Reductions of Ferryl Heme by Hydroperoxides; Reduction of Perferryl Heme via the Oxidation of a Tyrosine Residue; Heme-to-Protein Cross-Linking

It helps me to go through these reactions and to thereby avoid "having" to make use of these types of diagrams or equations in other contexts. If I can understand these things, I won't have to catalog equations, as so many articles do, or even discuss most of these things. One reason that many of the articles are so confusing is that hydrogen peroxide or an organic hydroperoxide (or a protein "substrate") can reduce ferryl hemes to ferric hemes or perferryl hemes to ferryl hemes. Those same compounds usually act as oxidants, however, and they also oxidize ferric heme to perferryl heme or ferrous to ferryl hemes. But anyway, the reduction of ferryl heme by HOOH (hydrogen peroxide) is more or less the same reaction as the reduction by an organic hydroperoxide, such as linoleate hydroperoxide or another lipid hydroperoxide. I'm not showing the reduction of perferryl to ferric heme, but that's the reaction that allows for the true "peroxidase" activity of non-protein-bound heme (or at least that's one way of looking at it). The products are O2, water, and ferric heme, even though there's a superoxo-Fe(III)-heme "intermediate." That's supposedly one reason some peroxidase enzymes can exert antioxidant effects at some low-to-intermediate concentrations. There's an intermediate range at which the peroxide-to-protein molar ratio allows for the consumption of hydrogen peroxide, by allowing the perferryl-to-ferric reduction pathway to predominate over the more damaging ferryl-to-ferric reduction pathway, but that doesn't usually work out too well in vivo, seemingly. The reaction I'm showing for the one-electron reduction of ferryl heme (one proposed by Traylor and Xu, 1987, cited below) by HOOH is similar, however, to that perferryl-to-ferric pathway. The reduction of ferryl to ferric heme is thought to produce a perhydroxyl species [Nagababu and Rifkind, 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15548894)] or a peroxyl radical, etc. (that's the reason it's more damaging, under some conditions, than the other reduction pathway). The mechanisms aren't known (Traylor et al., 1993, cited below). Anyway, some antioxidants are likely to act by very similar one-electron reduction mechanisms. These two are adapted from the mechanisms proposed by Traylor et al. (1993) [Traylor et al., 1993: (http://pubs.acs.org/doi/abs/10.1021/ja00060a027)] and other authors [Traylor and Xu, 1987: (http://pubs.acs.org/doi/abs/10.1021/ja00254a059); Schaefer et al., 1985: (http://www.ncbi.nlm.nih.gov/pubmed/3927975)] and show the one-electron reduction of ferryl heme by an organic hydroperoxide, yielding ferric heme and an alkoxyl radical [the ROO radical shown, where R = a lipid or protein or other substrate, such as some antioxidants (ROO could also be RNO in some cases, etc.)] and, below that, a "hack" mechanism for the one-electron reduction of ferryl heme (to ferric heme) by hydrogen peroxide.

This is an adaptation of the mechanism proposed by Chu et al. (2000) for the formation of a tyrosyl phenoxyl radical via the reduction of a copper(II)-amine complex [Chu et al., 2000: (http://pubs.acs.org/cgi-bin/jtext?jpcbfk/104/i15/abs/jp994487d)(http://www.chem.yorku.ca/profs/hopkin/87.pdf)].
This shows the oxidation of a tyrosine residue by perferryl heme, and the reaction transfers the porphyrin radical and the "cation" of perferryl heme, in effect, to two different amino acid residues of a protein. This is known to occur to some extent, and the radical is delocalized throughout many amino acid residues of the protein, etc.

This is a hypothetical, proposed "bookkeeping" mechanism and shows a two-electron reduction
of perferryl heme to ferric heme that forms an intramolecular glycol and a heme-protein cross-link on one of the bridgehead carbons, I guess one would say: