S-腺苷甲硫氨酸辅因子修饰增强了小分子 C-烷基化的生物催化谱。
S-Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C-Alkylation.
机构信息
Department or Pure and Applied Chemistry, University of Strathclyde, 298 Cathedral Street, Glasgow, G1 1XL, UK.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK.
出版信息
Angew Chem Int Ed Engl. 2019 Dec 2;58(49):17583-17588. doi: 10.1002/anie.201908681. Epub 2019 Oct 21.
A tandem enzymatic strategy to enhance the scope of C-alkylation of small molecules via the in situ formation of S-adenosyl methionine (SAM) cofactor analogues is described. A solvent-exposed channel present in the SAM-forming enzyme SalL tolerates 5'-chloro-5'-deoxyadenosine (ClDA) analogues modified at the 2-position of the adenine nucleobase. Coupling SalL-catalyzed cofactor production with C-(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO forms C-(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influence C-alkylation provides the basis to develop a late-stage enzymatic platform for the preparation of high value small molecules.
一种串联酶策略，通过原位形成 S-腺苷甲硫氨酸 (SAM) 辅因子类似物来增强小分子的 C-烷基化范围，本文对此进行了描述。SAM 形成酶 SalL 中存在一个暴露在溶剂中的通道，能够容忍腺嘌呤核苷碱基 2 位修饰的 5'-氯-5'-脱氧腺苷 (ClDA) 类似物。将 SalL 催化的辅因子生成与由甲基转移酶 (MTase) NovO 催化的香豆素底物的 C-(m) 甲基转移偶联，相对于使用缺乏核碱基修饰的辅因子获得的产物，可形成 C-(m) 甲基香豆素，从而获得更高的产率和更广泛的底物范围。确定影响 C-烷基化的分子决定因素为开发用于制备高价值小分子的后期酶学平台奠定了基础。
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