Two-Electron Oxidation of Ferric Heme to "Perferryl" Heme: Cleavage of the Dioxygen Bond is Normally Heterolytic in Protic Solvents, for God's Sake

I'm basically putting these up for my own benefit and to see if it's possible to see them on Google's "2-inch-wide" blog space. It helps me to keep track of the "bookkeeping" of the electron distributions and formal charges to do this, even though perferryl heme has a net charge of 0, as far as I can tell, in the physiological pH range (and even though this is unlikely to be of interest to anyone). This type of thing is more like "meditation" than anything else, and doing it lets me use the obnoxious drawing program. The wireless is down, and, as a result, I'm "grounded" in nerd tasks.

The mechanism for the formation of perferryl heme {a.k.a. "Compound I," an intermediate that forms during the enzymatic cycling of ferryl and ferric heme, in peroxidase and catalase enzymes and in cytochrome P450-containing enzymes, and that also forms during the ferric-ferryl cycling of heme in aqueous solutions of non-protein-bound, monomeric or dimeric heme [initially as hemin (chloro-coordinated heme) & hematin (hydroxo-coordinated Fe(III), etc.)]} is my adaptation (meaning a "loser" electron-bookkeeping venture that makes sense) of the intramolecular mechanism proposed by Schaefer et al. (1985) [Schaefer et al., 1985: (http://www.ncbi.nlm.nih.gov/pubmed/3927975)] for the formation of a glycol, as an intermediate species in the degradation of heme to "oligopyrroles" and maleimides, and a cation radical (such that the electron density is "localized," in the porphyrin radical that's delocalized across the entire ring system, primarily on the meso carbons and pyrollic nitrogens, as it's supposed to be [La Mar et al., 1981: (http://www.jbc.org/cgi/reprint/256/1/237.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/7451437)]) and the mechanisms proposed by Ozaki et al. (2001) [Ozaki et al., 2001: (http://pubs.acs.org/doi/abs/10.1021/ar9502590)]. Perferryl heme, or Fe(V)-heme, is actually Fe(IV)-heme with a porphyrin radical, and researchers don't use consistent forms of notation in their descriptions of it as being either a pentavalent species or a tetravalent species with a pi-cation radical on the porphyrin ring. It's tetravalent, though, and it's almost impossible for me to make sense of the reactions without doing some electron bookkeeping and getting a crude understanding of the electron distribution in the different species.

I've shown a way of viewing the formation of the porphyrin radical that helps me understand the electron donation. One electron of the iron-oxygen "double bond," which is really a mess of complex d(pi)-p(pi) interactions and d(pi)-p*(pi), or whatever, backbonding interactions (it's basically intramolecular hyperconjugation that they're talking about, as far as I can tell), comes from iron, and one comes from the porphyrin ring, from a bookkeeping standpoint. The bond order is larger than 2 for the ferryl (it's analogous to a "carbonyl," C=O, group) oxygen-iron bond. In any case, it's a two-electron oxidation of iron and of the porphyrin ring, as a whole, from a formal-charge-sort-of oxidation state of Fe(3+) to Fe(5+), even though the heme iron is hexacoordinated or maybe pentacoordinated in the physiological pH range and is likely to be neutral, except in the "crypto-" protonated ferryl and perferryl heme species, in which the net charge is +1 [Carlsen et al., 2005: (http://cat.inist.fr/?aModele=afficheN&cpsidt=16551176)]. The site(s) of protonation are unknown but are near the heme iron in an unidentified location (Carlsen et al., 2005) [maybe on the nitrogens and the oxygen, rapidly exchanged by proton transfers in perferryl heme (a.k.a. compound I)? (http://scholar.google.com/scholar?hl=en&q=%22proton+transfer%22+nitrogen+pyrrolic+heme+cation+radical&as_ylo=&as_vis=0)]. I say the oxygen because there's evidence that the ferryl oxygen can be protonated at physiological pH values in some chloroperoxidase enzymes [Newcomb et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18174331)]. Damn, that's exciting--"basic ferryl groups" (Newcomb et al., 2008, p. 8179) on some heme-containing enzymes. But one way of looking at the internal electron transfer that forms perferryl heme, as shown in Figure 11 of Schaefer et al. (1985) and Figure 1 of Pan et al. (2006) [Pan et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16500709)], is to view pentavalent heme as being an "intermediate" or resonance form that doesn't really exist as a distinct species or that involves an abstraction, in another step that doesn't really work that way, of a second electron from the porphyrin ring.

I've shown the heterolytic cleavage of the dioxygen bond of an organic hydroperoxide (RO-OH of ROOH), and the upshot of a lot of articles is that the cleavage of that bond is heterolytic and not homolytic, under most conditions (except in the presence of micellar aggregates, to some extent). But lipid hydroperoxides (LOOH) and other ROOH compounds can still be oxidized by ferryl heme species to form radical products (Traylor et al., 1993: (http://pubs.acs.org/doi/abs/10.1021/ja00060a027)]. I'm showing the oxidation of ferric heme (to perferryl heme) by an ROOH species (this includes hydrogen peroxide, or HOOH). I'm too tired to upload my proposed mechanism for the transfer of a cation radical from the porphyrin ring to a tyrosine residue, to form a tyrosyl phenoxyl radical. Why not save some fun for another day.

Here's the initial step, showing the oxidation of ferric heme by an organic hydroperoxide or hydrogen peroxide, and the participation of or "catalysis" by a generic base, B(-):

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