Note on Lysine pKa's and Potential Crosslinking Mechanisms, With Reference to B6 Neurotoxicity

I was going to note that a "high pKa" lysine residue would be more likely to be deprotonated at physiological pH than a low-pKa one, and I wanted to correct that, in reference to the posting I made yesterday on the potential for pyridoxal-derived Schiff bases to participate in the formation of crosslinks within or between proteins. I did most of this stuff in April, and I was also thinking of these other articles that describe the "pH gating" of lysine residues near the active sites of proteins. In the pH gating phenomenon, the pKa's of some lysine residues can shift in response to changes in the conformations of proteins or the like. I should say that the issue of lysine residues as being mediators of electrostatic protein-protein interactions, such as in histone proteins, has been a persistent point of confusion and complexity in the literature (http://scholar.google.com/scholar?q=histone+lysine+cationic&hl=en&btnG=Search&as_sdt=100000001) and in some textbooks, also. It's very complex and becomes confusing when one attempts to make generalizations. I remember becoming confused in looking at the notes in one of my classes, in which there was an attempt to make a "bottom-line" generalization about the interaction of "negatively-charged phosphate backbones" of DNA with cationic lysine residues of histone proteins, and there was some serious problem with the generalization. I'm not sure that it's even the case that the nucleophilicity of lysine residues increases in some kind of linear manner, with increasing pKa values. Also, in the reversible inhibition of some RNA polymerase enzymes by pyridoxal 5'-phosphate (PLP), for example, low-pKa lysine residues are the ones that form Schiff bases with PLP [Bull et al., 1975: (http://www.ncbi.nlm.nih.gov/pubmed/237508)] and thereby mediate the inhibition of the enzymes. It's worth noting that the formation of pyridoxal-containing Schiff bases does not necessarily guarantee that the pyridoxal moiety will be irreversibly bound to the protein, but the formation of pyridoxal-containing Schiff bases is apparently kinetically-favorable. Anyway, here's an example of the type of crosslink, resulting from a nucleophilic attack, by a nucleophilic serine residue, on the carbon of a pyridoxal-containing Schiff base [see Weng and Leussing, 1983: (http://pubs.acs.org/doi/abs/10.1021/ja00350a056); Hedstrom, 2002: (http://pubs.acs.org/doi/abs/10.1021/cr000033x)]. I'm not sure if this could be called a transimination reaction. I think it's only a transimination if an amine nitrogen attacks the Schiff-base carbon.