Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.

ABSTRACT: The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2. Potential "off-target" effects of BT2 have not been considered, however. We therefore tested for metabolic off-target effects of BT2 in Bckdk^-/- animals. As expected, BT2 failed to activate BCAA oxidation in these animals. Surprising

SUBMITTER: Bowman CE 

PROVIDER: S-EPMC10942310 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature