Mevalonate diphosphate kinase

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. 

The conversion of mevalonate (1) to isopentenyl pyrophosphate (IPP) (4) involves two consecutive phosphorylations at position 5 by successive action of mevalonate kinase (EC 2.7.4.2) and a decarboxylation and dehydration of the tertiary alcohol group by mevalonate 5-pyrophosphate decarboxylase (EC 4.1.1.33) (Fig. 18.4) (Crotean Johnson, 1985 Gershenzon and Croteau, 1990). One mole of ATP is required for each phosphorylation reaction. Mevalonate kinase converts mevalonic acid to (5/ )-phosphomevalonate (5). The second phosphorylation is catalyzed by phospho-mevalonate kinase. The subsequent decarboxylation and dehydration is mediated by the enzyme mevalonate diphosphate decarboxylase (di- or pyrophosphomevalonate decarboxylase EC 4,1.1.3.3) this enzyme requires Mg " or Mn + and ATP for activity (Beale and MacMillan, 1988 Harrison, 1988). All three of these enzymes are found in a number of plants. 

Then (Scheme 11.41) mevalonate [(l )-3,5-dihydroxy-3-methylpentanoic acid] is phosphorylated by the enzyme mevalonate kinase (EC 2.7.1.36) at the primary hydroxyl. The phosphate that is added is obtained (an addition-elimination reaction or a displacement reaction) from the terminal phosphate group of ATP forming ADP in turn. Another phosphorylation, again using ATP yields mevalonate diphosphate, this time by the enzyme phosphomevalonate kinase (EC 2.7.4.2) and then, after one more phosphorylation, this time on the tertiary hydroxyl, decarboxylation and dehydration co-occur, catalyzed by the enzyme mevalonate diphosphate decarboxylase (EC 4.1.1.43). The products are inorganic phosphate, carbon dioxide, and isopentenyl diphosphate (diphosphoric acid mono[3-methylbut-3-enyl] ester). Isopentenyl diphosphate isomerase (EC S.3.3.2) catalyzes the isomerization, via loss of the C2 pro-R hydrogen, between isopentenyl diphosphate and dimethylallyl 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. 

Step 2—Formation of Isoprenoid Units Mevalonate is phosphorylated sequentially by ATP by three kinases, and after decarboxylation (Figure 26-2) the active isoprenoid unit, isopentenyl diphosphate, is formed. 

Mevalonate kinase deficiency. Mevalonate kinase and farnesyl-diphosphate synthase are localized in the peroxisome and are involved in the synthesis of isoprenoids. Mevalonate kinase deficiency causes severe developmental delay, dysmorphic features and early death. Mevalonate deficiency has also been observed in the hyperimmuno-globulinemia-and periodic fever syndrome. 

LANGE, B.M., CROTEAU, R., Isopentenyl diphosphate biosynthesis via a mevalonate-independent pathway isopentenyl monophosphate kinase catalyzes the terminal enzymatic step, Proc. Natl. Acad. Sci. USA, 1999,96,13714-13719. 

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

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... 

The hydroxyl groups in mevalonate are then esterified in a stepwise fashion to their phosphates by phosphorylating enzymes, called kinases. The overall result is the intermediate 1-4 in which the terminal hydroxyl is a diphosphate and the tertiary hydroxyl is present as a monophosphate, the latter comprising a very good leaving group. The next step consists of decarboxylation with concomitant departure of the tertiary phosphate group. This transformation finally affords the latent isoprene unit 1-5. The product from this sequence, IPP (1-5), is reversibly converted to its isomer with the internal double bond (1-6) by yet another enzyme. 

Mevalonate is metabolized to famesyl-diphosphate (famesyl-PP) by a series of enzymes localized in peroxisomes (Fig. 2). First, mevalonate kinase phosphorylates the... 

MVA is phosphorylated in two steps to the mono- and the diphosphate (MVAP and MVAPP), by the specific ATP-dependent enzymes MVA kinase (ATP-mevalonate-phosphotransferase, EC 2.7.1.36) and MVAP kinase (EC 2.7.4.2), respectively. MVAPP is converted into IPP by a decarboxylase (EC 4.1.1.33). The kinases and the decarboxylase have not yet been given as much attention as HMG-CoA reductase, and have only been characterized in a few plant species. Recently, MVA kinase was partially purified from C. roseus suspension cultures. The enzyme proved to be unstable and was present only at low activity levels (90). 

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. " ... 

Once mevalonate has been formed it is sequentially phosphorylated by two separate kinases yielding mevalonate 5-diphosphate. A third ATP-consuming reaction involving a decarboxylase then generates the universal isoprene unit, isopentenyl pyrophosphate (Figure 7.18). The function of the ATP in this reaction appears to be to act as an acceptor for the leaving OH group in the dehydration part of the reaction. 

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