CHEMICAL STRUCTURE 



metric by attachment of one of the two terminal isopropyhdene 

 groups to a cationic site on the enzyme surface, leaving only one 

 portion of the chain free to cyclize. It is evident that the same 

 purpose would be achieved by the formation of a nonsymmetric 

 derivative of squalene in the course of its synthesis. 



From what has been said it is clear that knowledge of the 

 structure of lanosterol has permitted the formulation of a 

 plausible mechanism for the cyclization of squalene. Equally 

 important, it has indicated the direction and the area in which 

 further biochemical experimentation might be pursued. As an 

 example the results of some recent experiments may be cited. 

 Lanosterol has in the past been isolated only from two natural 

 sources, from yeast (kryptosterol) and from wool fat, which con- 

 tains three other closely related sterols, dihydrolanosterol, 

 agnosterol, and dihydroagnosterol. Once its structure was 

 established it became reasonable to ask whether lanosterol is a 

 metabolic side product or a normal intermediate in the syn- 

 thesis of the more conventional sterols (cholesterol, ergosterol, 

 or the plant sterols). As the example of squalene had demon- 

 strated earlier, the general significance of a tissue constituent is 

 frequently missed simply because it is primarily associated with 

 somewhat unconventional sources. Evidence has now been 

 obtained that lanosterol also is more widely distributed than had 

 earlier been suspected. With the aid of the carrier technique, 

 it can be shown that mammalian liver synthesizes lanosterol from 

 acetate at a rapid rate, and this establishes lanosterol as a nor- 

 mal constituent of cholesterol-producing tissues (6). Besides, a 

 conversion of lanosterol to cholesterol can be demonstrated in the 

 sam^e liver system. The rate of this reaction is sufficiently fast to 

 suggest that the pathway from squalene to cholesterol goes in- 

 deed by way of lanosterol (7). The inclusion of lanosterol in 

 the normal process of cholesterol biogenesis reduces at least 

 partially the complexity of the reaction sequence and thereby 

 greatly improves prospects for an enzymatic characterization of 

 individual steps. 



Details of the cyclization of squalene to lanosterol have 



485 



