V. P. Reddy
2015
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Abstract
Through combined X-ray crystallography and DFT calculations, it is now established that fluorinase enzyme catalyzes the S N 2 fluorination reaction of S-adenosylmethionine by fluoride anion to give 5′-fluoro-5′-deoxyadenosine, which is an intermediate for the biosynthesis of fluoroacetate and fluorothreonine. Therapeutics based on reversible and mechanism-based inactivation of enzymes are used in the treatment of a variety of diseases, such as depression and anxiety disorders, cancer, and African sleeping sickness. Trifluoromethyl and difluoromethyl ketones serve as transition state analog inhibitors of serine proteases. Serotonin reuptake inhibitors such as fluoxetine exert their enzyme inhibition through reversible binding at the enzyme active sites, whereas 5-Fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) is a mechanism-based irreversible inhibitor of thymidylate synthase. This chapter outlines the mechanisms of enzyme inhibition by organofluorine compounds. The X-ray structural characterization of the enzyme–substrate complexes is also discussed.