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

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...

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Veröffentlicht in:	Journal of the American Chemical Society 2021-04, Vol.143 (16), p.6043-6047
Hauptverfasser:	Liu, Nicholas, Abramyan, Elizabeth D, Cheng, Wei, Perlatti, Bruno, Harvey, Colin J.B, Bills, Gerald F, Tang, Yi
Format:	Artikel
Sprache:	eng
Schlagworte:	14-alpha Demethylase Inhibitors - metabolism Antifungal Agents - chemistry Antifungal Agents - metabolism Biological Products - chemistry Biological Products - metabolism Cytochrome P450 Family 51 - genetics Cytochrome P450 Family 51 - metabolism Fungal Proteins - genetics Fungal Proteins - metabolism Fungi - genetics Multigene Family Pyrans - chemistry Pyrans - metabolism
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Zusammenfassung:	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.
ISSN:	0002-7863 1520-5126
DOI:	10.1021/jacs.1c01516