Catalytic cycle, of cytochrome

N—Fe(IV)Por complexes. Oxo iron(IV) porphyrin cation radical complexes, [O—Fe(IV)Por ], are important intermediates in oxygen atom transfer reactions. Compound I of the enzymes catalase and peroxidase have this formulation, as does the active intermediate in the catalytic cycle of cytochrome P Q. Similar intermediates are invoked in the extensively investigated hydroxylations and epoxidations of hydrocarbon substrates cataly2ed by iron porphyrins in the presence of such oxidizing agents as iodosylbenzene, NaOCl, peroxides, and air. 

Scheme 10.4 The catalytic cycle of cytochrome P450. Only one possible valence structure of the oxoferrous species IV has been depicted for clarity. See text for details.

Figure 2.5 Catalytic cycle of cytochrome P450 including postulated structures of putative intermediates. RH represents the substrate and R(0)H the product. The porphyrin ring is abbreviated as a parallogram with nitrogens at the comers. Adapted with permission from Sato et ah, 1996. Copyright (1996) American Chemical Society.

Fig. 5. Catalytic cycle of cytochrome P450. The substrate HR binds to the resting enzyme A to form intermediate B, which is reduced by one electron to form C and then reacts with dioxygen. The resulting ferric-peroxo intermediate D is reduced by one equivalent to form the transient oxyferrous intermediate E, which proceeds quickly to intermediate F with release of a molecule of water. F is designated Fe(V)=0 to indicate that it is oxidized by two equivalents greater than A and not to imply anything about the true oxidation state of the iron. Intermediate F then transfers an oxygen atom to the substrate to regenerate the resting enzyme. The peroxide shunt refers to the reaction of B with hydrogen peroxide to produce the intermediate F, which can then proceed to product formation.

In step (1) of the catalytic cycle of Cytochrome P450 the substrate is bound, at or near the iron atom, and... 

Figure 18-11 Possible catalytic cycle of cytochrome c oxidase at the cytochrome a3 - CuB site. The fully oxidized enzyme (O left center) receives four electrons consecutively from the cyt c —> CuA —> cyt a chain. In steps a and b both heme a and CuB, as well as the CuA center and cyt a3/ are reduced to give the fully reduced enzyme (R). In the very fast step c the cyt a3 heme becomes oxygenated and in step d is converted to a peroxide with oxidation of both the Fe and Cu. Intermediate P was formerly thought to be a peroxide but is now thought to contain ferryl iron and an organic radical. This radical is reduced by the third electron in step/ to give the ferryl form F, with Cu2+ participating in the oxidation. The fourth electron reduces CuB again (step g) allowing reduction to the hydroxy form H in step h. Protonation to form H20 (step ) completes the cycle which utilizes 4 e + 4 H+ + 02 to form 2 H20. Not shown is the additional pumping of 4 H+ across the membrane from the matrix to the intermembrane space.

In conclusion it looks as if the reactive oxo-iron(IV) intermediate of the catalytic cycle of cytochrome P450 operates by different mechanisms depending on the structure and electronic nature of the unsaturated substrates. 

Oxometalloporphyrins were taken as models of intermediates in the catalytic cycle of cytochrome P-450 and peroxidases. The oxygen transfer from iodosyl aromatics to sulfides with metalloporphyrins Fe(III) or Mn(III) as catalysts is very clean, giving sulfoxides, The first examples of asymmetric oxidation of sulfides to sulfoxides with significant enantioselectivity were published in 1990 by Naruta et al, who used chiral twin coronet iron porphyrin 27 as the catalyst (Figure 6C.2) [79], This C2 symmetric complex efficiently catalyzed the oxidation... 

Though the investigation of photocatalytic oxygenations performed of the laboratory scale are often motivated by attempts to understand and mimic the catalytic cycle of cytochrome P450 (a natural catalyst of monooxygenation reactions), the results obtained [159, 253, 266] could be applied to industrial processes as well. 

Figure 7 Catalytic cycles of cytochrome P-450, involving either 02 and reduced nicotinamide-adenine dinucleotide phosphate (NADPH) or a single oxygen atom donor AO.

In cytochrome P-450, this reaction is avoided as NADPH has no access to the P-450 active site. Therefore, it is clear that the alternate, shortened catalytic cycle of cytochrome P-450 using an oxygen atom donor AO, instead of 02 and NADPH (Figure 7), is easier to mimic. 

In step (1) of the catalytic cycle of Cytochrome P450 the substrate is bound, at or near the iron atom, and in step (2) reduction is affected by another enzymatic system. In step (3) the (RH)Fell species binds an 02 molecule. In step (4) another one electron reduction occur to give an iron(III) peroxo complex. In step (5), this complex loses H20 to give the crucial high oxidation state (RH)FeIV=0. 

From Iron(III) Tetraarylporphyrins and Alkenes. N-alkyl porphyrins are formed via side reactions of the normal catalytic cycle of cytochromes P-450 with terminal alkenes or alkynes. N-alkylpor-phyrins formed from terminal alkenes (with model iron porphyrin catalysts under epoxidation conditions) usually have a covalent bond between the terminal carbon atom of the alkene and a pyrrole nitrogen. The double bond is oxidized selectively to an alcohol at the internal carbon. Mansuy (23) showed that, in isolated examples, terminal alkenes can form N-alkylated products in which the internal carbon is bound to the nitrogen and the terminal carbon is oxidized to the alcohol. Internal alkenes may also form N-alkyl porphyrins (24, 25). 

One motivation for the characterization of the above compounds has been to more fully understand the involvement of such higher valent manganese porphyrin complexes in model systems which imitate the catalytic activity of monooxygenase cytochrome P-450 and related enzymes. The catalytic cycle of cytochrome P-450 appears to involve the binding and reduction of molecular oxygen at a haem centre followed by the ultimate formation of a reactive iron oxo complex which is responsible for oxidation of the substrate. For example, cytochrome P-450 is able to catalyse alkane hydroxylation with great selectivity. 

Various porphyrin compounds such as NFevOEP are known.62 The i Fe=N) stretching frequency of 853 cm-1 is lower than that of the Cr and Mn analogues the nitrido Fev complex is stable only at very low temperature ( 30 K). It is widely accepted that one of the intermediate species in the catalytic cycle of cytochrome P-450 (see later) contains pentavalent iron. The reduction of an R3CFev moiety is an accepted part of the mechanism of dismutation of hydrogen peroxide to water and oxygen catalyzed by catalase. 

Figure 8.2 Generalized scheme showing the catalytic cycle of cytochrome P450 enzymes in monooxygenation reactions. Fe = iron atom in P450 heme. RH = substrate. ROH = product. b5 = cytochrome bs. ox and red indicate the reduced and (1 electron) oxidized states of the reductase involved in the electron transfer. See text for details. (From Guengerich, F.P., Client. Res. Toxicol. 14, 611, 2001. With permission.)...

Oxoiron(IV) tefraphenylchlorin complexes have been prepared as the first models of a reaction intermediate in the catalytic cycle of cytochrome d Optical absorption spectra show a characteristic red-shified band at 630 nm as observed in the oxoferryl intermediate of cytochrome d, and the proton NMR spectra of the N-Melm complex exhibit very small hyperfine shifts of the pyrrole protons, as is true for oxoferryl porphyrin complexes. The pyrroline protons of the saturated pyrrole ring show unusual splitting into upheld and downfield resonances. The N-Melm complex also shows normal Fe =0 stretching frequencies as compared to the corresponding oxoferryl porphyrin complexes. And finally, for iron porphycenes, both peroxo and ferryl intermediates have been detected by H NMR spectroscopy during the oxygenation of the Fe complexes. ... 

Figure 1 Catalytic cycle of cytochromes P450. Main path (1) through (7) is shown in bold arrows forming a circle. Uncoupling pathways are shown in dashed lines. Reproduced with permission from the American Chemical Society from Reference 2, p. 2257.

The catalytic cycle of cytochrome P-450, typical of monooxygenases, is presented in Figure 13.12 (Johnston, Ouellet, Podust, Ortiz de Montellano, 2011). This substrate hydroxylation reaction is mediated by the Compound I -like ferryl species formed during the catalytic turnover of P450 enzymes. The Fe(lV) haem iron... 

FIGURE 13.12 Catalytic cycle of cytochrome P450. The cytochrome P450 catalytic cycle with the compound 1-Uke ferryl species highlighted by a blue square. The haem is represented by the iron between two bars, which stand for the porphyrin framework. RH is a hydrocarbon substrate and ROH its alcohol product. (From Johnston et al, 2011. Copyright 2011, with permission from Elsevier.)... 

FIGURE 32.2 Catalytic cycle of cytochrome P450 associated with monooxygenase reactions. [Fe ] = ferricytochrome P450 hs = high spin Is = low spin [Fe ] = ferrocytochrome P450 Fpi = flavoprotein 1 = NADPH-cytochrome P450 reductase Fp2 = NADH-cytochrome 65 reductase cyt 65 = cytochrome 65 XH = substrate (modified from ). 

FIGURE 33.2 Catalytic cycle of cytochrome P450 (CYP) monooxygenase. 

J. T. Groves, Y. Watanabe, Reactive iron porphyrin derivatives related to the catalytic cycles of cytochrome P-450 and peroxidase. Studies of the mechanism of oxygen activation, ]. Am. Chem. Soc. no (1988) 8443. 

Figure 2-3. Catalytic cycle of cytochrome c oxidase. The figure depicts different states of the binuclear haem arCue centre (squares, see the text), and shows the reaction steps where an electron is transferred to the centre from cytochrome c via haem a. If tlie enzyme is deprived of an electron donor, the oxidised state Oh decays into a relaxed fonn O. The latter may be reduced back to state R with uptake of two substrate protons (not shown), but this is not coupled to proton translocation (blue arrows). Note that otherwise each electron transfer into the binuclear site is coupled to proton translocation, and to uptake of a substrate proton (not shown). Thus each blue arrow represents uptake of two protons from the A -side and release of one proton to the P-side of the membrane (see also Fig. 2-1).

Figure 13.2. Catalytic cycle of cytochrome P450 associated with monooxygenase reactions. (Fe " ), ferricytochrome P450 hs, high spin Is, low spin (Fe " ), ferrocytochrome P450 Fpi, flavoprotein 1-NAJDPH-cytochrome P450 reductase Fpg, NADH-cytochrome bg reductase cyt b cytochrome b, XH, substrate (modified from Ref 6).

Figure 16.1-4. The catalytic cycle of cytochrome P450 enzymes.

Figure 19 Proposed general catalytic cycle of cytochrome P-450s (reactions (1)-(3) are abortive). Adapted from I. G. Denisov T. M. Makris S. G. Sligar I. Schlichting, Chem. Rev. 2005, 105, 2253-2277.

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