Heme catalysis

Four-valent iron centers are well known as catalytic intermediates in enzymatic heme catalysis. The catalytic cycles of, for example, catalase, peroxidase, and cytochrome P450, all have in common an intermediate that is comprised of a ferryl Fe(lV) and a further oxidation equivalent located either on the heme ring or on the protein moiety. This reaction intermediate is called compound 1 (cpd 1) and has a system spin of 5 = 1/2 (e.g., in chloroperoxidase) or 5 = 3/2 (e.g.. 

Solomon El, Decker A, Lehnert N. Non-heme iron enzymes contrasts to heme catalysis. Proc. Natl. Acad. Sci. 2003 100 3589-3594. 

Application of data obtained from simple clean reaction systems in biological or chemical studies of heme catalysis also has its problems. Chemical model systems use chelators, model hemes, and substrate structures that are quite different from those existing in foods. Reaction sequences change with heme, substrate, solvent, and reaction conditions. Intermediates are often difficult to detect (141), and derivations of mechanisms by measuring products and product distributions downstream can lead to erroneous or incomplete conclusions. It is no surprise, then, that there remains considerable controversy over heme catalysis mechanisms. Furthermore, mechanisms determined in these defined model systems with reaction times of seconds to minutes may or may not be relevant to lipid oxidation being measured in the complex matrices of foods stored for days or weeks under conditions where phospholipids, fatty acid composition, heme state, and postmortem chemistry complicate the oxidation once it is started (142). Hence, the mechanisms outlined below should be viewed as guides rather than absolutes. More research should be focused on determining, by kinetic and product analyses, which reactions actually occur and are of practical importance in specific food systems. 

Current evidence indicates that hypervalent iron complexes—ferryl iron (FelV, Fe02, Fe(IV)=0) or perferryl iron (FeV)—are involved in the catalytic mechanism, but there is stiU controversy over the details of reaction mechanisms and what proportion of heme catalysis it accounts for. Very recently, some very elegant chemistry has elucidated binding and 0—0 bond scission mechanisms and identified heme structural elements critical for oxidation catalysis (143, 144). Paradoxically, although the early theories of heme catalysis have been largely dismissed, they nevertheless are consistent with aspects of hypervalent iron behavior. Ferryl iron chemistry encompasses and explains the most important features noted in early studies (99) ... 

D. B. Goodin, When an amide is more like histidine than imidazole The role of axial ligands in heme catalysis, ]. Biol. Inorg. Chem. 1 (1996) 360. 

During heme catalysis, a Fe + protoporphyrin complex (P-Fe +), like in myoglobin, will be oxidized by air to P-Fe + as indicated in Formula 3.66. The formed superoxide radical anion O2, whose properties are discussed... 

In order for the cyclooxygenase to function, a source of hydroperoxide (R—O—O—H) appears to be required. The hydroperoxide oxidizes a heme prosthetic group at the peroxidase active site of PGH synthase. This in turn leads to the oxidation of a tyrosine residue producing a tyrosine radical which is apparendy involved in the abstraction of the 13-pro-(5)-hydrogen of AA (25). The cyclooxygenase is inactivated during catalysis by the nonproductive breakdown of an active enzyme intermediate. This suicide inactivation occurs, on average, every 1400 catalytic turnovers. 

Ambient temperature catalysis of O2 reduction at low overpotentials is a challenge in development of conventional proton exchange membrane fuel cells (pol5mer electrolyte membrane fuel cells, PEMFCs) [Ralph and Hogarth, 2002]. In this chapter, we discuss two classes of enz5mes that catalyze the complete reduction of O2 to H2O multi-copper oxidases and heme iron-containing quinol oxidases. 

The simple porphyrin category includes macrocycles that are accessible synthetically in one or few steps and are often available commercially. In such metallopor-phyrins, one or both axial coordinahon sites of the metal are occupied by ligands whose identity is often unknown and cannot be controlled, which complicates mechanistic interpretation of the electrocatalytic results. Metal complexes of simple porphyrins and porphyrinoids (phthalocyanines, corroles, etc.) have been studied extensively as electrocatalysts for the ORR since the inihal report by Jasinsky on catalysis of O2 reduction in 25% KOH by Co phthalocyanine [Jasinsky, 1964]. Complexes of all hrst-row transition metals and many from the second and third rows have been examined for ORR catalysis. Of aU simple metalloporphyrins, Ir(OEP) (OEP = octaethylporphyrin Fig. 18.9) appears to be the best catalyst, but it has been little studied and its catalytic behavior appears to be quite distinct from that other metaUoporphyrins [CoUman et al., 1994]. Among the first-row transition metals, Fe and Co porphyrins appear to be most active, followed by Mn [Deronzier and Moutet, 2003] and Cr. Because of the importance of hemes in aerobic metabolism, the mechanism of ORR catalysis by Fe porphyrins is probably understood best among all metalloporphyrin catalysts. 

Although impressive progress has been made in unraveling the mechanism of ORR catalysis by cofacial porphyrins, much remains to be learned before we can understand how this mechanism relates to those in heme enzymes and simple metalloporphyrins and use our mechanistic knowledge to rationally design improved metalloporphyrin catalysts for the ORR. 

Based on the well-studied catalytic mechanism in series 2 metalloporphyrins (Fig. 18.20), further developments of the heme/imidazole motif in the context of fuel cell catalysis have to be directed towards the following ... 

I. M.C.M., Reversible formation of high-valent-iron-oxo prophyrin intermediates in heme-based catalysis revisiting the kinetic model for horseradish peroxidase, Inorg. Chim. Acta, 275/276, 98-105, 1998. 

It has the heme prosthetic group covalently bonded to protein cytochrome c does not lose its heme catalytic group in these systems, while peroxidases do (catalysis in organic solvents)... 

Torres, E. Baeza, A., and Vazquez-Duhalt, R., Chemical modification of heme group improves hemoglobin affinity for hydrophobic substrates in organic media. Journal of Molecular Catalysis, B-Enzymatic, 2002. 19 pp. 437—441. 

Zhou, Y., Hu, N., Zeng, Y. and Rusling, J.F. (2002) Heme protein-clay films Direct electrochemistry and electrochemical catalysis. Langmuir, 18, 211-219. 

Simultaneous generation of nitric oxide and superoxide by NO synthases results in the formation of peroxynitrite. As the reaction between these free radicals proceeds with a diffusion-controlled rate (Chapter 21), it is surprising that it is possible to detect experimentally both superoxide and NO during NO synthase catalysis. However, Pou et al. [147] pointed out that the reason is the fact that superoxide and nitric oxide are generated consecutively at the same heme iron site. Therefore, after superoxide production NO synthase must cycle twice before NO production. Correspondingly, there is enough time for superoxide to diffuse from the enzyme and react with other biomolecules. 

Studies in this laboratory (69) of the water soluble ferri-heme model Fem(TPPS) in aqueous solution have shown that this species also undergoes reductive nitrosylation in solutions that are moderately acidic (pH 4-6) (Eq. (32)). The rate of this reaction includes a buffer dependent term indicating that the reaction of the Fem(TPPS)(NO) complex with H20 is subject to general base catalysis. The reaction depicted in Eq. (33) is not observable at pH values < 3, since the half-cell reduction potential for the nitrite anion (Eq. (1)) is pH dependent, and Eq. (33) is no longer thermodynamically favorable. 

In the field of enzyme catalysis, heme-proteins such as cytochrome P450, for example, exhibit both types of 0-0 bond cleavages in organic hydroperoxides and peroxy acids (178). Heterolytic cleavage of HOOH/ROOH yields H20 or the corresponding alcohol, ROH and a ferryl-oxo intermediate (Scheme 4). Homolytic 0-0 bond cleavage results in the formation of a hydroxyl (HO ) or an alkoxyl (RO ) radical and an iron-bound hydroxyl radical. 

The Stamler group (Gow et al., 1999) then proposed that the estimated 1% of the 02-vacant hemes in the R-state could be the sites of S-NO catalysis. The implication of this was that NO would not be consumed (via Eq. (2)) since oxygen is absent from these sites. The evidence presented to support this hypothesis was mainly from EPR data on heme-Fe(II)-NO formation yields as a function of NO added to Hb that had varying saturations of 02. The EPR data indicated that in the T-state heme nitrosylation was competitive with heme oxidation (via Eq. (2)). However, in the R-state, at low 02 saturation (<20%), heme nitrosylation displayed cooperativity. 

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