Inversion of Enantioselectivity Dramatically Improves Catalytic Activity

Run Substrate G74C G74C/V43A Increase (Fold) 

7 INVERSION OF ENANTIOSELECTIVITY DRAMATICALLY IMPROVES CATALYTIC ACTIVITY 

Profens are an important group of NSAIDs. The biological activity of these drugs resides exclusively in the (S)-enantiomer, so considerable effort has been invested in developing efficient routes for their preparation. For instance, (S)-naproxen has been prepared via recrystallization of diastereomeric mixtures. The carboxylesterase-catalyzed kinetic resolution of R/S)-naproxen methyl ester achieves excellent optical purity of the product. Nevertheless, the AMDase-catalyzed as5unmetrizahon of prochiral a-aryl-a-methylmalonates gives rise to a 100% theoretical 5deld of profens, a clear improvement from kinetic resolution (50%). Unfortunately, wild-type AMDase produces only the undesirable (R)-enantiomers. 

TABLE 3.3 Specific Activity of Wild-Type AMDase and (S)-Selective Variants 

Structure of the active site of AMDase and reaction mechanism. 

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