Activity-based probes and chemical proteomics uncover the biological impact of targeting HMG-CoA Synthase 1 in the mevalonate pathway.

ABSTRACT: Mevalonate is a precursor for essential metabolites, such as isoprenoids and sterols. Its synthesis starts with 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) producing HMG-CoA, which is then converted to mevalonate by HMG-CoA reductase (HMGCR), a target of statins. Cancer cells often upregulate enzymes in the mevalonate pathway to meet their metabolic demands, leading to the development of inhibitors targeting several enzymes in this pathway. However, current inhibitors have not yet shown significant anticancer activity. While HMGCS1 has unique biochemical properties that distinguish it from other mevalonate pathway enzymes, the effects of inhibiting HMGCS1 have not been thoroughly investigated. Here, we present a set of chemical probes that enable us to systematically assess t

SUBMITTER: Yi SA 

PROVIDER: S-EPMC12514577 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature