Computer-aided, resistance gene-guided genome mining for proteasome and HMG-CoA reductase inhibitors

Jenkinson, Cory B.; Podgorny, Adam R.; Zhong, Cuncong; Oakley, Berl R.

doi:10.1093/jimb/kuad045

Title: Computer-aided, resistance gene-guided genome mining for proteasome and HMG-CoA reductase inhibitors

Journal Article · Thu Dec 07 00:00:00 UTC 2023 · Journal of Industrial Microbiology and Biotechnology

DOI: https://doi.org/10.1093/jimb/kuad045 · OSTI ID:2471090

Jenkinson, Cory B. ^[1]; Podgorny, Adam R. ^[1];

^[1];

^[1]

Univ. of Kansas, Lawrence, KS (United States)

Secondary metabolites (SMs) are biologically active small molecules, many of which are medically valuable. Fungal genomes contain vast numbers of SM biosynthetic gene clusters (BGCs) with unknown products, suggesting that huge numbers of valuable SMs remain to be discovered. It is challenging, however, to identify SM BGCs, among the millions present in fungi, that produce useful compounds. One solution is resistance gene-guided genome mining, which takes advantage of the fact that some BGCs contain a gene encoding a resistant version of the protein targeted by the compound produced by the BGC. The bioinformatic signature of such BGCs is that they contain an allele of an essential gene with no SM biosynthetic function, and there is a second allele elsewhere in the genome. We have developed a computer-assisted approach to resistance gene-guided genome mining that allows users to query large databases for BGCs that putatively make compounds that have targets of therapeutic interest. Working with the MycoCosm genome database, we have applied this approach to look for SM BGCs that target the proteasome β6 subunit, the target of the proteasome inhibitor fellutamide B, or HMG-CoA reductase, the target of cholesterol reducing therapeutics such as lovastatin. Our approach proved effective, finding known fellutamide and lovastatin BGCs as well as fellutamide- and lovastatin-related BGCs with variations in the SM genes that suggest they may produce structural variants of fellutamides and lovastatin. Gratifyingly, we also found BGCs that are not closely related to lovastatin BGCs but putatively produce novel HMG-CoA reductase inhibitors.

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Research Organization:: USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2471090

Journal Information:: Journal of Industrial Microbiology and Biotechnology, Journal Name: Journal of Industrial Microbiology and Biotechnology Journal Issue: 1 Vol. 50; ISSN 1367-5435

Publisher:: SpringerCopyright Statement

Country of Publication:: United States

Language:: English

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