Dr. Marc Garcia-Borràs (IQCC) is part of an international multidisciplinary research team led by Prof. Katherine Ryan (University of British Columbia, Canada) that has recently published a new study in PNAS entitled “A shared mechanistic pathway for pyridoxal phosphate–dependent arginine oxidases”. Pyridoxal phosphate (PLP)-dependent enzymes rarely react with oxygen, but an emerging group of PLP- and oxygen-dependent enzymes oxidize L-arginine. Two types of oxidases are known: hydroxylases and desaturases. The mechanism by which molecular oxygen is activated by the PLP organic cofactor for oxidation reactions remains poorly understood.
This study demonstrates that arginine desaturases have a minor hydroxylase activity; through X-ray crystallographic, mutagenesis, spectroscopic, and computational studies it is shown that the reaction mechanism involves two rounds of single-electron transfer to oxygen and superoxide rebound, ultimately producing a conjugated hydroperoxyl intermediate. Water can attack to give a hydroxylated product and release H2O2; without water present the intermediate can be deprotonated, giving a desaturated product and H2O2 instead. The precise positioning of a water molecule in the active site is proposed to control the final reaction outcome. The proposed mechanism provides a unified framework to understand how oxygen can be activated by PLP-dependent enzymes for oxidation of arginine and elucidates a shared mechanistic pathway and intertwined evolutionary history for arginine desaturases and hydroxylases. This study sets the stage for engineering these enzymes to catalyze new oxidative reactions.
The study was recently published in the Proceedings of the National Academy of Sciences of the United States of America:
E.R. Hoffarth, K. Caddell Haatveit, E. Kuatsjah, G.A. MacNeil, S. Saroya, C.J. Walsby, L.D. Eltis, K.N. Houk, M. Garcia-Borràs, and K.S. Ryan
“A shared mechanistic pathway for pyridoxal phosphate–dependent arginine oxidases”
Proc Natl Acad Sci USA 2021, 118, e2012591118
Girona, Oct. 5, 2021
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