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

DOI: 10.1038/s41467-021-26673-2 DOI Help

Authors: Yu Nakashima (University of Oxford) , Lennart Brewitz (University of Oxford) , Anthony Tumber (University of Oxford) , Eidarus Salah (University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: November 2021

Open Access Open Access

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 2OG oxygenase activity by 2-oxo acids. The human 2OG oxygenases studied, factor inhibiting hypoxia-inducible transcription factor HIF-α (FIH) and aspartate/asparagine-β-hydroxylase (AspH), catalyze C3 hydroxylations of Asp/Asn-residues. Of 35 tested 2OG derivatives, 10 enhance and 17 inhibit FIH activity. Comparison with results for AspH reveals that 2OG derivatives selectively enhance or inhibit FIH or AspH. Comparison of FIH structures complexed with 2OG derivatives to those for AspH provides insight into the basis of the observed selectivity. 2-Oxo acid derivatives have potential as drugs, for use in biomimetic catalysis, and in functional studies. The results suggest that the in vivo activity of 2OG oxygenases may be regulated by natural 2-oxo acids other than 2OG.

Journal Keywords: Oxidoreductases; Small molecules

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 17/11/2021 11:10


Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)