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Insights into the biosynthesis of icumazole unveiling a distinctive family of crotonyl-CoA carboxylase/reductase
bioRxiv - Biochemistry Pub Date : 2022-11-22 , DOI: 10.1101/2022.11.22.517467
Feng Xie, Alexander F. Kiefer, Anna K.H. Hirsch, Olga Kalinina, Chengzhang Fu, Rolf Mueller

Icumazoles are potent antifungal polyketides with intriguing structural features. Here, we present the polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) hybrid biosynthetic gene cluster of icumazoles. Surprisingly, an unusual non-terminal thioesterase domain divides the PKS/NRPS assembly line. The succeeding PKS modules potentially form a rare precursor 4-methyl-2-hexenoyl-ACP thus deviating from the previously proposed polyoxypeptin pathway. The 4-methyl-2-hexenoyl-ACP is further reductive carboxylated to 2-methylbutylmalonyl-ACP essential for icumazole biosynthesis by IcuL, representing a new type of crotonyl-CoA carboxylase/reductase (CCR). We characterize IcuL and its homologs TgaD and Leu10 in vitro, suggesting a stricter substrate specificity of this new family of CCRs than found in canonical ones. Intriguingly, we also find that TgaD unprecedently utilizes both NADPH and NADH as cofactors with similar efficiency, diverging from the NADPH-specific characteristic of canonical CCRs. Furthermore, a sequence similarity network-based bioinformatic survey reveals that the IcuL-like CCRs are evolutionarily separated from canonical CCRs.

中文翻译:

深入了解 icumazole 的生物合成,揭示了一个独特的巴豆酰辅酶 A 羧化酶/还原酶家族

Icumazole 是一种有效的抗真菌聚酮化合物,具有有趣的结构特征。在这里,我们介绍了 icumazole 的聚酮化合物合酶 (PKS)/非核糖体肽合成酶 (NRPS) 杂交生物合成基因簇。令人惊讶的是,一个不寻常的非末端硫酯酶结构域将 PKS/NRPS 装配线分开。随后的 PKS 模块可能形成罕见的前体 4-甲基-2-己烯酰-ACP,从而偏离先前提出的聚氧肽素途径。4-甲基-2-己烯酰-ACP 进一步还原羧化为 2-甲基丁基丙二酰-ACP,这是 IcuL 生物合成艾克唑所必需的,代表一种新型巴豆酰辅酶 A 羧化酶/还原酶 (CCR)。我们在体外对 IcuL 及其同系物 TgaD 和 Leu10 进行了表征,表明这个新的 CCR 家族比在经典家族中发现的更严格的底物特异性。有趣的是,我们还发现 TgaD 前所未有地利用 NADPH 和 NADH 作为辅助因子,效率相似,这与典型 CCR 的 NADPH 特异性特征不同。此外,基于序列相似性网络的生物信息学调查表明,类 IcuL 的 CCR 在进化上与规范的 CCR 是分开的。
更新日期:2022-11-24
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