TY - JOUR
T1 - Human Oxygenase Variants Employing a Single Protein FeII Ligand Are Catalytically Active
AU - Brasnett, Amelia
AU - Pfeffer, Inga
AU - Brewitz, Lennart
AU - Chowdhury, Rasheduzzaman
AU - Nakashima, Yu
AU - Tumber, Anthony
AU - McDonough, Michael A.
AU - Schofield, Christopher J.
N1 - Publisher Copyright:
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
PY - 2021/6/21
Y1 - 2021/6/21
N2 - 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.
AB - 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.
KW - 2-oxoglutarate dependent oxygenase
KW - aspartate/asparagine-β-hydroxylase
KW - biomimetic catalysis
KW - facial triad
KW - metallo-enzymes
UR - http://www.scopus.com/inward/record.url?scp=85106324520&partnerID=8YFLogxK
U2 - 10.1002/anie.202103711
DO - 10.1002/anie.202103711
M3 - 学術論文
C2 - 33887099
AN - SCOPUS:85106324520
SN - 1433-7851
VL - 60
SP - 14657
EP - 14663
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 26
ER -