Human Oxygenase Variants Employing a Single Protein FeII Ligand Are Catalytically Active

Amelia Brasnett, Inga Pfeffer, Lennart Brewitz, Rasheduzzaman Chowdhury, Yu Nakashima, Anthony Tumber, Michael A. McDonough, Christopher J. Schofield*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Aspartate/asparagine-β-hydroxylase (AspH) is a human 2-oxoglutarate (2OG) and FeII oxygenase that catalyses C3 hydroxylations of aspartate/asparagine residues of epidermal growth factor-like domains (EGFDs). Unusually, AspH employs two histidine residues to chelate FeII rather than the typical triad of two histidine and one glutamate/aspartate residue. We report kinetic, inhibition, and crystallographic studies concerning human AspH variants in which either of its FeII binding histidine residues are substituted for alanine. Both the H725A and, in particular, the H679A AspH variants retain substantial catalytic activity. Crystal structures clearly reveal metal-ligation by only a single protein histidine ligand. The results have implications for the functional assignment of 2OG oxygenases and for the design of non-protein biomimetic catalysts.

Original languageEnglish
Pages (from-to)14657-14663
Number of pages7
JournalAngewandte Chemie - International Edition
Volume60
Issue number26
DOIs
StatePublished - 2021/06/21

Keywords

  • 2-oxoglutarate dependent oxygenase
  • aspartate/asparagine-β-hydroxylase
  • biomimetic catalysis
  • facial triad
  • metallo-enzymes

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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