CHEMICAL STRUCTURE 



mechanism B shown in Figure 2 was therefore proposed (25). 

 It will be noted that this formulation incorporates some of the 

 features of the scheme suggested by Bryant (Figure 1) many 

 years ago, but it recognizes the fact that it cannot be carotene 

 which is the polyisoprenoid precursor. 



From the work of Cornforth and Popjak (10) the isotopic 

 composition of biosynthetic squalene is now known to conform 

 with the pattern expected for isoprene derivatives, and hence one 

 can more safely predict in which way the distribution pattern of 

 acetate carbon in the steroidal transformation product will be 

 altered by substituting one mechanism for the other. If 

 squalene were to cyclize according to B instead of A, the deriva- 

 tion of 4 of the 27 carbon atoms of cholesterol will be reversed, 

 methyl carbon atoms of acetate appearing now at C7 and C13 and 

 acetate carboxyl at Cg and Cio. Degradation experiments have 

 verified this prediction for C7 and C13 (3,11,25), and hence 

 scheme A is no longer tenable. The same results bear also 

 on the interesting suggestion made by Mondon (16) that the 

 aliphatic precursor of the steroids is not squalene, but an as yet 

 unknown isomeric hydrocarbon "isosqualene" (Fig. 2) in which 

 the irregular junction between two isoprene units is displaced 

 from the center of the molecule towards the end of the chain by 

 one isoprene unit. According to Mondon's hypothesis G13 of 

 cholesterol should be derived from a carboxyl group of acetate, 

 but this has since been ruled out by experiment (25). 



The modified cyclization scheme {B) removes some of the 

 objections which have been properly raised against the proposed 

 role of squalene as visualized earlier, but by postulating the 

 shifting of methyl groups, i.e., a rearrangement of the original 

 carbon skeleton, it introduces another feature which is unusual 

 at least as a biochemical reaction.* 



* The rearrangement which occurs in the conversion of /;-hydroxyphenyI- 

 pyruvic acid to homogentisic acid is the only biochemical example of an intra- 

 molecular shift which is well established. A pinacol rearrangement of aceto- 

 lactic acid to an isovaleric acid derivative has been suggested as a mechanism 

 for the biosynthesis of the amino acid valine in yeast (21), but it lacks direct 

 experimental support so far. 



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