美国加利福尼亚大学Yi Tang团队报道了通过靶向基因组挖掘揭示天然产物CYP51抑制剂的生物合成基因簇。相关研究成果于2021年4月15日发表在国际顶尖学术期刊《美国化学会杂志》。

羊角甾醇14α-脱甲基酶（CYP51）是抗真菌药物开发的重要目标。真菌衍生的限制素1和相关分子是唯一能够抑制CYP51的天然产物。

该文中，研究人员利用编码自抗CYP51基因的共定位作为查询，鉴定并验证了1的生物合成基因簇（BGC）。与CYP51相关的BGCs的额外基因组挖掘产生了相关的Lanomycin 2。从未知的产生这些化合物的真菌中鉴定出1和2的途径，凸显了自我抗性酶（SRE）引导的生物活性天然产物发现方法的前景。

附：英文原文

Title: Targeted Genome Mining Reveals the Biosynthetic Gene Clusters of Natural Product CYP51 Inhibitors

Author: Nicholas Liu, Elizabeth D. Abramyan, Wei Cheng, Bruno Perlatti, Colin J.B. Harvey, Gerald F. Bills, Yi Tang

Issue&Volume: April 15, 2021

Abstract: Lanosterol 14α-demethylase (CYP51) is an important target in the development of antifungal drugs. The fungal-derived restricticin 1 and related molecules are the only examples of natural products that inhibit CYP51. Here, using colocalizations of genes encoding self-resistant CYP51 as the query, we identified and validated the biosynthetic gene cluster (BGC) of 1. Additional genome mining of related BGCs with CYP51 led to production of the related lanomycin 2. The pathways for both 1 and 2 were identified from fungi not known to produce these compounds, highlighting the promise of the self-resistance enzyme (SRE) guided approach to bioactive natural product discovery.

DOI: 10.1021/jacs.1c01516

Source: https://pubs.acs.org/doi/10.1021/jacs.1c01516