Histone Butyrylation and Propionylation by Histone Acetyltransferases; Histone Debutyrylation and Depropionylation by Histone Deacetylases

This is a really interesting article [Leemhuis et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18247445)], and it's the first article I've seen that actually sheds some light on the mechanism by which butyrate and its derivatives could produce histone deacetylase inhibition. The authors found that the P/CAF enzyme [P/CAF stands for CBP-associated factor, CBP stands for CREB binding protein, and CREB stands for cyclic adenosine 5'-monophosphate (cAMP) response element binding protein; hence, P/CAF is cAMP response element binding protein binding protein-associated factor: Soutoglou et al., 2001: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=125231)(http://www.ncbi.nlm.nih.gov/pubmed/11296231)], a human histone acetyltransferase enzyme, can catalyze the propionylation or butyrylation of the Lys14 residue of the histone H3 protein, using propionyl-CoA or butyryl-CoA, respectively, as substrates. The authors also note that the SIRT2 and SIRT3 histone deacetylase enzymes, which are class I sirtuins, can catalyze histone depropionylation reactions. The authors found that the butyrylation of H3 histones occurred less readily than the propionylation of the H3 histones. Also, the P/CAF enzyme didn't exhibit acyltransferase activity when malonyl-CoA, methylmalonyl-CoA, isovaleryl-CoA, or hexanoyl-CoA were provided as substrates.

It sounds like increases in the percentages of butyrylated histone proteins, in response to sodium butyrate (at, for example, high but not low concentrations), could render those butyrylated histones resistant to deacylation by histone deacetylases. That could be a mechanism for their histone deacetylase inhibition. Who knows, though. It looks like there's some evidence that SIRT2 and SIRT3 can catalyze the debutyrylation of histones (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=histone+debutyrylation+OR+%22butyryl+transferase%22+OR+butyrylation+OR+butyryltransferase). The histone propionylation might be important for understanding some of these genetic disorders (such as for understanding mitochondrial DNA depletion in methylmalonic aciduria, in which propionyl-CoA accumulates), but that process also could be important for understanding vitamin B12 deficiency and the mechanisms underlying all of the pathologies associated with vitamin B12 deficiency (hematological and central-nervous-system-related). Propionyl-CoA also can accumulate intracellularly as a result of biotin deficiency. That's a really important series of articles. That could be a really important mechanism for understanding mitochondrial dysfunction, because acyl-CoA's accumulate in all sorts of disorders. If other histone acetyltransferases can utilize methylmalonyl-CoA or other organic acyl-CoAs as substrates, that would be interesting, too. But it's noteworthy that propionyl-CoA is maybe the most or at least among the most highly toxic of the acyl-CoAs. One reason for that might be its capacity to serve as a good substrate for histone acetyltransferase enzymes, such as P/CAF. It's hard to know, though, because it looks like a lot of different deacetylases can debutyrylate histones. But maybe the butyryllysine residues are poor substrates for those deacetylases.

Butyrate is converted to butyryl-CoA by one or more short chain acyl-CoA synthetase enzymes that display butyryl-CoA synthetase activity [Cremin et al., 2003: (http://ajpgi.physiology.org/cgi/content/full/285/1/G105)(http://www.ncbi.nlm.nih.gov/pubmed/12637251?dopt=Abstract)]. Another possibility is that some transcription factor or other non-histone protein is butyrylated by an acyltransferase enzyme that can use butyryl-CoA as a substrate, and the butyrylated protein might then influence the activity of one or more histone deacetylase enzymes [some hastily-chosen info. on protein acylation: Ozawa et al., 2009: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2672172)]. That type of mechanism could account for the effects of HMB (3-hydroxyisovalerate), which is converted into 3-hydroxyisovaleryl-CoA and could then serve as a substrate for the 3-hydroxyisovalerylation of transcription factors, etc. (or it could be that HMG-CoA serves as a substrate for enzymes with histone or non-histone protein acyltransferase activities).