S -Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C -Alkylation
S -Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C -Alkylation
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S-腺苷甲硫氨酸辅因子修饰增强小分子 C-烷基化的生物催化能力
DOI：
10.1002/ange.201908681
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发表时间：
2019
影响因子：
--
通讯作者：
McKean I
中科院分区：
文献类型：
--
作者：
McKean I
描述了一种通过在 中原位形成FS-腺苷蛋氨酸辅因子类似物来扩大小分子烷基化范围的串联酶促策略。SAM形成酶SAL中存在一个暴露在溶剂中的通道，它能耐受腺嘌呤核苷酸碱基2位上修饰的5‘-氯-5’-脱氧腺苷(ClDA)类似物。将SAL催化的辅因子生产与甲基转移酶(MTase)催化的C-(M)乙基转移到香豆素底物相结合，形成了C-(M)乙基化香豆素，与没有碱基修饰的辅因子相比，产率更高，底物范围更大。建立影响C-烷基化反应的分子决定因素，为开发制备高价值小分子的后期酶促平台奠定了基础。
A tandem enzymatic strategy to enhance the scope ofC‐alkylation of small molecules via the in situ formation ofS‐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 withC‐(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO formsC‐(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influenceC‐alkylation provides the basis to develop a late‐stage enzymatic platform for the preparation of high value small molecules.