Some Aspects of the Metabolism of Leucine and Valine*

Cholesterol, which is formed by biological synthesis, contains angular methyl groups and branched side chains. A few other tissue constituents exist which contain branched chains, notably valine and leucine, but these are all essential dietary constituents. It has been shown (1) that acetic acid participates in the synthesis of the entire structure of cholesterol, but no obvious mechanism is known by which acetic acid could react to form branched carbon chains. Our attempts to find specific cholesterol precursors other than acetic acid have been unsuccessful; in all instances in which the administration of a labeled test substance led to the formation of deuterio cholesterol, the effect has been attributable to the intermediary formation of deuterio acetic acid (2). Experiments were carried out to test the effect of deuterio valine and deuterio leucine on the biological formation of cholesterol. Cholesterol isolated from animals which had received deuterio leucine contained significant concentrations of isotope, but only normal cholesterol was formed when deuterio valine was the test substance. Of the two branched chain fatty acids which are likely to be degradation products of leucine and valine respectively, deuterio isovaleric acid gave an effect similar to that of leucine, whereas deuterio isobutyric acid, like valine, failed to produce isotopic cholesterol. The appearance of deuterium in’cholesterol following administration of deuterio leucine is evidence of the ability of leucine to supply carbon atoms for sterol synthesis, but provides no proof of a specific utilization of the isopropyl groups. Leucine is a ketogenic substance; i.e., a source of acetoacetic acid. Though it is recognized that in ketosis the acetone bodies can arise either as primary oxidation products or by recondensation of acetic acid, little is known as to the metabolism of acetoacetate or other ketogenic substances under normal conditions. In the preceding paper evidence is presented that extensive hydrolysis of acetoacetate to acet.ate can occur in normal animals. Intermediary formation of acetic acid may be detected by the appearance of deuterio acetyl groups in acetylamino acids. This