Acarbose glycosylation by AcbE for the production of acarstatins with enhancedα-amylase inhibitory activity  

作　　者：Xin Zhang Qungang Huang Ziyue Guo Feifei Cai Qianjin Kang Linquan Bai 

机构地区：[1]State Key Laboratory of Microbial Metabolism,School of Life Sciences and Biotechnology,Shanghai Jiao Tong University,Shanghai,200240,China [2]College of Life Science,Tarim University,Alar,843300,China

出　　处：《Synthetic and Systems Biotechnology》2024年第2期359-368,共10页合成和系统生物技术（英文）

基　　金：This work was supported by the National Key Research and Development Program of China(grant No.2021YFC2100600);National Natural Science Foundation of China(grant No.31830104);Science and Technology Commission of Shanghai Municipality(grant Nos.19JC1413000 and 19430750600)to L.B.We thank the Core Facility and Technical Service Center for SLSB and the Instrumental Analysis Center in SJTU for data collection.

摘　　要：Acarbose is a potent glycosidase inhibitor widely used in the clinical treatment of type 2 diabetes mellitus(T2DM).Various acarbose analogs have been identified while exploring compounds with improved pharmacological properties.In this study,we found that AcbE from Actinoplanes sp.SE50/110 catalyzes the production of acarbose analogs that exhibit significantly improved inhibitory activity towardsα-amylase than acarbose.Recombinant AcbE mainly catalyzed the formation of two new compounds,namely acarstatins A and B,using acarbose as substrate.Using high-resolution mass spectrometry,nuclear magnetic resonance,and glycosidase hydrolysis,we elucidated their chemical structures as O-α-d-maltosyl-(1→4)-acarbose and O-α-d-maltotriosyl-(1→4)-acarbose,respectively.Acarstatins A and B exhibited 1584-and 1478-fold greater inhibitory activity towards human salivaryα-amylase than acarbose.Furthermore,both acarstatins A and B exhibited complete resistance to microbiome-derived acarbose kinase 1-mediated phosphorylation and partial resistance to acarbose-preferred glucosidase-mediated hydrolysis.Therefore,acarstatins A and B have great potential as candidate therapeutic agents for T2DM.

关 键 词：Acarbose analogs α-amylase inhibitory activity Actinoplanes sp. Transglycosylase 

分 类 号：O62[理学—有机化学]