Pfizer Handbook of Microbial Metabolites 680 



liver enzyme preparation has suggested that 1 mole of 

 each is involved in the biosynthesis of squalene.®° The 

 condensation of these two substances would then be anal- 

 ogous to that of isopentenylpyrophosphate with 3,3-di- 

 methylaUyl pyrophosphate (or geranyl pyrophosphate). 



CH=-OPO.H, 



Nerolidyl Pyrophosphate 



Squalene 



The significant points of the chemical mechanism of 

 squalene biosynthesis were summarized as follows: 

 (a) The process is not a concerted reaction, but proceeds 

 in steps with well-defined stable intermediates, (b) Dur- 

 ing isomerization of isopentenylpyrophosphate there is an 

 uptake of one proton in the terminal methylene group, 

 and this proton appears finally in one of the terminal 

 methyl groups at each end of squalene, which means the 

 entry into each molecule of squalene of two protons not 

 contained originally in mevalonic acid, (c) There are no 

 reductive steps involved in the synthesis of geranyl or 

 farnesyl pyrophosphates, (d) Farnesyl pyrophosphate 

 and the nerolidyl derivative are the two sesquiterpenoids 

 condensing to the symmetrical dihydroterpene, squalene, 

 a stable intermediate being dihydrosqualene. (e) During 

 stabilization of the condensation product of the farnesyl 

 and nerolidyl derivatives, elimination of two protons, orig- 

 inally attached to C-5 of mevalonate occurs, (f) The 

 final step is a reduction, introducing into squalene two 

 further hydrogen atoms not contained originally in 

 mevalonic acid. 



80 J. W. Cornforth and G. W. Popjak, Tetrahedron Letters No. 19 

 29 (1959). 



