| Literature DB >> 34381247 |
Mark R Woodford1,2,3, Alexander J Baker-Williams1,2,3, Rebecca A Sager1,2,3, Sarah J Backe1,2,3, Adam R Blanden2,3, Fiza Hashmi1,2,3, Priyanka Kancherla1, Alessandro Gori4, David R Loiselle5, Matteo Castelli6, Stefano A Serapian6, Giorgio Colombo6, Timothy A Haystead5, Sandra M Jensen7, William G Stetler-Stevenson7, Stewart N Loh2,3, Laura S Schmidt8,9, W Marston Linehan9, Alaji Bah2,3, Dimitra Bourboulia1,2,3, Gennady Bratslavsky10,11,12, Mehdi Mollapour13,14,15.
Abstract
Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.Entities:
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Year: 2021 PMID： 34381247 PMCID： PMC9278990 DOI： 10.1038/s41594-021-00633-2
Source DB: PubMed Journal: Nat Struct Mol Biol ISSN： 1545-9985 Impact factor: 18.361