Biosynthesis of the Unusual Epoxy Isonitrile-Containing Antibiotics Aerocyanidin and Amycomicin,Journal of the American Chemical Society

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Biosynthesis of the Unusual Epoxy Isonitrile-Containing Antibiotics Aerocyanidin and Amycomicin
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-07-23 , DOI: 10.1021/jacs.4c06411
Ziyang Zheng ₁ , Jon Clardy ₂ , Hung-Wen Liu _{1,

3}

Affiliation

Aerocyanidin and amycomicin are two antibiotics derived from long-chain acids with a rare epoxy isonitrile moiety, the complexity of which renders the total synthesis of these two natural products rather challenging. How this functionality is biosynthesized has also remained obscure. While the biosynthetic gene clusters for these compounds have been identified, both appear to be deficient in genes encoding enzymes seemingly necessary for the oxidative modifications observed in these antibiotics. Herein, the biosynthetic pathways of aerocyanidin and amycomicin are fully elucidated. They share a conserved pathway to isonitrile intermediates that involves a bifunctional thioesterase and a nonheme iron α-ketoglutarate-dependent enzyme. In both cases, the isonitrile intermediates are then loaded onto an acyl carrier protein (ACP) catalyzed by a ligase. The isonitrile-tethered ACP is subsequently processed by polyketide synthase(s) to undergo chain extension, thereby assembling a long-chain γ-hydroxy isonitrile acid skeleton. The epoxide is installed by the cupin domain-containing protein AecF to conclude the biosynthesis of aerocyanidin. In contrast, three P450 enzymes AmcB, AmcC, and AmcQ are involved in epoxidation and keto formation to finalize the biosynthesis of amycomicin. These results thus explain the sequence of oxidation events that result in the final structures of aerocyanidin and amycomicin as well as the biosynthesis of the key γ-hydroxy epoxy isonitrile functional group.

中文翻译：

不寻常的含环氧异腈抗生素气花青素和阿霉素的生物合成

气花青素和阿霉素是两种源自长链酸的抗生素，具有稀有的环氧异腈部分，其复杂性使得这两种天然产物的全合成相当具有挑战性。这种功能是如何生物合成的也仍然不清楚。虽然这些化合物的生物合成基因簇已被鉴定，但两者似乎都缺乏编码酶的基因，而这些酶似乎是在这些抗生素中观察到的氧化修饰所必需的。在此，气花青素和阿霉素的生物合成途径得到了充分阐明。它们共享异腈中间体的保守途径，涉及双功能硫酯酶和非血红素铁 α-酮戊二酸依赖性酶。在这两种情况下，然后将异腈中间体加载到由连接酶催化的酰基载体蛋白（ACP）上。异腈束缚的 ACP 随后被聚酮化合物合酶加工以进行扩链，从而组装长链 γ-羟基异腈酸骨架。环氧化物由含有 cupin 结构域的蛋白质 AecF 安装，完成气花青素的生物合成。相比之下，三种 P450 酶 AmcB、AmcC 和 AmcQ 参与环氧化和酮形成，以完成阿霉素的生物合成。因此，这些结果解释了导致气花青素和阿霉素的最终结构的氧化事件的顺序，以及关键的γ-羟基环氧异腈官能团的生物合成。

更新日期：2024-07-23

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