NocU is a cytochrome P450 oxygenase catalyzing N-hydroxylation of the indolic moiety during the maturation of the thiopeptide antibiotics nocathiacins
NocU is a cytochrome P450 oxygenase catalyzing N-hydroxylation of the indolic moiety during the maturation of the thiopeptide antibiotics nocathiacins
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DOI：
10.1039/d1ob01284c
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发表时间：
2021-09-02
影响因子：
3.2
通讯作者：
Liu, Wen
中科院分区：
文献类型：
--
作者：
Guo, Heng;Bai, Xuebing;Liu, Wen
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nocathiacins （NOCs）和nosiheptide （NOS）是结构相关的双环成员，在侧环系统中具有吲哚部分。与NOS相比，noc具有额外的功能，可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，因此在抗感染药物开发中具有临床应用潜力。翻译后修饰（PTMs）提供这些功能的过程尚不清楚。在本研究中，利用一种工程的nos生产菌株，研究了ptm中特有的细胞色素P450加氧酶NocU在NOC生物合成中的作用。利用nosiheptide U （NOS-U）的分离和结构表征，我们报道了nosiheptide U （NOS-U）是一种新的nos型化合物，在吲哚氮上有一个额外的羟基，nosiheptide U在NOCs成熟过程中负责吲哚部分的n -羟基化。这一发现揭示了NOCs在吲哚氮上结构差异的原因，这不仅将加快NOCs的生物合成研究，而且还将利用硫肽抗生素生物合成机制的相容性促进新的类似物的开发。
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.