Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases.,Communications Chemistry

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Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases.
Communications Chemistry ( IF 5.9 ) Pub Date : 2019-01-24 , DOI: 10.1038/s42004-018-0106-z
Refaat B Hamed ₁ , J Ruben Gomez-Castellanos ₁ , Luc Henry ₁ , Sven Warhaut ₁ , Timothy D W Claridge ₁ , Christopher J Schofield ₁

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There is a need to develop asymmetric routes to functionalised β-lactams, which remain the most important group of antibacterials. Here we describe biocatalytic and protein engineering studies concerning carbapenem biosynthesis enzymes, aiming to enable stereoselective production of functionalised carbapenams with three contiguous chiral centres. Structurally-guided substitutions of wildtype carboxymethylproline synthases enable tuning of their C-N and C-C bond forming capacity to produce 5-carboxymethylproline derivatives substituted at C-4 and C-6, from amino acid aldehyde and malonyl-CoA derivatives. Use of tandem enzyme incubations comprising an engineered carboxymethylproline synthase and an alkylmalonyl-CoA forming enzyme (i.e. malonyl-CoA synthetase or crotonyl-CoA carboxylase reductase) can improve stereocontrol and expand the product range. Some of the prepared 4,6-disubstituted-5-carboxymethylproline derivatives are converted to bicyclic β-lactams by carbapenam synthetase catalysis. The results illustrate the utility of tandem enzyme systems involving engineered crotonases for asymmetric bicyclic β-lactam synthesis.

中文翻译：

使用工程巴豆酶生物催化生产具有三个连续手性中心的双环 β-内酰胺。

需要开发不对称途径来获得功能化的 β-内酰胺，这仍然是最重要的抗菌剂组。在这里，我们描述了有关碳青霉烯类生物合成酶的生物催化和蛋白质工程研究，旨在实现具有三个连续手性中心的功能化碳青霉烯类的立体选择性生产。野生型羧甲基脯氨酸合酶的结构引导取代能够调整它们的 CN 和 CC 键形成能力，以从氨基酸醛和丙二酰辅酶 A 衍生物产生在 C-4 和 C-6 处取代的 5-羧甲基脯氨酸衍生物。使用包含工程化羧甲基脯氨酸合酶和烷基丙二酰辅酶A形成酶（即丙二酰辅酶A合成酶或巴豆酰辅酶A羧化酶还原酶）可以改善立体控制并扩大产品范围。一些制备的4,6-二取代-5-羧甲基脯氨酸衍生物通过碳青霉烯合成酶催化转化为双环β-内酰胺。结果说明了串联酶系统在不对称双环β-内酰胺合成中的应用，包括工程巴豆酶。

更新日期：2019-02-21

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