Cytochrome concerted mechanism

Drawing a parallel of the compound Q to the cytochrome P450 Compound I (Newcomb et al., 2000), a nonsynchronous concerted mechanism in MMO was suggested. According to this mechanism, the difference in the bond vibration of C-H and Fe-0 bonds causes the insertion of oxygen atoms across the C-H bond via a transition state in which the substrate possesses a radical character. Such an elementary process is possible in the approach of the substrate to the ferry 1 oxygen. 

Traylor (38) has also shown that biomimetic iron N-alkylporphyrins themselves are competent catalysts for epoxidation of alkenes with a rate constant of about 104 M-1 s-1. On the basis of these observations and rearrangement reactions of specific alkenes, Traylor has proposed the reaction sequence outlined in Scheme 3 as representative of the oxidation and N-alkylation reactions of the P-450 model systems. In this scheme, the epoxide and the N-alkylated heme are derived from a common, electron-transfer intermediate (caged ferrylporphyrin-alkene cation radical). Collman and co-workers (28, 29) prefer a concerted mechanism (or a short-lived, acyclic intermediate) for epoxidation and N-alkylation reactions. Both authors note that the reactions catalyzed by cytochrome P-450 (and biomimetic reactions) probably can not be ascribed to any single mechanism. 

Two-step concerted mechanism for the hydrocarbon hydroxylation by cytochrome P450. Bull. Chem. Soc. Jpn. 73, 401-407. 

Newcomb M, Le Tadic-Biadatti MH, Chestney DL, Roberts ES, Hollenberg PF (1995) Anonsynchronous concerted mechanism for cytochrome P450 catalyzed hydroxylation. J Am Chem Soc 117 12085-12091... 

Ogliaro F, Harris N, Cohen S, et al. A model rebound mechanism of hydroxylation by cytochrome P450 stepwise and effectively concerted pathways, and their reactivity patterns. J Am Chem Soc 2000 122(37) 8977-8989. 

Figure 3. Possible mechanisms of actions of Bcl-2 members. Two prevailing models through which Bcl-2 membas trigger cytochrome c release have been suggested. In both models phospholipids in the bilayer stnicture either individually and/or collectively induce a conformational change in Bcl-2 members, allowing them to insert into the outer mitochondrial membrane. In model 1 proapoptotic proteins destabilize the outer mitochondrial membrane, oligomerize and form channels through which cytochrome c and other proteins of the intermembrane space can escape.BcI-2 proteins such as Bax or tBid act in concert with other proteins of the BcI-2 family to form channels. In model 2 Bcl-2 members such as Bax interact with residoit proteins in the outer membrane (OM) such as the voltage-dependent anion...

F. Ogliaro, N. Harris, S. Cohen, M. Filatov, S. R de Visser, and S. Shaik, A Model Rebound Mechanism of Hydroxylation by Cytochrome P450. Stepwise and Effectively Concerted Pathways, and Their Reactivity Patterns, J. Am. Chem. Soc. 2000,122, 8977. Calculations explain puzzling aspects of cytochrome P450 hydroxylation reactions in terms of two, different, reactive spin states of the enzyme. 

Insertion of oxygen atom from Cpd I into the carbon-carbon double bond with formation of epoxide (Scheme Ic) reveals features characteristic for a concerted process, although formation of radical intermediates is possible in many cases. A unified description of this alternative is also provided by the two-state mechanism of catalysis by Cpd I (see the section on Hydroxylation of hydrocarbons). Essentially, the concerted oxygen insertion represents a low-spin reaction surface, whereas the distinct radical intermediate is formed on the high-spin reaction pathway. In the latter case, the carbon radical may attack the nearby heme nitrogen and modify the heme covalently. This reaction is also an important inactivation pathway of cytochromes P450 during oxidative transformations of terminal double and triple bonds. 

The mechanism of reduction of dioxygen has been partially clarified, mainly thanks to the low temperature trapping technique designed by Chance et al. [129], Although the precise mechanism is still not understood, it seems probable that dioxygen is reduced to water in two concerted two-electron steps (Fig. 3.3) in which certain intermediates have been identified (see Refs. 8, 92, 97-100, 129-133). One important feature of this particular mechanism is that it affords a switch from one-electron transfer reactions (of cytochromes c, a and Cu ) to effective two-electron steps in the reduction of Oj. The latter is necessary for thermodynamic and kinetic reasons and to effectively prevent release of toxic oxygen radicals from the active site (see Ref. 99). 

Fig. 3.3. Tentative mechanism of reduction of dioxygen. The scheme shows some of the more significant reaction steps at the haem iron-Cug centre of cytochrome oxidase. The reaction may be initiated by delivery of dioxygen to the reduced enzyme (in anaerobiosis top of figure). An initially formed oxy intermediate is normally extremely short-lived, but can be stabilised and identified in artificial conditions (see Refs. 92, 99,129, 134). Concerted transfer of two electrons from Fe and Cu to bound dioxygen yields a peroxy intermediate. This, or its electronic analogue, is stabilised in the absence of electron donors (ferrocytochrome a and/or reduced Cu ), and has been termed Compound C [129,130,132). It may also be observed at room temperature, and is then probably generated from the oxidised state by partial oxidation of water in the active site, in an energy-linked reversed electron transfer reaction [29] (see also Refs. 92, 99). Also the ferryl intermediate [92,99,100] has been tentatively observed in such conditions [29]. In aerobic steady states the reaction is thought to involve the cycle of intermediates in the centre of the figure (dark frames). The irreversible step is probably the conversion of g = 6 (see Refs. 98, 133) to peroxy .

Although the molecular basis for the 2e"/2H+ concerted step performed by cytochrome c3, as well as its implication in the energy generation mechanism, has not been unequivocally demonstrated, we can now propose a mechanism... 

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