At low pH, such as under anoxic conditions relevant to diseases like cancer, some metabolic enzymes like LDHA can shift their substrate preferences and cause the accumulation of metabolites that lock the cell into pathogenic states. The mystery of how and why these enzymes start to prefer alternative substrates has lingered.
In a paper from the Thompson laboratory at MSKCC just published in Nature Chemical Biology, graduate student Ariën S. ("Bas") Rustenburg in the lab, together with collaborators from the Gunner lab at CCNY, used modeling to show how protonation state effects explain why substrates like alpha-ketoglutarate that position a carboxylate tail proximal to LDHA's Q100 greatly increase turnover rates at low pH.
L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH.
Andrew M. Intlekofer, Bo Huang, Hui Liu, Hardik Shah, Carlos Carmona-Fontaine, Ariën S. Rustenburg, Salah Salah, M R Gunner, John D. Chodera, Justin R. Cross, and Craig B. Thompson.
Nature Chemical Biology, in press. [DOI] [GitHub]