Crystal structure of vinorine synthase, the first representative of the BAHD superfamily
Crystal structure of vinorine synthase, the first representative of the BAHD superfamily
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DOI：
10.1074/jbc.m414508200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Stöckigt, J
中科院分区：
文献类型：
--
作者：
Ma, XY;Koepke, J;Stöckigt, J
长春碱合成酶是一种乙酰基转移酶，在萝芙木属植物中的抗肿瘤单萜吲哚生物碱阿娇的生物合成中占据中心作用。长春碱合酶属于苄醇乙酰基-、花青素-O-羟基-肉桂酰基-、邻氨基苯甲酸酯-N-羟基-肉桂酰基/苯甲酰基-、脱乙酰基文多灵乙酰转移酶（BAHD）酶超家族，其成员参与几种重要药物的生物合成，如吗啡、紫杉醇或文多灵，其是抗癌药物长春新碱和长春新碱的前体。在2.6埃分辨率下描述了长春碱合酶的X射线结构。尽管低序列同一性，长春碱合酶的两个结构域的结构显示出惊人的相似性与几个CoA依赖性酰基转移酶，如二氢硫辛酰转乙酰酶，聚酮相关蛋白A5，肉毒碱乙酰转移酶的结构。BAHD家族典型的所有保守残基都存在于结构域1中。HXXXD基序的His（160）在催化过程中作为通用碱基发挥作用。它位于两个域的界面处的反应通道的中心，并且可以从两侧接近。该通道贯穿整个分子，允许底物和共底物独立结合。Asp（164）点远离催化位点，似乎具有结构重要性而不是催化重要性。令人惊讶的是，DFGWG基序，这是必不可少的催化反应和独特的BAHD家族，位于远离活性位点，似乎只发挥结构作用。长春碱合酶代表BAHD超家族的第一个解决的蛋白质结构。
Vinorine synthase is an acetyltransferase that occupies a central role in the biosynthesis of the antiarrhythmic monoterpenoid indole alkaloid ajmaline in the plant Rauvolfia. Vinorine synthase belongs to the benzylalcohol acetyl-, anthocyanin-O-hydroxy-cinnamoyl-, anthranilate-N-hydroxy-cinnamoyl/benzoyl-, deacetylvindoline acetyltransferase (BAHD) enzyme superfamily, members of which are involved in the biosynthesis of several important drugs, such as morphine, Taxol, or vindoline, a precursor of the anti-cancer drugs vincaleucoblastine and vincristine. The x-ray structure of vinorine synthase is described at 2.6-angstrom resolution. Despite low sequence identity, the two-domain structure of vinorine synthase shows surprising similarity with structures of several CoA-dependent acyltransferases such as dihydrolipoyl transacetylase, polyketide-associated protein A5, and carnitine acetyltransferase. All conserved residues typical for the BAHD family are found in domain 1. His(160) of the HXXXD motif functions as a general base during catalysis. It is located in the center of the reaction channel at the interface of both domains and is accessible from both sides. The channel runs through the entire molecule, allowing the substrate and co-substrate to bind independently. Asp(164) points away from the catalytic site and seems to be of structural rather than catalytic importance. Surprisingly, the DFGWG motif, which is indispensable for the catalyzed reaction and unique to the BAHD family, is located far away from the active site and seems to play only a structural role. Vinorine synthase represents the first solved protein structure of the BAHD superfamily.