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Studies on the Biosynthesis of Cholesterol

XX. STERIC COURSE OF DECARBOXYLATION OF 5-PYROPHOSPHOMEVALONATE AND OF THE CARBON TO CARBON BOND FORMATION IN THE BIOSYNTHESIS OF FARNESYL PYROPHOSPHATE

From the ¹ From Shell Research, Ltd., Milstead Laboratory of Chemical Enzymology, Sittingbourne, Kent, England

The decarboxylation-dehydration of 5-pyrophosphomevalonate to isopentenyl pyrophosphate (isopentenyl-PP) and the mechanism of the carbon to carbon bond formation between an allyl pyrophosphate (3,3-dimethylallyl or geranyl pyrophosphate) and isopentenyl-PP have been studied with the aid of two specimens of mevalonate labeled stereospecifically with deuterium at C-2 (2R-2D₁-mevalonate and 2S-2D₁-mevalonate). Preparation of these specimens from stereospecifically labeled 4D₁-mevalonates by an interchange of the carboxyl and carbinol groups is described.

Both of these substrates have been converted enzymically into isopentenyl-PP, and one of them, the 2R-2D₁-mevalonate, has been converted into farnesyl pyrophosphate from which the free alcohols were isolated for chemical study.

A chemical method has been evolved for the determination of the steric positions of hydrogen and deuterium attached to the terminal doubly bound methylene carbon atom of isopentenol.

It was shown that the 2R-mevalonate gave cis-4D₁-isopentenol and the 2S-mevalonate gave trans-4D₁-isopentenol, indicating that the decarboxylation of 5-pyrophosphomevalonate was a trans elimination of the tertiary hydroxyl and of the carboxyl group.

It was deduced from the steric position of deuterium at C-4 and C-8 of farnesol biosynthesized from 2R-2D₁-mevalonate that the allyl pyrophosphate was added to C-4 of isopentenyl-PP from that side of the molecule on which the four substituents, —CH₂CH₂OPP, —CH₃, —H, and —H, around the double bond of isopentenyl-PP appeared in a clockwise order. These observations, taken in conjuction with the authors' previous findings, show that there are probably two steps in the formation of the C—C bond between an allyl pyrophosphate and isopentenyl-PP. First the allyl residue and an as yet unidentified nucleophilic X group are added across the double bond in a trans manner; this is then followed by a trans elimination of X and of a proton from C-2 of isopentenyl-PP.

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