3-Methylcrotonyl-CoA Carboxylase Converts HMB-CoA into HMG-CoA: Relevance to the Supposed Role of HMB as a Ketogenic Substrate in the Brain and Liver

This article [Woessner et al., 1958: (http://www.jbc.org/cgi/reprint/233/2/520.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/13563531)] shows that biotin is required as a cofactor for the enzymatic conversion of HMB-CoA (which is also called beta-hydroxyisovaleryl-CoA or 3-hydroxyisovaleryl-CoA) into 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), which can then be converted into ketones or cholesterol or other fatty acids. This article [Knappe et al., 1961: (http://www.ncbi.nlm.nih.gov/pubmed/14457200)] provides evidence that the biotin-dependent enzyme is, in fact, 3-methylcrotonyl-CoA carboxylase (MCCC). That's one of the four biotin-dependent carboxylase enzymes. That's pretty important, and none of the articles on HMB has ever mentioned that the utilization of HMB for cholesterol biosynthesis requires the activity of a biotin-dependent enzyme. Some articles have mentioned that HMB accumulates during biotin deficiency or in people with genetic hypofunctionality of either biotinidase, which recycles biotin and is involved in the biotin-status-dependent upregulation of the expression of biotin-dependent enzymes (biotinidase has histone biotinyltransferase activity and can thereby catalyze the biotinylation of histones, and this allows for the regulation of gene expression in interesting ways, in response to changes in biotin status/availability), deficiency (genetic deficiency or hypofunctionality) or isolated MCCC deficiency, but none of the articles has said why HMB accumulates in those situations. One reason is that MCCC is the enzyme or at least one of the enzymes that converts HMB-CoA to HMG-CoA. The articles that show that (the ones I've cited) have only been cited 2 or 3 times in 50 years, and that tells me that very few people are even aware of the reason that HMB (3-hydroxyisovalerate) accumulates in these conditions of diminished MCCC activity.

HMB also accumulates in several other genetic disorders [beta-ketothiolase deficiency, propionyl-CoA carboxylase deficiency (another disorder producing hypofunctionality of another biotin-dependent enzyme), HMG-CoA lyase deficiency, etc.], and part of the reason for the confusion is probably that the carboxylation of 3-methylcrotonyl-CoA (MC-CoA) itself, by MCCC, also would be expected to decrease the formation of HMB-CoA, in the absence of exogenous HMB, by converting MCC into 3-methylglutaconyl-CoA [Wendel and de Baulny, 2006: (http://www.springerlink.com/content/gnk7414290467321/)]. So MC-CoA (a.k.a. beta-methylcrotonyl-CoA) can either be converted into HMB-CoA by the enzyme crotonase [shown in this cited reference as beta-hydroxyisovaleryl-CoA: Bachhawat et al., 1956: (http://www.jbc.org/cgi/reprint/219/2/539.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/13319276)] or into 3-methylglutaconyl-CoA, which can then also be converted into HMG-CoA by 3-methylglutaconyl-CoA hydratase (Wendel and de Baulny, 2006). This article on HMB as a nutritional supplement [Nissen and Abumrad, 1997: (http://linkinghub.elsevier.com/retrieve/pii/S095528639700048X)] identifies some of the enzymes but doesn't say, for example, that MCCC converts HMB-CoA to HMG-CoA. I think it's one of those situations in which no one does searches on HMB under its alternate names, such as 3-hydroxyisovalerate. Some of these articles, though, are a bit obscure.

These articles are important for the supposed metabolism of HMB into ketones, in astrocytes or meningeal fibroblasts, or into cholesterol in those and other cell types in the brain, etc. MCCC is expressed in many parts of the brain, and this would suggest, in my opinion, that HMB could easily be used for cholesterol formation in the brain or liver or any tissue that contains the enzymes of cholesterol biosynthesis (i.e. the skin) or for ketogenesis in the brain or liver, etc. HMB would have to be converted into a CoA thioester, obviously, but that clearly occurs readily.