Inhibition of Pyridoxal Phosphate Enzymes

Among the numerous enzymes that utilize pyridoxal phosphate (PLP) as cofactor, the amino acid racemases, amino acid decarboxylases (e.g., aromatic amino acids, ornithine, glutamic acid), aminotransferases (y-aminobutyrate transaminase), and a-oxamine synthases, have been the main targets in the search for fluorinated mechanism-based inhibitors. Pharmaceutical companies have played a very active role in this promising research (control of the metabolism of amino acids and neuroamines is very important at the physiological level). 

Inhibition processes can highly depend on the number of fluorine atoms. Thus, while mono- and trifluoroalanine are good inhibitors of alanine racemase. 

Complexity of inhibition of PLP-dependent enzymes is highlighted by detailed investigations on the inhibition of y-aminobutyric acid aminotransferase (GABA-AT), the enzyme responsible for the degradation of y-aminobutyric acid (GABA), one of the major inhibitory neurotransmitters in the mammalian central nervous system. Inhibition of GAB A-AT results in an increased concentration of GABA in the brain and could have therapeutic applications in neurological disorders (epilepsy, Parkinson disease, and Alzheimer disease). 

Ornithine decarboxylase catalyzes the conversion of ornithine into putrescine. Like other polyamines, the latter is involved in the regulation of cell development. Inhibition of this enzyme has been an important goal in medicinal chemistry. In this context, difluoroornithine has been shown to be an excellent inhibitor 

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Inhibition of pyridoxal phosphate enzymes by fluoroalanines has been widely studied. Among the numerous examples, alanine racemase, tyrosine phenol... 

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