The tracing of the pathway of mevalonate's metabolism to other than sterols.

Specifically 14C-labeled mevalonic acids were administered to rats in diabetic ketosis, and the distribution of 14C was determined in the hydroxybutyric acid each rat excreted. Also, the distributions of 14C were determined in hydroxybutyric acid formed by slices of livers and kidneys from rats in diabetic ketosis and incubated with the specifically labeled mevalonic acids. The distributions found are in accord with the conversion of mevalonate to hydroxymethylglutaryl-CoA by the shunt pathway proposed by J. Edmond and G. Popják ((1974) J. Biol. Chem. 249, 66-71). That is, carbon 5 of mevalonate was metabolized to form the carboxyl of acetyl-CoA and carbons 2 and 3 of mevalonate were converted in large measure to hydroxybutyric acid without acetyl-CoA as an intermediate, i.e. the bond between carbon 2 and 3 was not cleaved, while the bond between 1 and 2, traced with [1,2-14C]mevalonate, was cleaved. Similar distributions of 14C were found in hydroxybutyric acid excreted by rats in diabetic ketosis administered specifically 14C-labeled isovaleric acids, isovaleric acid having in its metabolism intermediates common to those in the shunt pathway.