Mevalonates

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. 

Strategy Problem 6 A labelled compound for biosynthetic studies. Mevaloitic acid (TM 418) is an intermediate in the biosynthesis of terpenes and steroids (Tedder, volume 4, p.217 ff). To study exactly what happens to each carbon atom during its transformation into, say, hmonene (418A), we need separate samples of mevalonic acid labelled with in each carbon atom in the molecule. This turns our normal strategy on its head since we must now look for one carbon discoimections. You can use reagents like Na CN, and... 

Isoprenoid compounds are biosynthesized from acetate by a process that involves sev eral stages The first stage is the formation of mevalonic acid from three molecules of acetic acid... 

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... 

The product of this reaction 3 hydroxy 3 methylglutaryl coenzyme A (HMG CoA) has the carbon skeleton of mevalonic acid and is converted to it by enzymatic reduction... 

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... 

The statins lower cholesterol by inhibiting the en zyme 3 hydroxy 3 methylglutaryl coenzyme A reduc tase which is required for the biosynthesis of meva Ionic acid (see Section 26 10) Mevalonic acid is an obligatory precursor to cholesterol so less mevalonic acid translates into less cholesterol... 

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

Methyl group (Section 2 7) The group —CH3 Mevalonic acid (Section 26 10) An intermediate in the biosyn thesis of steroids from acetyl coenzyme A Micelle (Section 19 5) A sphencal aggregate of species such as carboxylate salts of fatty acids that contain a lipophilic end and a hydrophilic end Micelles containing 50-100 car boxylate salts of fatty acids are soaps Michael addition (Sections 18 13 and 21 9) The conjugate ad dition of a carbanion (usually an enolate) to an a 3 unsatu rated carbonyl compound... 

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... 

When racemic mevalonic acid as the corresponding lactone and labeled at C-2 with is fed to the Chilean shmb SJ tanthus acutusM.ejen. labeled p-skytanthine [24282-31-3] (115) is obtained. Skjtanthus alkaloids are reputed to be tremorgenic (85). 

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... 

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

Other multifunctional hydroxycarboxylic acids are mevalonic and aldonic acids which can be prepared for specialized uses as aldol reaction products (mevalonic acid [150-97-0] (13)) and mild oxidation of aldoses (aldonic acids). 

Mevalonic acid 5-phosphate [1189-94-2] M 228.1, pKes,(d 1.5 (PO4H2), pKEst(2) 4.4 (CO2H), pKEst(3) (P04H ). Purified by conversion to the tricyclohexylammonium salt (m 154-156°) by treatment with cyclohexylamine. Crystd from water/acetone at -15°. Alternatively, the phosphate was chromatographed by ion-exchange or paper (Whatman No 1) in a system isobutyric acid/ammonia/water (66 3 30 Rp 0.42). Stored as the cyclohexylammonium salt. 

A synthesis of the important biosynthetic intermediate mevalonic acid starts with the enzymatic hydrolysis of the diester A by pig liver esterase. The pro-R group is selectively hydrolyzed. Draw a three-dimensional structure of the product. 

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