Cytochrome proposed mechanism

FIGURE 2.4 Proposed mechanism for monooxygenation by cytochrome P450. 

Only three steps of the proposed mechanism (Fig. 18.20) could not be carried out individually under stoichiometric conditions. At pH 7 and the potential-dependent part of the catalytic wave (>150 mV vs. NHE), the —30 mV/pH dependence of the turnover frequency was observed for both Ee/Cu and Cu-free (Fe-only) forms of catalysts 2, and therefore it requires two reversible electron transfer steps prior to the turnover-determining step (TDS) and one proton transfer step either prior to the TDS or as the TDS. Under these conditions, the resting state of the catalyst was determined to be ferric-aqua/Cu which was in a rapid equilibrium with the fully reduced ferrous-aqua/Cu form (the Fe - and potentials were measured to be within < 20 mV of each other, as they are in cytochrome c oxidase, resulting in a two-electron redox equilibrium). This first redox equilibrium is biased toward the catalytically inactive fully oxidized state at potentials >0.1 V, and therefore it controls the molar fraction of the catalytically active metalloporphyrin. The fully reduced ferrous-aqua/Cu form is also in a rapid equilibrium with the catalytically active 5-coordinate ferrous porphyrin. As a result of these two equilibria, at 150 mV (vs. NHE), only <0.1%... 

Our proposed mechanism is outlined in Figure 6, with a tentative assumption that once the acyl chains of cardiolipin are peroxidized, their hydrophobicity will diminish and a resulting conformational change cannot be accommodated within the cavity between the heme plane and the iimer surface of cytochrome c. 

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

Reed J. R., Quilici D. R., Blomquist G. J. and Reitz R. C. (1995) Proposed mechanism for the cytochrome P450 catalyzed conversion of aldehyde to hydrocarbon in the house fly, Musca domestica. Biochemistry 34, 16221-16227. 

Figure 6. Proposed mechanism underlying a cytosolic release of cytochrome c from mitochondrial inner membrane during apoptosis induced by reactive oxygen species.

C. Proposed Mechanisms of Proton Pumping by Cytochrome c Oxidase... 384... 

Scheme 7 Proposed mechanism for the activation of O2 for the monooxygenation of substrates (RH) by cytochrome P-450...

Sulfite oxidase contains an oxo-molybdenum center and a 6-type cytochrome. The proposed catalytic sequence (254-256) for the enzyme is shown in Fig. 16. Oxidation of sulfite to sulfate, a two-electron process, occurs at the molybdenum center with concomitant reduction of the molybdenum from VI to IV. Electrons are removed from the enzyme by interactions of the heme of the 6-type cytochrome with exogenous cytochrome c, a one-electron process. Thus, the proposed mechanism of Fig. 16 involves two separate intramolecular electron transfers be-... 

A 77-year-old woman taking verapamil and propranolol for hypertrophic cardiomyopathy and paroxysmal atrial fibrillation developed symptomatic bradycardia on two separate occasions within days of taking either erythromycin or clarithromycin. The proposed mechanism of the interaction was inhibition of cytochrome P450, since verapamil is a substrate of an isoenzyme that is inhibited by some macrolides (180,181). 

The proposed mechanism of NO release is shown in Scheme 1. Molsidomine (31) is converted to SIN-1 (32) by the action of liver esterases. SIN-1 (32) undergoes oxidation in the presence of oxygen or, in vivo, possibly by redox enzyme such as cytochrome c or by ferric myoglobin to release NO through a radical cation. 

The proposed mechanism [1317,1637,1846] for CO biotransformation by the haem system and cytochrome P-450 (porH = TPPHj or cytochrome P-450 RH, R H = 1,2- hydroxybenzene or nucleophilic groups of microsomal proteins. 

Scheme 4-8 Proposed mechanism for the HOOH/cytochrome-c reaction cycle of cytochrome-c peroxidase...

Scheme 6-4 Proposed mechanism for O2 reduction via cytochrome c oxidase (Cu lheme 03)...

Several cases of hepatotoxicity associated with chaparral use have been described (see Section 16.5). The mechanism of chaparral-associated hepatotoxicity is unknown. It is not known if chaparral is an intrinsic hepatotoxin (i.e., toxic to everyone if the dose is sufficient) or an idiosyncratic hepatotoxin (i.e., toxic only to those who have certain genetically aberrant metabolic pathways or immune system defects). Proposed mechanisms of chaparral-associated hepatotoxicity include (1) inhibition of cyclooxygenase or cytochrome P-450, (2) an immune-mediated reaction, (3) formation of a toxic metabolite, (4) impairment of liver function by phytoestrogens found in chaparral, and (5) cholestatic mechanisms causing impairment of bile formation or excretion. There is likely overlap between the two categories and the various mechanisms. In addition, toxicity may be influenced by age, weight, nutritional status, exposure to other drugs and chemicals, cumulative dose, and preparation (i.e., tea, dried plant parts, etc.) (Sheikh et al., 1997). 

Enzyme inhibition is also a proposed mechanism of chaparral-induced hepatotoxicity (Sheikh et al., 1997). NDGA inhibits cytochrome P-450 activity in rat epidermal and hepatic microsomes (Agarwal, 1991). 

Despite the considerable evidence supporting the foregoing proposed mechanism of cytochrome P450, there are also considerable conflicting data. Debate continues about the precise nature of the active oxidant and whether Scheme 18-1 accurately describes the reaction sequence. Unless it becomes possible to evaluate the invisible mechanistic steps directly by spectroscopy or structural studies, such debate will probably continue. 

The overall oxidation reactions catalyzed by cytochrome P450 and sMMO yield water as a byproduct, arising from double protonation of one of the oxygen atoms of O2. The two proposed mechanisms for sMMO differ with respect to the step during which water is released. Recent studies of the M. trichosporium 0B3b enzyme indicate that one proton is transferred in the Hperoxo and Q formation steps [59b]. Although this result has not yet been confirmed for sMMO from M. capsu-latus (Bath), these data are most consistent with the mechanism in Scheme 18-4. 

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