NocU is a cytochrome P450 oxygenase catalyzing N-hydroxylation of the indolic moiety during the maturation of the thiopeptide antibiotics nocathiacins,Organic & Biomolecular Chemistry

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NocU is a cytochrome P450 oxygenase catalyzing N-hydroxylation of the indolic moiety during the maturation of the thiopeptide antibiotics nocathiacins
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2021-09-02 , DOI: 10.1039/d1ob01284c
Heng Guo ₁ , Xuebing Bai ₂ , Qian Yang ₁ , Yufeng Xue ₁ , Dandan Chen _{1,

3} , Jiang Tao ₂ , Wen Liu _{1,

3}

Affiliation

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 N-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.

中文翻译：

NocU 是一种细胞色素 P450 加氧酶，在硫肽抗生素诺卡沙星成熟过程中催化吲哚部分的 N-羟基化

核糖体合成和翻译后修饰肽 (RiPP) 天然产物包括硫肽抗生素家族，其中诺卡沙星 (NOC) 和那西肽 (NOS) 是结构相关的双环成员，在侧环系统内具有吲哚部分。与NOS相比，NOC具有额外的功能，可以改善水溶性和生物利用度，这是大多数硫肽抗生素固有的问题，因此具有临床用于抗感染药物开发的潜力。翻译后修饰 (PTM) 提供这些功能的过程仍不清楚。在这项研究中，应用工程化的 NOS 生产菌株来研究 NocU 的功能，NocU 是 NOC 生物合成 PTM 过程中独特的细胞色素 P450 加氧酶。受益于那西肽 U (NOS-U)（一种在吲哚氮上具有额外羟基的新型 NOS 型化合物）的分离和结构表征，我们报告 NocU 负责成熟过程中吲哚部分的N-羟基化国家奥委会。这一发现揭示了NOCs吲哚氮结构差异的原因，不仅将加速NOCs的生物合成研究，而且还可以利用硫肽抗生素生物合成机制的兼容性促进新类似物的开发。

更新日期：2021-09-15

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