I 10 



INTERMEDIARY METABOLISM AND GROWTH 



Squalene 



Lanosterol 



Cholesterol 



Ergosterol 



Zymosterol 



A -7- Dehydrocholesterol 



• = Carboxyl carbon of acetate 

 o = Methyl carbon of acetate 



Vitamin D 



Fig. 49. Structure of cholesterol and related compovinds. The distribution of acetate 

 carbon atoms found experimentally in cholesterol, the hypothetical distribution of acetate 

 carbon in squalene and a possible mechanism of squalene cyclization is denoted by the 



closed and open circles. 



takes place with the introduction of '^O: into the lanosterol molecule but with little or no 

 addition of D2O (Tchen and Bloch, 1956). 7-dehydrocholesterol may be a late intermediate 

 in cholesterol synthesis. In feeding experiments, this steroid behaves in a manner very 

 similar to that found for cholesterol and A-7-cholestenol. It causes an increase in hepatic 

 cholesterol concentration and a decreased rate of sterol synthesis by liver. However, the 

 ingestion of squalene by rats results in the accumulation in liver of A-7-cholestenol, but 

 not of 7-dehydrocholesterol (Langdon, 1954). The incorporation of acetate-i^C into 

 squalene and of squalene into liver cholesterol has been demonstrated in vitro, p-hydroxy- 

 (i-methylglutarate is also incorporated into squalene by liver enzymes. Non-labelled 

 farnesol or farnesenic acid, compounds having 15 carbon atoms, can reduce the incorpo- 

 ration of acetate- '^C into squalene. At the same time, the recovered farnesenic acid 

 becomes radioactive (Dituri et al., 1956) suggesting that farnesenic acid or a related 

 compound may be an intermediate in squalene synthesis. 



For the biosynthesis of squalene and cholesterol from acetate- i-^''C to occur 

 in vitro, both microsomes and soluble cell constituents are reqviired, along with a 

 glycolytic substrate, ATP, and DPN^. Under anaerobic conditions, radioactivity 

 accumulates in squalene whereas in an oxygen atmosphere, cholesterol is formed. 

 Thus, oxygen is apparently required for the conversion of squalene to cholesterol 



