Ketogenic Amino Acids and the Regulation of Cholesterol Biosynthesis

The authors of this article [Noda and Ichihara, 1976: (http://www.ncbi.nlm.nih.gov/pubmed/1002682)] discuss research showing that the oxidation of ketogenic amino acids to CO2 (under conditions in which they are completely oxidized), such as tyrosine and leucine, provides twice as much ATP as the oxidation of gluconeogenic amino acids. The authors refer to a book, as the cited reference for that statement, and so I'm not sure what they actually mean. I'm assuming they mean that the oxidation of the carbons of acetyl-CoA, derived from the oxidation of the ketones that contain the leucine or tyrosine carbons, in the tricarboxylic acid cycle can serve to generate twice as much net ATP as the oxidation of the amino-acid-derived carbons in glucose formed by gluconeogenesis from amino acids.

It's interesting that the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) is one of two enzymes that forms HMB, a lipogenic/ketogenic leucine metabolite discussed in previous postings, and is also a key enzyme involved in the oxidation of tyrosine to acetoacetate (ketone formation from tyrosine) [reference 65, p. 728, discussed in: Schofield and Zhang, 1999: (http://alpha.life.nthu.edu.tw/~d888206/Pdf%20papers/2-OXO.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/10607676)]. 4-HPPD is sometimes referred to, in articles about HMB, as "KIC dioxygenase," or alpha-ketoisocaproate (KIC) dioxygenase, but it's more appropriate to say that 4-HPPD has KIC dioxygenase activity, in addition to its usual role of catalyzing the formation of homogentisate, an intermediate in tyrosine catabolism, from 4-hydroxyphenylpyruvate (Schofield and Zhang, 1999). Looking at the factors regulating that enzyme might be a starting point for understanding the mechanisms by which exogenous HMB could reduce leucine catabolism slightly (an effect that has been shown to occur, recently, in an animal study) etc. HMB can also be formed from isovaleryl-CoA, as discussed previously, by crotonase, which is more commonly known as enoyl-CoA hydratase [Rodriguez et al., 2004: (http://www.jbc.org/cgi/content/full/279/6/4578)(http://www.ncbi.nlm.nih.gov/pubmed/14612443?dopt=Abstract)]. Rodriguez et al. (2004) also discuss the fact that HMG-CoA can be converted into various isoprenoids (geranyl-CoA, etc.), which are intermediates in cholesterol biosynthesis, and then recycled back into 3-methylcrotonyl-CoA and HMB-CoA, by the enzymes of the so-called "mevalonate shunt." The authors also mention Smith-Lemli-Opitz syndrome, which is a genetic disorder that causes pathologically low plasma cholesterol levels and psychiatric symptoms. The disorder prevents the conversion of delta7-dehydrocholesterol into cholesterol, because of loss-of-function mutations in 7-DHC reductase, and causes toxic cholesterol precursors to accumulate and cause brain damage, etc. (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=7-dehydrocholesterol+Smith+Lemli+Opitz). Rodriguez et al. (1999) also mention that plasma 3-methylglutaconic acid can increase in people who have that genetic disorder, and researchers could investigate the possibility that the accumulation of intermediates in cholesterol biosynthesis or in the mevalonate pathway contribute to psychiatric symptoms associated with low plasma cholesterol. If that were the case, one might expect HMB or increases in ketone availability from other ketone precursors (other ketogenic substrates, other than HMB) to transiently worsen psychiatric symptoms but ultimately increase cholesterol formation and improve psychiatric symptoms, given that the normalized pool of cholesterol would be able to exert feedback inhibition of HMG-CoA reductase activity and prevent the accumulation of the intermediates. But these are just my opinions and avenues of thought in this area.