Open AccessTargeted Genome Mining Reveals the Biosynthetic Gene Clusters of Natural Product CYP51 Inhibitors
Author(s) -
Nicholas Liu,
Elizabeth D Abramyan,
Wei Cheng,
Bruno Perlatti,
Colin J. B. Harvey,
Gerald F. Bills,
Yi Tang
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c01516
Subject(s) - natural product , demethylase , gene cluster , gene , chemistry , lanosterol , genome , computational biology , drug discovery , biochemistry , biology , epigenetics , sterol , cholesterol
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.