Key elements of the chemistry of cytochrome P-450: The oxygen rebound mechanism

Abstract

The heme-containkg monooxygenase, cytochrome P-450, has attracted considerable attention because of the central role this enzyme plays in oxidative mechanisms. Several forms of this protein found in the liver apparently protect the body from foreign chemical assult by oxidizing toxic compounds to more manageable, hydrophilic materials. Thus, for example, drugs that contain alkyl amines are oxidatively cleaved by cytochrome P-450 to give aldehydes. I t is now recognized that some of the metabolic transformations mediated bv cvtochrome P-450 nroduce toxic or carcinoeenic products. '['he epoxide prodived from 5,inyl chloride by liver cstochrome 1'-450 is known 11, Droduce tumors in that organ whereas benzpyrene, which is found in cigarette smoke, is oxidized in the lung to acarcinogenic diol-epoxide. Many of the oxidative transformations of organic compounds mediated by cytochrome P-450 are carefully designed metabolic events. A cascade of very specific forms of cytochrome P-450 found in the adrenal cortex, for example, is involved in manv of the imoortant stens of lioid metaho-~ ~ lism. After its hiosynthesis, cholesterol undergoes a series of oxidations in which cvtochrome P-430 is involved. The removal of the alkyl side chain from ring-D is known t o proceed bv two successive and stereoselective hvdroxvlations a t '2-20 and '2-22 followed by a glycol cleavage. ~h k eventual hydroxylation of C-11 in ring-C on the way to the corticosteroids is also a P-450 mediated process.

Recent density functional theory model calculations of drug metabolism by cytochrome P450

“…The HS and LS routes are close to each other during the H-abstraction step and then bifurcate, while the HS forms a radical that has a significant barrier for rebound, the LS rebound is virtually barrierless. The TSR mechanism corroborated the conventional Groves' rebound mechanism [21,22] and resolved the "rebound controversy" by rationalizing the experimental ultrafast radical clock data [23][24][25]. Later, the Yoshizawa group studied the kinetic isotope effect of the C H bond activation of alkane [26,27] and the mechanism of camphor hydroxylation by Cpd I [28].…”

Non‐Heme Fe(IV)—Oxo Intermediates

“…9 Reaction mechanisms proposed for these enzymes have invoked several intermediates following the addition of oxygen to the Fe(II) center. 1,2 10 and formally involves recombination of a coordinated hydroxyl radical equivalent with the substrate radical, yields the hydroxylated product and a coordinatively unsaturated Fe(II) center. In addition to substrate hydroxylation, many other outcomes following H-atom abstraction by the Fe(IV)-oxo are documented.…”

Substrate positioning controls the partition between halogenation and hydroxylation in the aliphatic halogenase, SyrB2

“…A mechanism for the (pro)collagen-modifying prolyl-4-hydroxylase (P4H) originally proposed by Hanauske-Abel and Günzler (5) has accounted well for ensuing experimental data on multiple enzymes in the family. Its central tenets are the abstraction of a hydrogen atom (H • ) from the substrate by an Fe(IV)-oxo (ferryl) complex (Scheme 1A, black arrows) and the subsequent ''rebound'' of the coordinated hydroxyl radical to the substrate radical (red arrows) (6). The most compelling evidence for this mechanism was provided by the detection and spectroscopic characterization of the ferryl intermediates in taurine:␣KG dioxygenase (TauD) from Escherichia coli and a P4H from Paramecium bursaria Chlorella virus 1 (7,8).…”