Derivatives of the Clinically Used HIF Prolyl Hydroxylase Inhibitor Desidustat Are Efficient Inhibitors of Human γ-Butyrobetaine Hydroxylase.

ABSTRACT: The 2-oxoglutarate (2OG)/Fe(II)-dependent γ-butyrobetaine hydroxylase (BBOX) catalyzes the final step in l-carnitine biosynthesis, i.e., stereoselective C-3 oxidation of γ-butyrobetaine (GBB). BBOX inhibition is a validated clinical strategy to modulate l-carnitine levels and to enhance cardiovascular efficiency. Reported BBOX inhibitors, including the clinically used cardioprotective agent Mildronate, manifest moderate inhibitory activity in vitro, limited selectivity, and/or unfavorable physicochemical properties, indicating a need for improved BBOX inhibitors. We report that the clinically used hypoxia-inducible factor-α prolyl residue hydroxylase (PHD) inhibitors Desidustat, Enarodustat, and Vadadustat efficiently inhibit isolated recombinant BBOX, suggesting that BBOX in

SUBMITTER: Corner TP 

PROVIDER: S-EPMC12067446 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature