A Standalone β-Ketoreductase Acts Concomitantly with Biosynthesis of the Antimycin Scaffold,ACS Chemical Biology

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A Standalone β-Ketoreductase Acts Concomitantly with Biosynthesis of the Antimycin Scaffold
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-06-20 , DOI: 10.1021/acschembio.1c00229
Asif Fazal _{1,

2,

3} , Glyn R Hemsworth _{1,

2} , Michael E Webb _{1,

3} , Ryan F Seipke _{1,

2}

Affiliation

Antimycins are anticancer compounds produced by a hybrid nonribosomal peptide synthetase/polyketide synthase (NRPS/PKS) pathway. The biosynthesis of these compounds is well characterized, with the exception of the standalone β-ketoreductase enzyme AntM that is proposed to catalyze the reduction of the C8 carbonyl of the antimycin scaffold. Inactivation of antM and structural characterization suggested that rather than functioning as a post-PKS tailoring enzyme, AntM acts upon the terminal biosynthetic intermediate while it is tethered to the PKS acyl carrier protein. Mutational analysis identified two amino acid residues (Tyr185 and Phe223) that are proposed to serve as checkpoints controlling substrate access to the AntM active site. Aromatic checkpoint residues are conserved in uncharacterized standalone β-ketoreductases, indicating that they may also act concomitantly with synthesis of the scaffold. These data provide novel mechanistic insights into the functionality of standalone β-ketoreductases and will enable their reprogramming for combinatorial biosynthesis.

中文翻译：

一种独立的 β-酮还原酶与抗霉素支架的生物合成同时起作用

抗霉素是由混合非核糖体肽合成酶/聚酮化合物合成酶 (NRPS/PKS) 途径产生的抗癌化合物。这些化合物的生物合成得到了很好的表征，但独立的 β-酮还原酶 AntM 除外，该酶被提议用于催化抗霉素支架的 C8 羰基的还原。antM灭活和结构表征表明，AntM 不是作为 PKS 后定制酶发挥作用，而是作用于末端生物合成中间体，同时它被束缚在 PKS 酰基载体蛋白上。突变分析确定了两个氨基酸残基（Tyr185 和 Phe223），它们被提议用作控制底物进入 AntM 活性位点的检查点。芳香检查点残基在未表征的独立 β-酮还原酶中是保守的，表明它们也可能与支架的合成同时起作用。这些数据提供了对独立 β-酮还原酶功能的新机制见解，并将使其重编程用于组合生物合成。

更新日期：2021-07-16

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