KONRAD BLOCK 



they expressed were so diverse. These hypotheses, some of which 

 are shown in Figure 1, not only differ from each other in detail 

 but have invoked as precursors a great variety of carbon sources : 

 carotene, squalene, oleic acid, acetone, formate, or triose. The 

 biochemist has been inclined to view these speculative efforts 

 with considerable indifference, because they often tended to 

 disregard the biochemical facts. For example, carotene could 

 be ruled out as a cholesterol precursor because steroids are 

 synthesized in the animal body while carotenes are not. Simi- 

 larly, the squalene hypothesis of Heilbron et al. (14) and Robinson 

 (19) received scant attention because this hydrocarbon was then 

 known to occur in shark liver but not elsewhere, and was 

 regarded as a metabolic aberration rather than a normal 

 metabolite. Even though Channon had furnished some bio- 

 chemical evidence in favor of a squalene-cholesterol conversion 

 as early as 1926 (5), his experiments, which were of the balance 

 type and therefore inconclusive, aroused little comment. 



The experimental phase of the study of steroid biogenesis 

 dates from 1937, and the earlier hypotheses may now be con- 

 sidered in the light of what has since been learned : the steroidal 

 carbon skeleton is synthesized by the condensation of numerous 

 small molecular units (18) and these have been shown to be 

 identical with acetic acid (4). From the distribution pattern of 

 acetate carbon in cholesterol it was suspected that the over-all 

 transformation proceeded in several stages: (7) a condensation 

 of three acetate units to a branched-chain intermediate having 

 five (or possibly six) carbon atoms; (2) multiple condensation 

 or polymerization of these intermediate units to a polyisoprenoid 

 chain of high molecular weight, {3) formation of the steroidal 

 ring system by folding and cyclization of the high-molecular 

 aliphatic intermediate (26). Gradually then the weight of the 

 experimental evidence pointed to a terpene or polyisoprenoid 

 derivative as a key intermediate, bringing back to mind those 

 earlier schemes which had considered compounds of this general 

 type. The squalene hypothesis in particular seemed sufficiently 

 attractive to warrant an experimental check. There has now 



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