The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides.
The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides.
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DOI：
10.1002/anie.201804592
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发表时间：
2018-09-03
期刊：
影响因子：
--
通讯作者：
Grogan G
中科院分区：
文献类型：
--
作者：
Petchey M;Cuetos A;Rowlinson B;Dannevald S;Frese A;Sutton PW;Lovelock S;Lloyd RC;Fairlamb IJS;Grogan G
酰胺键的形成是药物合成化学中最重要的反应之一。因此，发展可持续的酰胺键形成方法，包括那些由酶催化的方法，是非常有意义的。耐热海洋放线菌的三磷酸腺苷依赖的酰胺键合成酶(ABS)酶MCBA催化酰胺的形成，作为生物合成途径的一部分。反应通过腺化中间体进行，腺化和酰胺化步骤都在一个活性中心内催化。在这项研究中，MCBA被应用于由一系列芳基羧酸与1-5摩尔当量的伙伴胺合成药用型酰胺。MCBA的结构揭示了芳香酸底物耐受性的结构决定因素，以及与催化的两个半反应相关的构象差异。MCBA的催化性能，再加上这种结构，表明该酶和其他ABS酶可能被设计用于药物相关(手性)酰胺的可持续合成。
Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.
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