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A human protein hydroxylase that accepts D-residues

DOI: 10.1038/s42004-020-0290-5 DOI Help

Authors: Hwanho Choi (University of Oxford; Sejong University) , Adam P. Hardy (University of Oxford) , Thomas M. Leissing (University of Oxford) , Rasheduzzaman Chowdhury (University of Oxford) , Yu Nakashima (University of Oxford) , Wei Ge (University of Oxford) , Marios Markoulides (University of Oxford) , John S. Scotti (University of Oxford) , Philip A. Gerken (University of Oxford) , Helen Thorbjornsrud (University of Oxford) , Dahye Kang (Institute for Basic Science (IBS), Korea; Korea Advanced Institute of Science and Technology (KAIST)) , Sungwoo Hong (Institute for Basic Science (IBS), Korea; Korea Advanced Institute of Science and Technology (KAIST)) , Joongoo Lee (Northwestern University) , Michael A. Mcdonough (University of Oxford) , Hwangseo Park (Sejong University) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Chemistry , VOL 3

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 18069

Open Access Open Access

Abstract: Factor inhibiting hypoxia-inducible factor (FIH) is a 2-oxoglutarate-dependent protein hydroxylase that catalyses C3 hydroxylations of protein residues. We report FIH can accept (D)- and (L)-residues for hydroxylation. The substrate selectivity of FIH differs for (D) and (L) epimers, e.g., (D)- but not (L)-allylglycine, and conversely (L)- but not (D)-aspartate, undergo monohydroxylation, in the tested sequence context. The (L)-Leu-containing substrate undergoes FIH-catalysed monohydroxylation, whereas (D)-Leu unexpectedly undergoes dihydroxylation. Crystallographic, mass spectrometric, and DFT studies provide insights into the selectivity of FIH towards (L)- and (D)-residues. The results of this work expand the potential range of known substrates hydroxylated by isolated FIH and imply that it will be possible to generate FIH variants with altered selectivities.

Subject Areas: Chemistry


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

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s42004-020-0290-5.pdf