Insights into the biosynthesis of septacidin L-heptosamine moiety unveils a VOC family sugar epimerase  

作　　者：Meng Chen Zhengyan Guo Jinyuan Sun Wei Tang Min Wang Yue Tang Pengwei Li Bian Wu Yihua Chen 

机构地区：[1]State Key Laboratory of Microbial Resources&CAS Key Laboratory of Microbial Physiological and Metabolic Engineering,Institute of Microbiology,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Laboratory of Microbial Metabolic Engineering,Institute of Medicinal Biotechnology,Chinese Academy of Medical Science&Peking Union Medical College,Beijing 100050,China [4]School of Biotechnology and Health Sciences,Wuyi University,Jiangmen 529020,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第2期765-774,共10页药学学报（英文版）

基　　金：financially supported by the Ministry of Science and Technology of China(2020YFA0907703);the National Natural Science Foundation of China(32025002,31870043)。

摘　　要：L-Heptopyranoses are important components of bacterial polysaccharides and biological active secondary metabolites like septacidin(SEP),which represents a group of nucleoside antibiotics with antitumor,antifungal,and pain-relief activities.However,little is known about the formation mechanisms of those L-heptose moieties.In this study,we deciphered the biosynthetic pathway of the L,L-gluco-heptosamine moiety in SEPs by functional characterizing four genes and proposed that SepI initiates the process by oxidizing the 4’-hydroxyl of L-glycero-α-D-manno-heptose moiety of SEP-328(2)to a keto group.Subsequently,SepJ(C5 epimerase)and SepA(C3 epimerase)shape the 4’-keto-L-heptopyranose moiety by sequential epimerization reactions.At the last step,an aminotransferase SepG installs the 4’-amino group of the L,L-gluco-heptosamine moiety to generate SEP-327(3).An interesting phenomenon is that the SEP intermediates with 4’-keto-L-heptopyranose moieties exist as special bicyclic sugars with hemiacetal-hemiketal structures.Notably,L-pyranose is usually converted from D-pyranose by bifunctional C3/C5 epimerase.SepA is an unprecedented monofunctional L-pyranose C3 epimerase.Further in silico and experimental studies revealed that it represents an overlooked metal dependent-sugar epimerase family bearing vicinal oxygen chelate(VOC)architecture.

关 键 词：Natural product Septacidin L-heptose BIOSYNTHESIS Hemiketal VOC epimerase Catalytic mechanism Deprotonation/reprotonation 

分 类 号：R914[医药卫生—药物化学]