BIOSYNTHESIS OF CHOLESTEROL 385 



isoprenoid units are believed to condense to form squalene, which there- 

 after cyclizes to the steroidal ring system. The existence of this pathway 

 is deduced from the following considerations: If the isoprene units were 

 condensed as such, there would be only six C'* atoms in a cholesterol (car- 

 bons 4, 8, 10, 14, 20, and 25) formed from a tertiary -labeled isoprenoid 

 unit. The specific activity of each of these carbons would be 4.5 times that 

 of the whole molecule (27/6). On the other hand, if the branched -chain 

 acids were utilized for cholesterol synthesis only after conversion to acetate, 



Fig. 1. The postulated distribution of C'^ (#) in squalene (or steroid) derived from 

 isoprenoid precursors labeled at the tertiar}- carbon atom.^^ 



then the labeling pattern would be similar to that noted when carboxyl- 

 labeled acetate was the intermediate. Under these conditions, twelve car- 

 bons would be labeled, and each labeled carbon would have a specific ac- 

 tivity 2.25 times that of the whole molecule (27/12). 



The data of Bloch et air"* support the first of these two possibilities. 

 Thus, the specific acti^'ities of C25 obtained after feeding the three branched- 

 chain acids (3-C^''-/3-hydroxj^-,S-methylglutarate, 3-C^^-/3-hydroxyisovaler- 

 ate, 3-C^^-/3-dimethylacrylate) were 3.85, 4.1, and 3.6 times greater than 

 that of the whole molecule; this contrasts with a specific activity of 1.57 

 reported-''* by Cornforth et al."'^^ for C25 when the cholesterol was formed 

 from l-C'*-acetate.^^^ In the case of Cio, the specific activity of the carbon 

 derived from methylacrylate was 444, as contrasted "s\ath a figure of 228 

 reported when the cholesterol was condensed from l-C'^-acetate.-"*-*'^ 

 These data strongly support the hypothesis that only six of the twenty- 

 seven atoms in cholesterol are labeled when the 3-C^*-branched-chain acids 



«>3 J. W. Cornforth, G. D. Hunter, and G. Popjdk, Biochem. J., 54, 597-601 (1953). 



