Friedel–Crafts‐Type Mechanism for the Enzymatic Elimination of Ammonia from Histidine and Phenylalanine

Abstract

The surprisingly high catalytic activity and selectivity of enzymes stem from their ability to both accelerate the target reaction and suppress competitive reaction pathways that may even be dominant in the absence of enzymes. For example, histidine and phenylalanine ammonia-lyases (HAL and PAL) trigger the abstraction of the nonacidic beta protons of these amino acids while leaving the much more acidic ammonium hydrogen atoms untouched. Both ammonia-lyases have a catalytically important electrophilic group, which was believed to be dehydroalanine for 30 years but has now been revealed by X-ray crystallography and UV spectroscopy to be a highly electrophilic 5-methylene-3,5-dihydroimidazol-4-one (MIO) group. Experiments suggest that the reaction is initiated by the electrophilic attack of MIO on the aromatic ring of the substrate. This incomplete Friedel-Crafts-type reaction leads to the activation of a beta proton and its stereospecific abstraction, followed by the elimination of ammonia and regeneration of the MIO group. The plausibility of such a mechanism is supported by a synthetic model. The application of the PAL reaction in the biocatalytic synthesis of enantiomerically pure alpha-amino beta-aryl propionates from aryl acrylates is also discussed.