The effect of acetylation on isocitrate dehydrogenase 1 regulation

Abstract

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme responsible for catalysis of isocitrate to α‐ketoglutarate using NADP+ as a cofactor. Cancerous mutations of IDH1 yield the neomorphic conversion of α‐ketoglutarate to D‐2‐hydroxyglutarate, a proposed oncometabolite. Various cancers such as gliomas, glioblastomas, acute myeloid leukemias, and bone cancers, are driven by IDH1 mutations. Although it has been established that IDH1 is an enzymatic driver of disease, more research is necessary to elucidate the molecular mechanisms of its regulation. Post‐translational modifications (PTMs), such as acetylation, serve as effective methods of protein regulation. Here, we hypothesize that acetylation may have a significant impact on IDH1 efficiency. To investigate this, we treated wild type IDH1 with acetyl group donors and generated wild type IDH1 mutants (K81Q, K224Q, K321Q) to mimic acetylation in a physiologically relevant setting. We then employed steady state enzyme kinetics to measure the rate of the normal reaction yielding α‐ketoglutarate. We report that acetylation has a notable effect on IDH1 catalytic efficiency in both the acetylation mimics and acetyl‐treated IDH1. Our data suggests that acetylation may be an essential post‐translational modification for regulating IDH1 catalytic efficiency, thus helping us understand pathways relevant to IDH1 activity. Support or Funding Information This work was funded by a Research Scholar Grant, RSG‐19‐075‐01‐TBE, from the American Cancer Society (C.D.S.), National Institutes of Health R00 CA187594 (C.D.S.), U54CA132384 (SDSU) & U54CA132379 (UC San Diego), MARC 5T34GM008303 (SDSU), and IMSD 5R25GM058906 (SDSU), as well as the California Metabolic Research Foundation (SDSU).

IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis

“…Studies have shown that when a single amino acid change occurs in a conserved arginine residue in the isocitrate-binding site of IDH1, it will lead to a decrease in the enzymatic activity of the oxidative decarboxylation of isocitrate to α-ketoglutarate [ 35 ]. In addition, it has been shown that acetylation may be an important posttranslational modification that regulates the catalytic efficiency of IDH1 and is associated with IDH1 activity [ 36 ].…”