Human oxygenase variants employing a single protein Fe(II) ligand are catalytically active

DOI: 10.1002/anie.202103711

Authors: Amelia Brasnett (University of Oxford) , Inga Pfeffer (University of Oxford) , Lennart Brewitz (University of Oxford) , Rasheduzzaman Chowdhury (University of Oxford) , Yu Nakashima (University of Oxford) , Anthony Tumber (University of Oxford) , Michael A. Mcdonough (University of Oxford) , Christopher Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: April 2021

Abstract: Aspartate/asparagine‐β‐hydroxylase (AspH) is a human 2‐oxoglutarate (2OG) and Fe(II) oxygenase that catalyzes C3 hydroxylations of aspartate/asparagine residues of epidermal growth factor‐like domains (EGFDs). Unusually, AspH employs two histidine residues to chelate Fe(II) 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 Fe(II) binding histidine residues are substituted for alanine. Both the H725A and, in particular, the H679A AspH variant 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.

Journal Keywords: Aspartate/asparagine-β-hydroxylase/AspH/BAH/HAAH; 2-oxoglutarate/α-ketoglutarate oxygenase; biomimetic catalysis; Fe(II) binding metallo-enzymes; Epigenetics

Diamond Keywords: Epigenetics; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 26/04/2021 13:17

Discipline Tags:

Biochemistry Catalysis Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)