Electrophilicity of the Oxene Oxygen of Tetravalent Hemes; Proton-Coupled Electron Transfer Mechanisms in Heme Reduction Reactions

These are some articles about, among other things, proton-coupled electron transport in hydrogen abstraction/hydrogen transfer reactions [Cheng and Li, 2007: (http://pubs.acs.org/doi/abs/10.1021/cr040077w); Sligar et al., 1980: (http://www.pnas.org/content/77/3/1240.full.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/6929480); Guallar et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12771375)(http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=165819); Stubbe et al., 2003: (http://pubs.acs.org/doi/abs/10.1021/cr020421u); Reece et al., 2006: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1647304)(http://www.ncbi.nlm.nih.gov/pubmed/16873123); Sutcliffe et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10973049)]. One of the reasons the articles on the cycling of ferryl and perferrryl and ferric heme are confusing is that the iron-oxygen "double" bond is depicted in a manner that makes the polarity of the bond appear to be similar to the polarity of a carbonyl C=O double bond. In fact, the oxygen can be treated as if it has a formal charge of +2, given that the oxygen, in the p(pi)-d(pi) overlap of the oxygen's pi orbitals with the d(xy) and d(yz) orbitals of iron (and also with a mess of empty or half-filled antibonding d-orbitals or hybrid orbitals of iron), only winds up, effectively, with six valence electrons (Sligar et al., 1980). The oxygen has the electron configuration of an oxene oxygen, which is "atomic oxygen." That's the number of electrons that "atomic oxygen" has, in its ground-state electron configuration. The +2 is the formal charge and is calculated [6-(1/2(4))-2] in the same way any other formal charge calculation is calculated [(ground state valence electrons) - 1/2(shared) - (unshared)], even though the reality is that it's a mess of d-orbitals and all of that and is probably 8/3rds or something crazy like that. I think another example of an "oxene" compound is that short-lived, unsaturated ethylene epoxide compound (an unsaturated, three-membered oxirane). I'm not sure of another good example of a true oxene-like compound, but it's really unusual. It means that the Fe=O bond polarity (in ferryl and perferryl hemes) is reversed, in comparison to the polarity of a C=O bond. The oxygen is electrophilic (electron-deficient), and I've drawn it as such in these "electrophilic loser" diagrams. But anyway, that's helpful to me. Many articles describe the iron-oxo moieties of perferryl and ferryl heme as being something like [Por-Fe(4+)=O(2-)]2+, but a better way to abbreviate the structure might be to write something like this: [Por-Fe=O(+)(+)]2+. It's really necessary to know that oxygen has, effectively, six valence electrons.

Anyway, it's interesting that the hydrogen abstraction reactions, such as the one shown below, are thought to be more like proton-coupled/proton-assisted electron transfer reactions than they are like run-of-the-mill homolytic cleavage reactions. I've shown the reduction of ferryl heme by an unsaturated lipid, to form an alkyl radical, and that can then rearrange and react with molecular oxygen and then epoxidize or participate in other reactions that mediate lipid peroxidation. In proton-coupled electron transport, the electron essentially is transferred to the oxidant, which is the electrophilic oxene oxygen on ferryl or perferryl heme, and the hydrogen atom (with its one electron) may not be transferred at all but is transferred "after" the electron is transferred. Sutcliffe et al. (2000) discussed that concept in a more popular forum (the "Trends" journals) and discussed the way that's thought to be the underlying, core mechanism for enzyme catalysis, in the sense that electron tunneling or "quantum tunneling" allows the enzyme to go "through" the activation free-energy barrier through vibration-associated electron tunneling. The electron can be transferred from one residue to another through the protein's single bonds, in effect, or via proton transfers, etc. The math describes or models enzyme catalysis in terms of quantum mechanical vibrational energy of different parts of the enzyme (http://scholar.google.com/scholar?hl=en&q=enzyme+activation+energy+barrier+quantum+mechanical+vibrational&as_ylo=&as_vis=0), but it's as if the enzyme as a whole, instead of just the active site and other discrete sites, participates in the catalysis and "cheats" the activation energy barrier. Here are the initiation reactions for heme-dependent lipid peroxidation [Fe(IV)=O(2+) + LH--->L(e-) + Fe(III)-OH(+)]. I actually botched the product--it's supposed to contain an Fe-O "single bond," but I'm not going to change it:

This is a mechanism, discussed by Reece et al. (2006), by which the perferryl species can undergo reduction to ferric heme by a long-range, "hard-wired" (Reece et al., 2006, p. 1355) proton transfer mechanism. The cytochrome P450 enzyme creates a "water channel" that allows for proton-coupled electron transfer. I've drawn only the deprotonations (fast proton transfers), but the overall reaction is also a two-electron reduction of perferryl heme to ferric heme. There's probably some way to draw it, but I think the idea, as discussed by Guallar et al. (2003) in another proton-coupled-electron-transfer reduction of perferryl heme, is that the proton transfer allows the electrons to be donated through the hydrogen bonds between the carboxylate groups of the alkyl substituents of the heme species (I haven't shown them on the porphyrin ring) and amino acid residues that they form the hydrogen bonds with (I've shown hydrogen bonds, between water molecules, as being dotted lines, but I haven't shown the carboxylate-containing substituents of heme or the hydrogen bonds they can form with amino acid residues on proteins, etc.). So it's like oxygen donates two electrons in its protonation, and two electrons are tunneled through the enzyme and the porphyrin ring to heme. I've drawn the two-electron transfer as if it's coming from the oxygen to the iron, and maybe Reece et al. (2006) was saying that the electrons would be transfered through the water and not the enzyme. That could be the case in the CYP450 case (Reece et al., 2006), because the water molecules are essentially "locked in" as part of the enzyme. The overall idea is that electrons can be transferred through hydrogen bonds and allow for these mind-bending, catalytic mechanisms for electron donation, such as to heme species, in enzymes. The electrons "sweep" up through....No, that's a little joke:

This is the product: