Mevalonate-5-diphosphate decarboxylase

Fig. 11 Natural rubber is produced from a side branch of the ubiquitous isoprenoid pathway, with 3-hydroxy-methyl-glutaryl-CoA (HMG-CoA) as the key intermediate derived from acetyl-CoA by the general mevalonic-acid pathway. Mevalonate diphosphate decarboxylase (MPP-D) produces IPP, which is isomeiized to DMAPP by IPP isomerase (IPI). IPP is then condensed in several steps with DMAPP to produce GPP, FPP and GGPP by the action of a trani-prenyltransferase (TPT). The cA-l,4-polymeiization that yields natural rubber is catalyzed by cA-prenyltransferase (CPT), which uses the non-allylic IPP as substrate. Reprinted from [248], with permission from Elsevier...

Mevalonate diphosphate decarboxylase (MVP EC4.1.1.33) catalyzes the conversion of mevalonate diphosphate to isopentenyl diphosphate, a key building block for a large family of functionally important terpenoids. Fig. (6). This reaction is the third step in the biosynthesis of steroids and terpenoids from the mevalonate pathway, and the last well characterized step in the mevalonate pathway for the biosynthesis of isopentenyl pyrophophaste, the isoprenoids precursor [296-298]. Some reports showed that MVP is located predominantly in the cytosolic fraction and its expression is independent of peroxisome proliferation [299-300]. 

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. 

Another reaction to isobutene is through decarboxylation and subsequent dehydration of 3-hydroxyisovalerate (3-hydroxy-3-methylbutyrate), catalysed by mevalonate diphosphate decarboxylase (MDD, EC 4.1.1.33) (Gogerty and Bobik 2010 Marliere 2010). This enzyme, from the class of carboxy-lyases, is part of terpenoid or ergosterol biosynthesis, and isobutene formation is its side reaction. Even though the MDD family of enzymes is present in many microorganisms, none of them are known to synthesise isobutene (van Leeuwen et al. 2012 Bloch et al. 1959) (Fig. 4). 

For example, Gogerty and Bobik (2010) used this pathway when they expressed a mevalonate diphosphate decarboxylase of Saccharomyces cerevisiae (ScMDD) in E. coli strain DG30. This strain formed isobutene at a rate of around 155 pmol/gceiis/h. 

Fig. 4 Mechanism of isobutene synthesis by mevalonate diphosphate decarboxylase (Marliere et al. 2013)...

Chambon C, Ladeveze V, Servouse M, Blanchard L, Javelof C, Vladescu B, Karst F (1991) Sterol pathway in yeast. Identification and properties of mutant strains defective in mevalonate diphosphate decarboxylase and famesyl diphosphate synthetase. Lipids 26(8) 633-636. doi 10.1007/bf02536428... 

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 mevalonate pyrophosphate decarboxylase, catalyzes the reaction of ATP with (i )-5-diphosphomevalonate to produce ADP, orthophosphate, carbon dioxide, and isopentenyl diphosphate. 

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. 

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. " ... 

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). 

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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