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Published on: June 13, 2022
Inhibition of mandelate racemase by alpha-fluorobenzylphosphonates
Martin St Maurice1, Stephen L Bearne, Wallach Lu
1Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
Abstract:
Mandelate racemase catalyzes the interconversion of the enantiomers of mandelic acid. The enzyme binds the intermediate analogues (R)- and (S)-alpha-fluorobenzylphosphonate, and alpha,alpha-difluorobenzylphosphonate with 100-2500 times less affinity than it exhibits for (R,S)-alpha-hydroxybenzylphosphonate at pH 7.5. This apparent low affinity, relative to that of alpha-hydroxybenzylphosphonate, arises from the altered pKa values of the alpha-fluorobenzylphosphonates. For example, (S)-alpha-fluorobenzylphosphonate is bound with the same affinity as the substrate at pH 7.5, but this affinity is increased approximately 6-fold at pH 6.3.
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