Mechanisms of Cytochrome

Chemical structure and reaction mechanisms of cytochrome c oxidase. R. Lemberg, Rev. Pure Appl. Chem., 1965,15,125-136 (132). 

Figure 8. Mechanism of cytochrome c oxidase. Explanation given in text.

Groves JT, Hang YZ (1995) Models and mechanics of cytochrome p-450 action. In Ortiz de Mon-tellano PR (ed) Cytochrome p-450 structure, mechanism and biochemistry, 2nd edn Plenum, New York, p 3... 

Although the oxidation (hydroxylation) of hydrocarbons is usually believed to occur via hydrogen atom abstraction [51], the one-electron transfer mechanism of cytochrome P-450 catalyzed oxidation has also been proposed for the oxidation of Ar, Ar-dialkylaniIines [52]. This mechanism (Figure 24.4) is generally preferred for the substrates with low reduction... 

Early steps involved in the mechanism of cytochrome P-450 oxidations have... 

A methodology that has turned out to be a very powerful tool in trying to unravel the intricacies of the mechanism of cytochrome P450-catalyzed oxidation reactions has been the use of deuterium isotope effects. The use of intramolecular deuterium isotope effects have been particularly important in this regard as will be described in chapter 4 where a number of such studies are presented. But, before describing the specific technique that intramolecular isotope effect studies entail, a quick mini review on the nature of deuterium isotope effects is probably in order. 

Nelson SD, Trager WF. The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab Dispos 2003 31(12) 1481—1498. 

FIGURE 4.48 Substrates (3,3,6,6-tetradeuterocyclohexene, methylenecyclohexane, and/ -pinene) used to determine the mechanism of cytochrome P450-catalyzed allylic hydroxylation. 

Obach RS. Mechanism of cytochrome P4503A4- and 2D6-catalyzed dehydrogenation of ezlopitant as probed with isotope effects using five deuterated analogs. Drug Metab Dispos 2001 29(12) 1599-1607. 

Shaik S, Kumar D, de Visser SP, et al. Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes. Chem Rev 2005 105(6) 2279-2328. 

Augusto, O., Beilan, H.S. and Ortiz de Montellano, P.R. (1982) The catalytic mechanism of cytochrome P-450. Spin-trapping evidence for one-electron substrate oxidation. Journal of Biological Chemistry, 257 (19), 11288-11295. 

Orrenius, S. Reaction mechanisms of cytochrome P-1+50. Proceedings Sixth International Congress of Pharmacology, Helsinki, Finland (1975) 6, 39-52. 

Fig. 9.11. Postulated mechanism of cytochrome P450 catalyzed phosphoric acid ester cleavage of the bisphophonate U-91502 (9.51) to produce a triester metabolite 9.52 [118]...

The mechanism of cytochrome P450 catalysis is probably constant across the system. It is determined by the ability of a high valent formal (FeO) species to carry out one-electron oxidations through the abstraction of hydrogen atoms or electrons. The resultant substrate radical can then recombine with the newly created hydroxyl radical (oxygen rebound) to form the oxidized metabolite. Where a heteroatom is the (rich) source of the electron more than one product is possible. There can be direct recombination to yield the heteroatom oxide or radical relocalization within the... 

Adrenodoxin. Adrenodoxin is the only iron-sulfur protein which has been isolated from mammals. This protein from mitochondria of bovine adrenal cortex was purified almost simultaneously by Kimura and Suzuki (32) and Omura et al. (33). It has a molecular weight of 12,638 (34) and the oxidized form of the protein shows maximal absorbances at 415 and 453 nm. Adrenodoxin acts as an electron carrier protein in the enzyme system required for steroid hydroxylation in adrenal mitochondria. In this system, electron transfer is involved with three proteins cytochrome P. gQ, adrenodoxin and a flavoprotein. Reduced NADP gives an electron to Tne flavoprotein which passes the electron to adrenodoxin. Finally, reduced adrenodoxin transfers the electron to cytochrome Pas shown in Fig. 3. The mechanism of cytochrome P cq interaction with steroid, oxygen and adrenodoxin in mixed-function oxidase of adrenal cortex mitochondria has been reviewed by Estabrook et al. (35). 

Mechanism of Cytochrome P450 Involvement in Drug Interactions... 

Guengerich, F.P. (2007) Mechanisms of cytochrome P450 substrate oxidation MiniReview. J. Biochem. Mol. Toxicol.,... 

Groves, J. T., and Y.-Z. Han, Models and mechanisms of cytochrome P450 action . In Cytochrome P450, Structure, Mechanism, and Biochemistry, P. R. Ortiz de Montellano, Ed., Plenum Press, New York, 1995, pp. 3-48. 

FIGURE 1. Mechanism of cytochrome P450 catalyzed oxidation. 

Scheme 2.10 Consensus mechanism of cytochrome P450 catalysis (S = substrate) [61, 62, 72].

In addition to their use for the calibration of rates for radical reactions, radical clocks can be employed to distinguish between ionic and radical pathways. In the simplest embodiment of this idea, a suitable clock reaction that undergoes a known fast rearrangement with easily identifiable products is incorporated into the reaction system to be studied. This approach has been exploited in the pioneering work of Newcomb and co-workers in studies of the mechanism of cytochrome P450 oxidation reactions [13]. Newcomb has developed a range of ultrafast radical clocks able to detect radical species with lifetimes of 80-200 fs. 

Figure 6.2 The mechanism of cytochrome-c-peroxidase complex formation, (a) Native enzyme, (b) Activated complex with the acid-base catalytic function of distal histidine (His) and stabilization of negative charge by arginine (Arg) residue of the active site, (c) Hypothetic intermediate oxene complex, (d) Complex I after intramolecular electron regrouping of oxene complex with Fe4+ and free radical X fragment formation.

Progress in decoding the mechanism of cytochrome P-450, which catalyzes epoxidation and hydroxylation of various hydrocarbons, has stimulated the search for comparatively simple and effective iron porphyrin systems [20-24], The reaction mechanism of monooxygenation can be illustrated by the following diagram ... 

Morgan ET, Li-Masters T, Cheng PY. Mechanisms of cytochrome P450 regulation by inflammatory mediators. Toxicology 2002 181-182 207-210. 

Hu Y, Ingelman-Sundberg M, Lindros KO. Induction mechanisms of cytochrome P450 2El in liver interplay between ethanol treatment and starvation. Biochem Pharmacol 1995 50 155 161. 

Korzekwa KR, Swinney DC, Trager WF. Isotopically labeled chlorobenzenes as probes for the mechanism of cytochrome P-450 catalyzed aromatic hydroxylation. Biochemistry 1989 28(23) 9019-9027. 

Modi S, Sutcliffe MJ, Primrose WU, et al. The catalytic mechanism of cytochrome P450 BM3 involves a 6 A movement of the bound substrate on reduction. Nat Struct Biol 1996 3 414-417. 

Savas U, Griffin KJ, Johnson EF. Molecular mechanisms of cytochrome P-450 induction by xenobiotics an expanded role for nuclear hormone receptors. Mol Pharmacol 1999 56 851-857. 

Goller, A. H., Clark, T. (2001) SAMI semiempirical calculations on the mechanism of cytochrome P450... 

Haem proteins that react with oxygen also utilise ferryl intermediates. Fig. 4 compares the (proposed) reaction mechanisms of cytochrome oxidase and cytochrome P-450 with those of peroxidases and catalases. As can be seen, several of the reaction intermediates have the same oxidation states (although the protonation steps and stage at which H2O is released may be different). However, in contrast to peroxidases, oxidases must react with molecular oxygen, and this requires a reaction cycle that includes Fe11. 

Groves, J.T. and Han, Y.Z., Models and Mechanisms of Cytochrome P450 Action, in Cytochrome P450 Structure, Mechanism, and Biochemistry, Second Edition. P.R. Ortiz de Montellano, Editor. 1995, Plenum Press New York and London, p. 3-48. 

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