2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases

• DOI: 10.1038/s41467-021-26673-2
• Publication Date: 2021-11-10T11:05:20Z
• Authors: Yu Nakashima; Lennart Brewitz; Anthony Tumber; Eidarus Salah; Christopher J. Sc...
• Keywords: 0301 basic medicine; 03 medical and health sciences; Science; Q; Oxygenases; Humans; Ketoglutaric Acids; Enzyme Inhibitors; Article; 3. Good health

Abstract 2-Oxoglutarate (2OG) oxygenases are validated agrochemical and human drug targets. The potential for modulating their activity with 2OG derivatives has not been explored, possibly due to concerns regarding selectivity. We report proof-of-principle studies demonstrating selective enhancement or inhibition of oxygenase by 2-oxo acids. studied, factor inhibiting hypoxia-inducible transcription HIF-α (FIH) aspartate/asparagine-β-hydroxylase (AspH), catalyze C3 hydroxylations Asp/Asn-residues. Of 35 tested derivatives, 10 enhance 17 inhibit FIH activity. Comparison results AspH reveals that selectively AspH. structures complexed those provides insight into the basis observed 2-Oxo acid have as drugs, use in biomimetic catalysis, functional studies. suggest vivo may be regulated natural acids other than 2OG.