浙江大学药学院Yi-Ling Du课题组的一项最新研究揭示了Luzopeptin生物合成中涉及细胞色素P450介导的碳氮键去饱和以形成腙的酶调节过程。2021年6月27日出版的《德国应用化学》杂志发表了这项成果。

研究组通过体内遗传学和体外生化方法重建了Luzopeptin A生物合成的生物合成裁剪途径。值得注意的是，该研究团队发现了一种多任务细胞色素P450酶，它可以催化它们的四次连续氧化，包括高度异常的碳氮键去饱和、形成含肼的4-OH-Thp残基。

此外，该团队鉴定了一种膜结合酰基转移酶，它可能介导细胞外随后的O-乙酰化，作为一种对产生菌株潜在的自我保护策略。对新型十肽和相关P450酶的进一步基因组挖掘为P450介导的碳氮键去饱和提供了机理上的见解。

他们的研究结果不仅揭示了双中间体十肽形成药效团的分子基础，而且扩大了P450家族酶的催化多功能性。

据介绍，Luzopeptins和相关的十肽是具有罕见酰基取代四氢吡啶-3-羧酸(Thp)亚基的双中间体非核糖体肽，对其生物活性至关重要。

附：英文原文

Title: Enzymatic Tailoring in Luzopeptin Biosynthesis Involves Cytochrome P450-Mediated Carbon-Nitrogen Bond Desaturation for Hydrazone Formation

Author: Xinjie Shi, Liming Huang, Kaihui Song, Guiyun Zhao, Yu Liu, Longxian Lv, Yi-Ling Du

Issue&Volume: 2021-06-27

Abstract: Luzopeptins and related decadepsipeptides are bisintercalator nonribosomal peptides featuring rare acyl-substituted tetrahydropyridazine-3-carboxylic acid (Thp) subunits that are critical to their biological activities. Herein, we reconstitute the biosynthetic tailoring pathway in luzopeptin A biosynthesis through  in vivo  genetic and  in vitro  biochemical approaches. Significantly, we revealed a multitasking cytochrome P450 enzyme that catalyzes four consecutive oxidations including the highly unusual carbon-nitrogen bond desaturation, forming the hydrazone-bearing 4-OH-Thp residues. Moreover, we identified a membrane-bound acyltransferase that likely mediates the subsequent  O  -acetylations extracellularly, as a potential self-protective strategy for the producer strain. Further genome mining of novel decadepsipeptides and an associated P450 enzyme have provided mechanistic insights into the P450-mediated carbon-nitrogen bond desaturation. Our results not only reveal the molecular basis of pharmacophore formation in bisintercalator decadepsipeptides, but also expand the catalytic versatility of P450 family enzymes.

DOI: 10.1002/anie.202105312

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202105312