A human protein hydroxylase that accepts D-residues

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Hypoxia-inducible factor (FIH) is an oxygenase which post-translationally hydroxylates proteins and is implicated in a range of biological processes. Here a wide substrate tolerance for FIH is demonstrated, including for d-amino acids, where double hydroxylation of d-leucine is observed. 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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2020-05
Language
English
Article Type
Article
Citation

COMMUNICATIONS CHEMISTRY, v.3, no.1

ISSN
2399-3669
DOI
10.1038/s42004-020-0290-5
URI
http://hdl.handle.net/10203/274316
Appears in Collection
CH-Journal Papers(저널논문)
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