SYNOPSIS. Tetrahymena pyriformis synthesizes tetrahymanol and “diplopterol” from acetate, mevalonate or squalene. The formation of these pentacyclic triterpenoid alcohols is inhibited by the addition of cholesterol to the culture fluid of the ciliates. Cholesterol also inhibits the biosynthesis of squalene from acetate or mevalonic acid. The synthesis of other terpene derivatives from acetate and mevalonate continues in the presence of cholesterol, thus suggesting that a major block occurs after “isoprene” formation and before squalene formation. Further, inhibition of squalene conversion to the pentacyclic alcohols by cholesterol has been established.

The influence of configuration at C-20 on rotation about the 17(20)-bond in steroids and euphoids was examined by x-ray crystallographic studies of the C-20 epimers euphol and tirucallol. The H atom on C-20 was in back next to C-18 in the crystal structures of both of the compounds, and C-22 was found to be cis-oriented ("left-handed") to C-13 in euphol and trans-oriented to it ("right-handed") in tirucallol.The results, which are consistent with the known left-handed crystal structure of 24(25)-dihydroeuphol and right-handed crystal structure of cholesterol and other natural sterols, lend further credence to the earlier suggestion that rotational isomerism at the 17(20)-bond can arise in C-20 epinters and that there is preference for an arrangement with the 20-H atom adjacent to C-18.It is known from x-ray data (1-3) that in the crystalline state, sterols with the natural configuration (20a-H atom, usually 20R in the sequence rule) have a conformation about the 17(20)-bond such that, in the usual view of the molecule, C-22 is to the right. As we suggested earlier (4, 5), the preference for this "right-handed" rotational isomer probably derives from its having the smallest of the groups on C-20 (the H atom) in front and, therefore, adjacent to C-18 in a pseudo-1,3-diaxial fashion. If this were the correct explanation, the H atom on C-20 should remain adjacent to C-18 after inversion. This would place C-22 on the left ("left-handed" isomer)We undertook a study of this stereochemistry, because the ability of the sterol side chain to assume a right-handed conformation without having a methyl group in front seems to be of biological importance. There is a clear correlation between the biological activities of (20R)-sterols (which can have this stereochemistry) and (E)-17(20)-dehydrocholesterol with C-22 fixed to the right (5)(6)(7)(8)(9)(10)(11). Similarly, the activities of (20S)-sterols correlate with (Z)-17(20)-dehydrocholesterol (5-10). If only one of the 17(20)-dehydrosterols is active, it is the right-handed (E)-isomer, and then of the C-20 epimers only the one with the (20R)-configuration is active (5-10). These correlations have been found in the ability of sterols to perform what is thought to be the bulk membrane function in yeast (5, 6), to be metabolized by a protozoan (7,8), and to induce formation of oospores in an oomycete (9, 10). If, on the other hand, both of the 17(20)-dehydrosterols are active, as they are in depressing hepatic cholesterol synthesis after being fed to mice (11), then both of the C-20 epimers of cholesterol are active (11).To determine whether inversion of the C-20 configuration of sterols is actually accompanied in the solid state by transfer of C-22 from the right to the left side of the molecule, we have tried to grow large enough crystals of 20-epicholesterol, prepared as described (12), to permit x-ray analysis.Unfortunately, crystals of adequate size have not been obtained, so we turned our attention to the naturally occurring (13) C-20 epirners euphol and tirucallol...

The principal sterol synthesized by L-cell mouse fibroblasts is desmosterol. Cholesterol was not detected in these cells when they were grown in a sterol-free culture medium. These findings indicate that, in cells, cholesterol can be replaced by desmosterol. Sterol analyses of six other tissue culture cell lines revealed cholesterol synthesis.

No abstract

No abstract