State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence on Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Department of General Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China.
Org Biomol Chem. 2021 Oct 6;19(38):8338-8342. doi: 10.1039/d1ob01284c.
The ribosomally synthesized and post-translationally modified peptide (RiPP) natural products include the family of thiopeptide antibiotics, where nocathiacins (NOCs) and nosiheptide (NOS) are structurally related bicyclic members featuring an indolic moiety within the side ring system. Compared with NOS, NOCs bear additional functionalities that lead to the improvement of water solubility and bioavailability, a problem inherent to most of the thiopeptide antibiotics, and thus hold potential for clinical use in anti-infective agent development. The process through which post-translational modifications (PTMs) occur to afford these functionalities remains unclear. In this study, an engineered NOS-producing strain is applied to study the function of NocU, a cytochrome P450 oxygenase unique during the PTMs in NOC biosynthesis. Benefiting from the isolation and structure characterization of nosiheptide U (NOS-U), a new NOS-type compound with an extra hydroxyl group at the indole nitrogen, we report that NocU is responsible for the -hydroxylation of the indolic moiety during the maturation of NOCs. This finding reveals the cause of structural differences at the indole nitrogen of NOCs, which will not only accelerate the biosynthetic studies of NOCs, but also promote new analog development by utilizing the compatibility of the biosynthetic machinery of thiopeptide antibiotics.
核糖体合成和翻译后修饰的肽（RiPP）天然产物包括硫肽抗生素家族，其中 nocathiacins（NOCs）和 nosiheptide（NOS）是结构相关的双环成员，其侧环系统内含有吲哚部分。与 NOS 相比，NOCs 具有额外的功能，可提高水溶性和生物利用度，这是大多数硫肽抗生素固有的问题，因此在抗感染药物开发中具有临床应用的潜力。导致这些功能的翻译后修饰（PTMs）过程尚不清楚。在这项研究中，应用工程化的 NOS 产生菌株来研究 NocU 的功能，NocU 是一种细胞色素 P450 加氧酶，在 NOC 生物合成的 PTMs 过程中是独特的。得益于 nosiheptide U（NOS-U）的分离和结构表征，NOS-U 是一种新的 NOS 型化合物，在吲哚氮上有额外的羟基，我们报告说 NocU 负责 NOCs 成熟过程中吲哚部分的 -羟化。这一发现揭示了 NOCs 中吲哚氮结构差异的原因，这不仅将加速 NOCs 的生物合成研究，而且还将通过利用硫肽抗生素生物合成机制的兼容性来促进新的类似物开发。
