The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides,Angewandte Chemie International Edition

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The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2018-08-07 , DOI: 10.1002/anie.201804592
Mark Petchey ₁ , Anibal Cuetos ₁ , Benjamin Rowlinson ₁ , Stephanie Dannevald ₁ , Amina Frese ₁ , Peter W. Sutton _{2,

3} , Sarah Lovelock _{2,

4} , Richard C. Lloyd ₂ , Ian J. S. Fairlamb ₁ , Gideon Grogan ₁

Affiliation

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.

中文翻译：

酰胺键合成酶McbA的宽芳酸特异性表明酰胺的生物催化合成潜力

酰胺键的形成是药物合成化学中最重要的反应之一。因此，引起酰胺键形成的可持续方法的发展，包括被酶催化的那些方法，引起了人们的极大兴趣。ATP依赖的酰胺键合成酶（ABS）酶McbA，来自Marinoctinospora thermotolerans，催化酰胺的形成，这是通向玛丽娜咔啉次生代谢物的生物合成途径的一部分。反应通过腺苷酸中间体进行，在一个活性位点内催化了腺苷酸化和酰胺化步骤。在这项研究中，McbA被用于由一系列芳基羧酸与伴侣胺以1-5摩尔当量提供的合成药物型酰胺。McbA的结构揭示了芳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的催化性能以及其结构表明，该酶和其他ABS酶可能经过工程改造，可用于药物相关（手性）酰胺的可持续合成。

更新日期：2018-08-07

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