Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Blavatnik Institute, Boston, Massachusetts 02115, United States.
J Am Chem Soc. 2024 Jul 31;146(30):21061-21068. doi: 10.1021/jacs.4c06411. Epub 2024 Jul 23.
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.
Aerocyanidin 和 amycomicin 是两种抗生素，它们都源自具有罕见环氧异腈部分的长链酸。由于其结构的复杂性，这两种天然产物的全合成颇具挑战性。这些功能的生物合成方式也一直不为人知。虽然已经鉴定出这两种化合物的生物合成基因簇，但似乎都缺乏编码在这些抗生素中观察到的氧化修饰所需酶的基因。本文中，阐明了 aerocyanidin 和 amycomicin 的生物合成途径。它们共享一条涉及双功能硫酯酶和非血红素铁 α-酮戊二酸依赖性酶的异腈中间体的保守途径。在这两种情况下，异腈中间体随后由连接酶加载到酰基载体蛋白（ACP）上。异腈键合的 ACP 随后被聚酮合酶（s）处理以进行链延伸，从而组装出长链γ-羟异腈酸骨架。环氧化物由含有 cupin 结构域的蛋白 AecF 安装，完成 aerocyanidin 的生物合成。相比之下，三个 P450 酶 AmcB、AmcC 和 AmcQ 参与环氧化和酮形成，以完成 amycomicin 的生物合成。这些结果解释了导致 aerocyanidin 和 amycomicin 最终结构以及关键的γ-羟环氧异腈功能基团生物合成的氧化事件的顺序。
