Mevalonic 5-phosphate

Step 4 of Figure 27.7 Phosphorylation and Decarboxylation Three addition reactions are needed to convert mevalonate to isopentenyl diphosphate. Th first two are straightforward phosphorylations that occur by nucleophilic sul stitution reactions on the terminal phosphorus of ATP. Mevalonate is first cor verted to mevalonate 5-phosphate (phosphomevalonate) by reaction wit ATP in a process catalyzed by mevalonate kinase. Mevalonate 5-phosphat then reacts with a second ATP to give mevalonate 5-diphosphate (diphosphc mevalonate). The third reaction results in phosphorylation of the tertiar hydroxyi group, followed by decarboxylation and loss of phosphate ion. 

Problem 27.6 1 Studies of the conversion of mevalonate 5-phosphate to isopentenyl diphosphate have shown the following result. Which hydrogen, pro-R or pro-S, ends up cis to the methyl group, and which ends up trans ... 

Bhat, C.S. and Ramasarma, T., Effect of phenyl and phenolic acids on mevalonate-5-phosphate kinase and mevalonate-5-pyrophosphate decarboxylase of the rat brain, J. Neurochem., 32, 1531, 1979. 

Skilleter, D.N. Kekwick, R.G.O. The enzymes forming isopentenyl pyrophosphate from 5-phosphomevalonate (mevalonate 5-phosphate) in the latex of Hevea brasiliensis. Biochem. J., 124, 407-417 (1971)... 

Phosphomevalonate kinase (PMK, EC 2.7.4.2) is the enzyme involved in the second step of the terpenoid biosynthesis and catalyzes the reversible conversion of mevalonate 5-phosphate and ATP to mevalonate 5-diphosphate and ADP, a key step in that synthesis. Fig. (6), [289-290]. Kinetic characterisation of PMK has been carried out using enzymes from mainly animal sources including human, S. cerevisiae and some plants. In addition, PMK has only been partially purified and characterized. It seems that this enzyme is quite a unique enzyme, but its characteristics reveal some remarkable differences among diverse sources. Thus, pig liver and human liver PMKs show molecular weights between 21 and 22 kDa [291-292], whereas the enzyme isolate from S. cerevisiae has a molecular weight of 47 kDa [293]. 

Mevalonic acid was discovered by Folker s group at Merck, Sharpe, and Dohme. The initial isolation was based upon the fact that it acted as a growth factor, or vitamin, for a strain of bacteria [35]. Once the structure had been determined, it was apparent that the molecule might well be the isoprenoid precursor that had been sought for many years. Subsequent experiments demonstrated that the sole (or nearly so) fate of the molecule was polyisoprenoid synthesis. In examining the role of cofactors necessary for the synthesis of cholesterol from mevalonate, only ATP and NADPH were found to be required. Experiments with a solubilized preparation from yeast demonstrated that there were 3 phosphorylated intermediates that could be isolated. These were shown to be mevalonic-5-phosphate, mevalonic-5-pyrophos-phate, and isopentenyl pyrophosphate [9]. These intermediates are derived from mevalonate in a sequence of phosphorylations, and the enzymes for all reactions have been obtained in homogeneous form. These enzymes, as well as the rest that lead to the synthesis of famesyl pyrophosphate, are cytosolic proteins. 

The next reaction in the transformations of mevalonate is unusual in that the transfer of a phosphoryl entity from ATP to mevalonate-5-phosphate forms the... 

As soon as mevalonate acid has formed, a series of enzymes are involved in order to transform MVA to IPP. Mevalonate kinase [EC 2.7.1.36] phosphorylates the primary alcohol to mevalonate 5-phosphate, whereas phosphomevalonate kinase [EC 2.7.4.2] produces 5-pyrophosphomevalonate... 

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