Mevalonate 5-diphosphate

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. 

The final decarboxylation of mevalonate 5-diphosphate appears unusual because decarboxylations of acids do not typically occur except in /3-keto acids and malonic acids, in which the carboxylate group is two atoms away from an additional carbonyl group (Section 22.7). The function of this second carbonyl group is to act as an electron acceptor and stabilize the charge resulting from loss of CC>2- In fact, though, the decarboxylation of a /3-kelo acid and the decarboxylation of mevalonate 5-diphosphate are closely related. 

Alvear, M., Jabalquinto, A.M., and Cardemil, E. (1989) Inactivation of chicken liver mevalonate 5-diphosphate decarboxylase by sulfhydryl-directed reagents Evidence of a functional dithiol. Biochim. Biophys. Acta 994, 7-11. 

This enzyme [EC 4.1.1.33] (also known as mevalonic acid 5-pyrophosphate anhydrodecarboxylase, mevalonate-5-diphosphate decarboxylase, and diphosphomevalonate decarboxylase) catalyzes the reaction of ATP with (R)-5-diphosphomevalonate to produce ADP, orthophosphate, isopentenyl diphosphate, and carbon dioxide. 

MEVALDATE REDUCTASE MEVALONATE KINASE Mevalonate-5-diphosphate decarboxylase,... 

In animals all isoprenoid compounds are apparently synthesized from mevalonate, which is converted by the consecutive action of two kinases21 23 into mevalonate 5-diphosphate (Fig. 22-1, step b). Mevalonate kinase is found predominantly in peroxisomes, which are also active in other aspects of steroid synthesis in humans.2124 A deficiency of this enzyme is associated with mevalonic aciduria, a serious hereditary disease in which both blood and urine contain very high concentrations of mevalonate.23 Mevalonate diphosphate kinase, which is also a decarboxylase, catalyzes phosphorylation of the 3-OH group of mevalonate (step c, Fig. 22-1) and decarboxylative elimination of phosphate (step d)25 to form isopentenyl diphosphate. 

First, mevalonate 5-diphosphate is converted to isopenteny] diphosphate (IPP) and dimethallyl diphosphate (DMAPP). 

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]. 

Mevalonate ((118), Figure 6.27) is a key intermediate, and mevalonate kinase is a key early enzyme, in isoprenoid and sterol synthesis. Inhibitors of this enzyme have potential applications for treatment of cardiovascular disease and cancer. Mevalonate kinase activity is controlled post-transcriptionally via competitive inhibition at the ATP site by prenyl phosphates, such as geranyl diphosphate (119). A bifunctional inhibitor with micromolar IC50 values against mevalonate kinase and mevalonate 5-diphosphate decarboxylase (a... 

Fig. 3.3 Relative basal expression levels of mevalonate pathway genes in adult male and female Ips pini. For all genes, mRNA levels were significantly higher in males (t-test, / <0.001). AACT, acetoacetyl-CoA thilase HMG-S, HMG-CoA synthase HMG-R, HMG-CoA reductase MPDC, mevalonate-5-diphosphate decarboxylase IPPI, isopentenyldiphosphate isomerase GPPS, geranyldiphosphate synthase FPPS,...

Bifunctional inhibitors of mevalonate kinase and mevalonate 5-diphosphate decarboxylase (15) have been synthesized. Both enzymes are in the cholesterol biosynthetic pathway and play an important role in the regulation of cholesterol biosynthesis. " ... 

The final decarboxylation of mevalonate 5-diphosphate appears unusual because decarboxylations of acids do not typically occur except in )3-keto acids... 

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