Law Brian J C, Bennett Matthew R, Thompson Mark L, Levy Colin, Shepherd Sarah A, Leys David, Micklefield Jason
School of Chemistry & Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
Angew Chem Int Ed Engl. 2016 Feb 18;55(8):2683-7. doi: 10.1002/anie.201508287. Epub 2016 Jan 21.
Catechol-O-methyltransferase (COMT), an important therapeutic target in the treatment of Parkinson's disease, is also being developed for biocatalytic processes, including vanillin production, although lack of regioselectivity has precluded its more widespread application. By using structural and mechanistic information, regiocomplementary COMT variants were engineered that deliver either meta- or para-methylated catechols. X-ray crystallography further revealed how the active-site residues and quaternary structure govern regioselectivity. Finally, analogues of AdoMet are accepted by the regiocomplementary COMT mutants and can be used to prepare alkylated catechols, including ethyl vanillin.
儿茶酚-O-甲基转移酶（COMT）是治疗帕金森病的一个重要治疗靶点，目前也正在被开发用于生物催化过程，包括香草醛的生产，尽管缺乏区域选择性阻碍了其更广泛的应用。通过利用结构和机理信息，设计出了区域互补的COMT变体，它们能够生成间位或对位甲基化的儿茶酚。X射线晶体学进一步揭示了活性位点残基和四级结构是如何控制区域选择性的。最后，区域互补的COMT突变体能够接受腺苷甲硫氨酸类似物，并可用于制备烷基化儿茶酚，包括乙基香草醛。
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