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Mechanistic and Computational Studies of the Reductive Half-Reaction of Tyrosine to Phenylalanine Active Site Variants of d-Arginine Dehydrogenase

The flavin-mediated enzymatic oxidation of a CN bond in amino acids can occur through hydride transfer, carbanion, or polar nucleophilic mechanisms. Previous results with d-arginine dehydrogenase from Pseudomonas aeruginosa (PaDADH) using multiple deuterium kinetic isotope effects (KIEs) and computational studies established preferred binding of the substrate protonated on the α-amino group, with cleavages of the NH and CH bonds occurring in asynchronous fashion, consistent with the three possible mechanisms. The hydroxyl groups of Y53 and Y249 are ≤4 Å from the imino and carboxylate groups of the reaction product iminoarginine, suggesting participation in binding and catalysis. In this study, we have investigated the reductive half-reactions of the Y53F and Y249F variants of PaDADH using substrate and solvent deuterium KIEs, solvent viscosity and pH effects, and quantum mechanical/molecular mechanical computational approaches to gain insights into the catalytic roles of the tyrosines and evaluate whether...

Authors:   Swathi Gannavaram; Sarah Sirin; Woody Sherman; Giovanni Gadda
Journal:   Biochemistry
Year:   2014
DOI:   10.1021/bi500917q
Publication date:   07-Oct-2014
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