Mevalonic acid pyrophosphate

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. 

MEVALONATE KINASE Mevalonic acid 5-pyrophosphate anhydrode-carboxylase,... 

Mevalonic acid lactone. Mevalonic acid 5-phosphate, Mevalonic acid 5-pyrophosphate... 

Mevalonic acid 5-pyrophosphate [1492-08-6] M 258,1, Purified by ion-exchange chromatography on Dowex-1 formate [Bloch et al. JBC 234 2595 7959], DEAE-cellulose [Skilletar and Kekwick, AB 20 171 7967], on by paper chromatography [Rogers et al. BJ99 381 7966]. Likely impurities are ATP and mevalonic acid phosphate. Stored as a dry powder or as a slightly alkaline (pH 7-9) soln at -20°. 

Elimination usually involves loss of a proton together with a nucleophilic group such as -OH, -NH3+, phosphate, or pyrophosphate. However, as in Eq. 13-18, step c, electrophilic groups such as -COO-can replace the proton. Another example is the conversion of mevalonic acid-5-pyrophosphate to isopentenyl pyrophosphate (Eq. 13-19) This is a key reaction in the biosynthesis of isoprenoid compounds such as cholesterol and vitamin A (Chapter 22). The phosphate ester formed in step a is a probable intermediate and the reaction probably involves a carbo-cationic intermediate generated by the loss of phosphate prior to the decarboxylation. 

This biosynthetic path consists of the Claisen-type condensation of two acetyl CoA units to form the four-carbon substance acetoacetyl CoA a third equivalent of acetyl CoA is then added in an aldol-type reaction giving, after hydrolysis of one of the thiol esters, hydroxymethylglutaryl CoA (HMG-CoA). HMG-CoA is then reduced by a net four electrons to mevalonic acid and is subsequently phosphorylated to mevalonic acid 5-pyrophosphate (MVA-5PP). This substrate is finally phosphorylated and decarboxylated with concomitant loss of inorganic phosphate to give the five-carbon isoprenoid isopentenyl pyrophosphate (IPP). IPP is then isomerized to DMAPP by an isomerase. 

D-Mevalonic acid is the fundamental intermediate in the biosynthesis of the terpenoids and steroids, together classed as poly-isoprenoids. The biogenetic isoprene unit is isopentenyl pyrophosphate which arises by enzymic decarboxylation-dehydration of mevalonic acid pyrophosphate. D-Mevalonic acid is almost quantitatively incorporated into cholesterol synthesized by rat liver homogenates. 

It is believed that the function of ATP is to phosphorylate mevalonic acid pyrophosphate at the 3-position. 

The biosynthesis of the juvenile hormones is not yet fully known. Their similarity to famesol, an intermediate product in the biosynthesis of steroles in mammals, leads one to assume that their formation is analogous to that of farnesol. This obvious assumption seems to be supported by publications that have appeared in the early 1970s. Barnes and Goodfellow (1971) showed that isoprenoid biosynthesis in the larva of Sarcophaga bullata proceeds with the participation of mevalonate kinase. This enzyme regulates the formation of mevalonic acid pyrophosphate, an important intermediate product in steroid biosynthesis of mammals. Isopentenyl pyrophosphate, the C, unit of isoprenoid biosynthesis, is formed from mevalonic acid pyrophosphate by decarboxylation and, with the participation of ATP, by dehydration. 

Lynen F, Eggerer H, Henning U, Kessel I (1958) Famesyl-pyrophosphat und 3-Methyl-A3-butenyl-l-pyrophosphat, die biologischen vorstufen des squalens. Angew Chem 70 738-742 Bloch K, Chaykin S, Phillips AH, de Waard A (1959) Mevalonic acid pyrophosphate and isopentenylpyrophosphate. J Biol Chem 234 2595-2604... 

The steps required to convert mevalonic acid to the active-isoprenoid intermediate have been worked out with some assurance. The initial step involves the phosphorylation of mevalonic acid to mevalonic acid-5-phosphate by an enzyme called mevalonic kinase. This enzyme was found in yeast by Tchen (1958). The properties of the mevalonic kinase of liver have been described in detail by Levy and PopjAK (1960). The kinase is inhibited by p-chloromercuribenzoate but not by iodoacetamide. The enzyme requires Mg++, Mn++, or Ca++ and ATP or inosine triphosphate. The kinase is specific for the (+) form of mevalonic acid. Mevalonic acid-5-phosphate is phosphorylated further to give mevalonic acid-5-pyrophos-phate (de Waard and Popjak, 1959 Henning et al. 1959). The purified enzyme (Bloch et al., 1959) requires a divalent metal ion for activity (Mg++ is preferable) and has no pronounced pH optimum. Mevalonic acid pyrophosphate then undergoes simultaneous dehydration and decarboxylation to yield isopentenylpyro-phosphate (Lynen et al., 1958 Chaykin et al., 1958). The enzyme concerned with the dehydration and decarboxylation has been purified (Bloch et al., 1959) and shown to have a pH optimum between 5.5 and 7.4 and to require a divalent metal ion (Mg++, Mn++, Fe++ or Co++). The series of reactions in which mevalonate is converted to isopentenylpyrophosphate is outlined in Figure 6. Brodie et al. (1963) have established a new pathway for the biosynthesis of mevalonic acid from malonyl CoA. The importance of this particular pathway in the synthesis of sterols is still unknown. 

Bloch K et al (1959) Mevalonic acid pyrophosphate and isopentenylpyrophosphate. J Biol Chem 234 2595-604... 

In the second stage mevalonic acid is converted to 3 methyl 3 butenyl pyrophosphate (isopentenyl pyrophosphate)... 

The introduction to Section 26 8 pointed out that mevalonic acid is the biosynthetic pre cursor of isopentenyl pyrophosphate The early steps m the biosynthesis of mevalonate from three molecules of acetic acid are analogous to those m fatty acid biosynthesis (Sec tion 26 3) except that they do not involve acyl earner protein Thus the reaction of acetyl coenzyme A with malonyl coenzyme A yields a molecule of acetoacetyl coenzyme A... 

In keeping with its biogenetic origin m three molecules of acetic acid mevalonic acid has six carbon atoms The conversion of mevalonate to isopentenyl pyrophosphate involves loss of the extra carbon as carbon dioxide First the alcohol hydroxyl groups of mevalonate are converted to phosphate ester functions—they are enzymatically phosphorylated with introduction of a simple phosphate at the tertiary site and a pyrophosphate at the primary site Decarboxylation m concert with loss of the terti ary phosphate introduces a carbon-carbon double bond and gives isopentenyl pyrophos phate the fundamental building block for formation of isoprenoid natural products... 

Section 26 10 The biosynthesis of isopentenyl pyrophosphate begins with acetate and proceeds by way of mevalonic acid... 

Introduction of Nitrogen into a Terpenoid Skeleton. The acetate-derived fragments (35) mevalonic acid (30), which yields isopentenyl pyrophosphate (31) and its isomer, 3,3-dimethyl ally pyrophosphate (32) a dimeric C -fragment, geranyl pyrophosphate (33), which gives rise to the iridoid loganin (34) and the trimer famesyl pyrophosphate (35), which is also considered the precursor to C q steroids, have already been mentioned (see Table 3... 

The principal steps in the mechanism of polyisoprene formation in plants are known and should help to improve the natural production of hydrocarbons. Mevalonic acid, a key intermediate derived from plant carbohydrate via acetylcoen2yme A, is transformed into isopentenyl pyrophosphate (IPP) via phosphorylation, dehydration, and decarboxylation (see Alkaloids). IPP then rearranges to dimethylaHyl pyrophosphate (DMAPP). DMAPP and... 

It is immediately clear that Acanthomyops need not rely on dietary sources of terpenes but can synthesize citronellal and citral from either acetate or mevalonate. The higher total activity of the citronellal as compared with the citral probably reflects the natural preponderance of citronellal (ca. 90%) in the ant secretion. As the specific activities show, these results are consistent with a common biogenetic origin of both terpenes. In the mevalonic acid pathway as described from other organisms (13), the radioactive carbon of l-C14-mevalonate is lost upon formation of isopentenyl pyrophosphate. 

During the second step, mevalonic acid is implicated in a number of enzymic reactions involving ATP, and is converted to isopentyl pyrophosphate and to its isomer 3,3-dimethylallyl pyrophosphate. Actually, the two compounds constitute the active isoprene , which... 

The CPPase substrate DMAPP (15) is formed from isopentenyl pyrophosphate (IPP) (14) via the IPP isomerase reaction. It had been assumed that IPP was generated only via mevalonic acid (12) (Fig. 2), but Rohmer discovered another route, 2-C-methyl-D-erythritol 4-phosphate (13) (MEP) pathway (Fig. 2) [22, 23]. A key step in the MEP pathway is the reaction catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (DXS), which combines hydroxyethyl thiamine pyrophosphate (hydroxyethyl TPP) generated from pyruvic acid (17) and TPP with glyceral-dehyde 3-phosphate (18) to yield 1-deoxy-D-xylulose 5-phosphate (19) containing five carbons. The mevalonate pathway operates in the cytosol of plants and animals, whereas the MEP pathway is present in the plastid of plants or in eubacteria [24-27]. 

Mevalonate pyrophosphate, role in cholesterol synthesis, 5 142 Mevalonic acid, 2 93 14 132 alkaloid precursor, 2 78 Mexican Molango ore, 15 544 Mexican oregano, 23 169 Mexico... 

In pepper as in many plants, there are two sources of isoprene monomers the mevalonic acid pathway and the plastidal pool from pymvate and glyceraldehyde-3-phosphate [26], Pepper carotenoid biosynthesis uses the plastidal pathway for the isopentyl pyrophosphate monomers and the resident terpenoid synthases and transferases [27], Using the 5-carbon isoprene pool, the prenyl transferases sequentially... 

Kinetic studies of the incorporation of the " C-labelled precursors mevalonic acid, isopentenyl pyrophosphate, and phytoene into C40 carotenes by Halobac-terium cutirubrum cell-free preparations" produced results consistent with the pathways outlined in Schemes 2 and 3. Only the trans-isomers seemed to be involved. A mutant strain, " PGl, of the green alga Scenedesmus obliquus accumulates phytoene (135), phytofluene (136), and -carotene (137) in place of the... 

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. 

Two molecules of farnesyl pyrophosphate combine, releasing pyrophosphate, and are reduced, forming the 30-carbon compound squalene. [Note Squalene is formed from six isoprenoid units. Because three ATP are hydrolysed per mevalonic acid residue converted to IPP, a total of eighteen ATP are required to make the polyisoprenoid squalene.]... 

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