Inhibition of mandelate racemase by α-fluorobenzylphosphonates

Mandelate racemase catalyzes the interconversion of the enantiomers of mandelic acid. The enzyme binds the intermediate analogues (R)- and (S)-α-fluorobenzylphosphonate, and α,α-difluorobenzylphosphonate with 100–2500 times less affinity than it exhibits for (R,S)-α-hydroxybenzylphosphonate at pH 7.5. This apparent low affinity, relative to that of α-hydroxybenzylphosphonate, arises from the altered pKa values of the α-fluorobenzylphosphonates. For example, (S)-α-fluorobenzylphosphonate is bound with the same affinity as the substrate at pH 7.5, but this affinity is increased 6-fold at pH 6.3.