More on Protein Carboxymethyltransferases

The article on PP2A methylation (I referred to it in a posting yesterday) is interesting. One thing the researchers found was that the SAM-e/SAH ratio in the striatum was insensitive to folate repletion and was still decreased. This didn't increase tau phosphorylation in the striatum, though, because, as the researchers discussed, the Balpha subunit of PP2A was being expressed at a high level in the striatum. The other main point of that article is that Balpha or PP2A overexpression, more broadly, can overcome a lack of PP2A methylation (produced by something like folate depletion).

I read a little bit on protein carboxymethyltransferase enzymes, and this article shows that PCMT enzymes can be either membrane-bound or soluble (the soluble PCMT enzymes exert their activity in the cytosol). This article also shows that the protein content of some PCMT isoforms is high in the brain:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1135729

It sounds like the substrate-specificity may be broad and that the same enzymes can methylate D-aspartyl residues or L-isoaspartyl residues or other residues, but I'm not sure about that. Those "residues" are actually sites at which asparagine residues have become spontaneously deamidated or undergone some other reaction to produce an inversion at a chiral carbon atom and produce D-aspartyl residues. I actually haven't read about the nomenclature and chemistry, but here's an article that shows some of it:(http://www.jstage.jst.go.jp/article/bpb/28/9/1585/_pdf). That article talks about the vulnerability of alpha-crystallin proteins, in the lens of the eye, to those spontaneous changes. I don't know if PCMTs are abundant enough, in the cells of the lens, to meaningfully repair the "damaged" proteins.

Another big action of PCMT enzymes is to methylate isoprenylated carboxyl terminals of proteins. I think this is one area in which research on folic acid and homocysteine overlaps with some of the effects of statins. This article shows that adenosine and homocysteine, by their effect of increasing S-adenosylhomocysteine levels, reduced the methylation of p21ras and thereby reduced the normal, mitogen-activated, p21ras- and ERK 1/2-mediated growth of endothelial cells. It's one mechanism of homocysteine atherogenicity:

http://www.jbc.org/cgi/content/full/272/40/25380
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/9312159?dopt=Abstract)

That's actually a good type of article because it shows the metabolic effects of elevated homocysteine (decreasing the hydrolysis of S-adenosylhomocysteine, which then inhibits the PCMT and other methyltransferase enzymes), as opposed to the less-physiologically-relevant, direct, toxic effects of homocysteine. I haven't read very much of it, but there's a lot of research on the protein targets and cellular effects of isoprenylcysteine carboxymethyltransferases.