その他 A new target region for changing the substrate specificity of amine transaminases

Guan, Li-Jun  ,  Ohtsuka, Jun  ,  Okai, Masahiko  ,  Miyakawa, Takuya  ,  Mase, Tomoko  ,  Zhi, Yuehua  ,  Hou, Feng  ,  Ito, Noriyuki  ,  Iwasaki, Akira  ,  Yasohara, Yoshihiko  ,  Tanokura, Masaru

52015-06-01 , Nature Publishing Group , Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo , Department of Ocean Sciences, Tokyo University of Marine Science and Technology , Biotechnology Development Laboratories, Kaneka Corporation , Research & Development Group, QOL Division, Kaneka Corporation
ISSN:2045-2322
内容記述
UTokyo Research掲載「さまざまな薬の合成に重要な酵素が作用する相手を認識する仕組み」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/how-an-important-enzyme-used-in-drug-production-recognizes-its-substrate.html
UTokyo Research "How an important enzyme used in drug production recognizes its substrate" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/how-an-important-enzyme-used-in-drug-production-recognizes-its-substrate.html
(R)-stereospecific amine transaminases (R-ATAs) are important biocatalysts for the production of (R)-amine compounds in a strict stereospecific manner. An improved R-ATA, ATA-117-Rd11, was successfully engineered for the manufacture of sitagliptin, a widely used therapeutic agent for type-2 diabetes. The effects of the individual mutations, however, have not yet been demonstrated due to the lack of experimentally determined structural information. Here we describe three crystal structures of the first isolated R-ATA, its G136F mutant and engineered ATA-117-Rd11, which indicated that the mutation introduced into the 136th residue altered the conformation of a loop next to the active site, resulting in a substrate-binding site with drastically modified volume, shape, and surface properties, to accommodate the large pro-sitagliptin ketone. Our findings provide a detailed explanation of the previously reported molecular engineering of ATA-117-Rd11 and propose that the loop near the active site is a new target for the rational design to change the substrate specificity of ATAs.
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http://repository.dl.itc.u-tokyo.ac.jp/dspace/bitstream/2261/57146/1/srep10753.pdf

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