diver-sity at the genetic level offers inspiration for the discovery of new natural products and even their bio-logical 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 im-munodeficiency 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 recog-nition of unconventional starter units of fungal PKSs and provides a new strategy for genome mining-guided drug discovery.
文献关键词：
中图分类号：
作者姓名：
Beifen Zhong;Jun Wan;Changhui Shang;Jiajia Wen;Yujia Wang;Jian Bai;Shan Cen;Youcai Hu
作者机构：
State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China
文献出处：
引用格式：
[1]Beifen Zhong;Jun Wan;Changhui Shang;Jiajia Wen;Yujia Wang;Jian Bai;Shan Cen;Youcai Hu-.Biosynthesis of rumbrins and inspiration for discovery of HIV inhibitors)[J].药学学报（英文版）,2022(11):4193-4203
A类：
rumbrins,rumbrin,Auxarthron,umbrinum,DSM3193,heterolo,HRPKS,pyrrolyl,starer,Sequent,munodeficiency,PKSs
B类：
Biosynthesis,inspiration,discovery,HIV,inhibitors,Investigation,nature,produces,natural,compounds,chemical,biological,diver,sity,genetic,level,offers,new,products,even,their,targets,polyketide,lipid,peroxide,production,calcium,accumulation,which,contains,chlorinated,pyrrole,moiety,that,rare,feature,fungal,Here,identify,biosynthetic,cluster,BGC,isomer,12E,from,elucidate,pathway,gous,expression,complementation,isotopic,labeling,We,show,assembled,by,highly,reducing,synthase,uniquely,incorporates,proline,derived,CoA,followed,methylation,chlorination,precursor,directed,biosynthesis,was,able,yield,group,analogues,Remarkably,inspired,presence,human,im,virus,Nef,associated,predicted,pharmacologically,demonstrated,potent,nanomolar,This,work,enriches,recog,nition,unconventional,starter,units,provides,strategy,genome,mining,guided,drug
AB值：
0.567921
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