Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol-O-Methyltransferase.
Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol-O-Methyltransferase.
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DOI：
10.1002/anie.201508287
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发表时间：
2016-02-18
期刊：
影响因子：
--
通讯作者：
Micklefield J
中科院分区：
文献类型：
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作者：
Law BJ;Bennett MR;Thompson ML;Levy C;Shepherd SA;Leys D;Micklefield J
儿茶酚-O-甲基转移酶(COMT)是治疗帕金森病的重要靶点，也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使其无法得到更广泛的应用。通过使用结构和机制信息，设计出了区域互补的COMT变体，可以传递间甲基化儿茶酚或对甲基化的儿茶酚。X射线结晶学进一步揭示了活性中心残基和四元结构是如何支配区域选择性的。最后，ADOMet的类似物被区域互补的COMT突变体接受，并可用于制备烷基化儿茶酚，包括乙基香草醛。
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.