9 Molecular Mechanism of Oxygen Activation by P-450

Abstract

Publisher Summary This chapter discusses the mechanistic features of P-450 reactions by comparing enzymic reactions with those of model porphyrin systems. Model porphyrin systems have allowed the complete dissection of the proposed mechanism of oxygen activation and transfer by P-450. The P-450 enzyme comprises a unique class of hemoprotein that has protoporphyrin IX at the active site as a prothetic group, an unusual cysteine thiolate ligand to the heme iron, and a characteristic absorption band at 450 nm. The physiological function of P-450 is the oxidative metabolism of foreign compounds (such as drugs and cancer reagents) and steroids in the liver, lung, and placenta, via an oxygen transfer mechanism. Estabrook and co-workers demonstrated for the first time the participation of P-450 in the C-12 hydroxylation of steroids catalyzed by adrenal cortex microsomes. The P-450 reaction cycle begins with binding of the substrate at the active site. This process can be observed spectroscopically as the incorporation of the substrate eliminates the iron-coordinated water molecule from the active site causing spin-state changes in some cases.