Structural insight into substrate specificity of human intestinal maltase-glucoamylase  

作　　者：Limei Ren Xiaohong Qin Xiaofang Cao LeleWang Fang Bai Gang Bai Yuequan Shen 

机构地区：[1]State Key Laboratory of Medicinal Chemical Biology,Nankai University,Tianjin 300071,China [2]College of Pharmacy,Nankai University,Tianjin 300071,China [3]College of Life Sciences,Nankai University,Tianjin 300071,China

出　　处：《Protein & Cell》2011年第10期827-836,共10页蛋白质与细胞（英文版）

基　　金：by the National Basic Research Program of China(973 Program)(Grant Nos.2007CB914301 and 2007CB 914803);the Natural Science Foundation of China(Grant Nos.30940015,30770428,21002052 and 31170684);the TBR Program(No.08QTPTJC 28200,08SYSYTC00200 and 10JCYB JC14300).

摘　　要：Human maltase-glucoamylase(MGAM)hydrolyzes linear alpha-1,4-linked oligosaccharide substrates,playing a crucial role in the production of glucose in the human lumen and acting as an efficient drug target for type 2 diabetes and obesity.The amino-and carboxyl-terminal portions of MGAM(MGAM-N and MGAM-C)carry out the same catalytic reaction but have different substrate specificities.In this study,we report crystal structures of MGAM-C alone at a resolution of 3.1Å,and in complex with its inhibitor acarbose at a resolution of 2.9Å.Structural studies,combined with biochemical analysis,revealed that a segment of 21 amino acids in the active site of MGAM-C forms additional sugar subsites(+2 and+3 subsites),accounting for the preference for longer substrates of MAGM-C compared with that of MGAM-N.Moreover,we discovered that a single mutation of Trp1251 to tyrosine in MGAM-C imparts a novel catalytic ability to digest branched alpha-1,6-linked oligosaccharides.These results provide important information for understanding the substrate specificity of alphaglucosidases during the process of terminal starch digestion,and for designing more efficient drugs to control type 2 diabetes or obesity.

关 键 词：MGAM C-terminal domain INHIBITOR crystal structure ACARBOSE type 2 diabetes 

分 类 号：O62[理学—有机化学]