Inactivation structural basis

Loll P. J., Picot D., Garavito M. The structured basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nature Struct Biol 1995 2,637-43. 

Uckun, F.M., Thoen, J., Chen, H., Sudbeck, E., Mao, C., Malaviya, R., Liu, X.-P. and Chen, C.-L. (2002) CYP1A-mediated metabolism of the janus kinase-3 inhibitor 4-(4 -hydroxyphenyl)-amino-6,7-dimethoxyquinazoline structural basis for inactivation by regioselective o-demethylation. Drug Metabolism and Disposition The Biological Fate of Chemicals, 30 (1), 74—85. 

Tomchick, D.R., Machius, M., Cole, P.A. and Yu, Fi. (2007) Structural basis of histone demethylation by LSDl revealed by suicide inactivation. Nature Structural si Molecular Biology, 14 (6), 535-539. 

Herzberg, O., Kapadia, G., Blanco, B., Smith, T.S., and Coulson, A. 1991. Structural basis for the inactivation of the P54 mutant of P-lactamase from Staphylococcus aureus PCI. Biochemistry 30 9503-9509. 

The action of most enzymes is inhibited by many substances. Inhibition is often specific, and studies of the relationship between inhibitor structure and activity have been important to the development of our concepts of active sites and of complementarity of surfaces of biomolecules. Inhibition of enzymes is also the basis of the action of a very large fraction of important drugs. Inhibition may be reversible or irreversible, the latter leading to permanent inactivation of the enzyme. Often, but not always, irreversible inhibition is preceded by reversible binding of the inhibitor at a complementary site on the enzyme surface. 

Rice and co workers prepared a variety of affinity labels on the basis of the structures of eto-nitazine, fentanyl, and oripavine (Fig. 7.39) (198, 461). The etonitazene derivative BIT (196) selectively inactivates /a receptors, whereas the fentanyl derivative FIT (fentanyl isothiocyanate, 197) and the oripavine derivative FAO (fumaramido oripavine, 200) selectively inactivate 6 receptors. The selective alkylation of S receptors by FIT, which is a derivative of the p-selective ligand fentanyl. 

Isoenzymes are multiple forms of an enzyme that possess the ability to catalyze the enzyme s characteristic reaction but that differ in structure because they are encoded by distinct structural genes. These enzyme variants may occur within a single organ or even within a single type of cell. The forms can be distinguished on the basis of differences in various physical properties, such as electrophoretic mobility or resistance to chemical or thermal inactivation. They often have significant quantifiable differences in catalytic properties. However, all the forms of a particular enzyme retain the ability to catalyze its characteristic reaction. 

---