Acyl-CoA's as Substrates or Competitive Inhibitors of Histone Deacetylases; Acyl-CoA's as Adenosine-Nucleotide Mimetics

This article [Kasantsev and Thompson, 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18827828)] is interesting, and the authors classify valproic acid (VPA) and sodium butyrate (SB) as "hydroxamate-based" histone deacetylase inhibitors. But SB, VPA, and 4-phenylbutyrate don't have hydroxamate moieties, which are groups in which a carbonyl carbon is bonded to some unspecified group and also to the nitrogen of a hydroxylamine group. And I think 4-phenylbutyrate is metabolized into phenylpyruvate rapidly. The authors say that the hydroxamate moieties of the other drugs that are grouped with SB and VPA bind to an active-site zinc atom on histone deacetylase enzymes. I don't doubt that that's true for those other drugs shown, but VPA and SB only have a carbonyl group in common with those other drugs. That's not a very specific feature (having a carbonyl group).

There are very few articles that even mention butyryl-CoA and histones in the same article, and that tells me that the possibility for the butyrylation or valproylation of histones hasn't really been widely recognized. It's possible that valproyl-CoA and butyryl-CoA just bind to the active sites of HDAC's, produce competitive inhibition, and don't serve as substrates. In any case, histone deacetylase inhibition seems unlikely, in my opinion, to be a major mechanism for the effects of low doses of sodium butyrate. I think it will mainly be ketogenic and be oxidized in the liver and other cell types, but that's just my opinion.

It's interesting that the authors of a review article [Vamecq et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15713528)] on the ketogenic diet suggested that the adenosyl moiety of coenzyme A, in different acyl-CoA's, may mediate some of the effects of acyl-CoA's (whose concentrations increase in the brain, along with ketones, in people who are following the ketogenic (80 percent fat) diet for refractory epilepsy or some other condition) on different types of potassium channels. They basically were saying that some acyl-CoA's could bind to potassium channels by binding to the ATP binding sites. That type of mechanism could also conceivably account for the HDAC inhibition or other effects of some of these short-chain acyl-CoA's, such as butyryl-CoA. If CoA had been named "pantetheinyl-phosphoadenosine," or something along those lines, instead of "coenzyme A," then maybe someone would have mentioned that possibility long ago. Before I read that article, I'd never seen anyone mention the purine moiety of coenzyme A as being potentially important for the toxic effects or regulatory effects of acyl-CoA's (and the possibility had never occurred to me, either).