期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 26, 页码 14657-14663出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202103711
关键词
aspartate/asparagine-beta-hydroxylase; biomimetic catalysis; facial triad; metallo-enzymes; 2-oxoglutarate dependent oxygenase
资金
- Wellcome Trust [106244/Z/14/Z]
- Cancer Research UK [C8717/A18245]
- Biotechnology and Biological Sciences Research Council [BB/J003018/1, BB/R000344/1, BB/M011224/1]
- Deutsche Forschungsgemeinschaft [BR 5486/2-1]
- JSPS [2020060219]
- Daiichi Sankyo Foundation of Life Science
- BBSRC [BB/J003018/1, BB/R000344/1] Funding Source: UKRI
The study on human AspH variants reveals insights into its catalytic mechanism, with implications for the functional assignment of 2OG oxygenases and the design of non-protein biomimetic catalysts. The crystal structures show the metal-ligation by only a single protein histidine ligand, indicating a unique approach in Fe-II binding compared to the typical triad of residues. Both H725A and H679A AspH variants exhibit substantial catalytic activity, highlighting their potential applications.
Aspartate/asparagine-beta-hydroxylase (AspH) is a human 2-oxoglutarate (2OG) and Fe-II 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 Fe-II 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.
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