4-Methyl-mevalonic acid

Pentanoic acid, 3,5-dihydroxy-5-methyl- mevalonic acid) 3973 ... 

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

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... 

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]. 

Fig. 2 Two possible biosynthetic pathways to pyrethrolone. The [l-13C]D-glucose-derived 13C labels that occur in the mevalonic acid and 2-C-methyl-D-erythritol 4-phosphate (13) pathways are colored in red and green, respectively. The phosphate moiety is indicated as P ...

Fig. 8. Most important steps in the biosynthesis of cholesterol. The reduction of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to yield mevalonic acid is an important rate-limiting step and also the site of attack of the HMG-CoA-reductase inhibitors (statins).

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...

MEP/DXPpathway. 2-C-methyl-D-erythritol4-phosphate/r-de-oxy-D-xylulose s-phosphate pathway, first reported in the late 1980s, is also known as non-mevalonate pathway or mevalonic acid independent pathway (MEP). This pathway is located in the plastids of plants and in the stmcture known as the api-complexan in protozoa as well as in many bacteria. 

Terpenes, biogenetically, arise from two simple five-carbon moieties. Isoprenyl-diphosphate (IPP) and dimethylallyldiphosphate (DMAPP) serve as universal precursors for the biosynthesis of terpenes. They are biosynthesised from three acetylcoenzyme A moieties through mevalonic acid (MVA) via the so-called mevalonate pathway. About 10 years ago, the existence of a second pathway leading to IPP and DMAPP was discovered involving l-deoxy-D-xylulose-5-phos-phate (DXP) and 2C-methyl-D-erythritol-4-phosphate (MEP). This so-called non-mevalonate or deoxyxylulose phosphate pathway starts off with the condensation of glyceraldehyde phosphate and pyruvate affording DXP. Through a series of reactions as shown in Fig. 4.1, IPP and DMAPP are formed, respectively [3,7, 42, 43]. 

It is difficult to identify the lipid moiety as a polyprenol, because of the small amounts present in tissues. Nevertheless, some information can be obtained by using glycosylated lipids labelled in the sugar moiety. The first indication of the presence of polyprenyl glycosyl phosphates comes from study of the properties just mentioned, namely, lability to mild acid, stability to mild alkali, and acidic properties. Information on the polyprenyl nature of the lipid may be obtained by labelling the lipid with radioactive 2,4-dideoxyO-C-methyl-D-g/ycero-pentono-l.S-lactone (mevalonic acid ). 

Formation of the biological isoprene unit from mevalonic acid has been shown to proceed by stepwise phosphorylation of both alcohol groups, then elimination and decarboxylation to yield 3-methyl-3-butenyl pyrophosphate, 9 (often called A3-isopentenyl pyrophosphate) ... 

It had already been stated earlier that clavine alkaloids are formed from L-tryptophan and mevalonic acid, the methyl group in position 6 originating from methionine (53, 54). There was also evidence that 4-dimethylallyltryptophan (3) is an early intermediate in the biosynthetic pathway (58). 

Since the 4 -hydrogen of mevalonic acid is eliminated during biosynthesis, the original dimethylallyl residue would be expected to carry the label from C-2 of the mevalonate in the trans-methyl group. The conversion of 3 to 4 therefore seems to involve hydroxylation at the cis-methyl group followed by cis-trans isomerization at the allylic double bond. Thus, the apparently normal labeling of the tetracyclic clavines in the trans (i.e., C-17) carbon after feeding with [2-14C]-mevalonate is merely the accidental result of a more complex series of reactions. 

HMG-CoA reductase catalyzes the rate-limiting conversion of 3-hydroxy-3-methyl-glutaryl coenzyme A to mevalonic acid which is a key intermediate in biosynthesis of cholesterol (Fig. 4.1)... 

Sterols are synthesized in nature from squalene and, therefore, ultimately from isoprene. Mevalonic acid is the immediate precursor of the isoprene unit, and the carboxylic acid group is lost as carbon dioxide when two mevalonic acid molecules combine head to tail. Thus, if the a carbon of mevalonic acid is labeled, then this carbon is always adjacent to the carbon bearing a side-chain methyl group. Examination of the way in which six isoprene units are linked in squalene (Example 6.2) shows that they are not all linked head to tail there is a point of symmetry in the structure of squalene (marked in the structure below). At this point a set of three isoprene units, linked head to tail, is joined head-to-head to a similar set of three isoprene units, to give the labeling pattern shown. 

At first glance, it is not at all clear that steroids are terpenoid in origin. The 5n numbers are absent— cholesterol is a C27 compound while the others variously have 20,21, or 23 carbon atoms. Studies with labelled mevalonic acid showed that cholesterol is terpenoid, and that it is formed from two molecules of farnesyl pyrophosphate (2 x C45 = C30 so three carbon atoms must be lost). Labelling of one or other of the methyl groups (two experiments combined in one diagram ) showed that two of the green carbon atoms and one of the black carbon atoms were lost during the biosynthesis. 

Melting points, factors influencing, 16 p-Mentha-1,6-diene, 236 Methionine, 238 —, S-adenosyl-L-, 233 Methylation, of chitin, 389 Mevalonic acid, 235... 

The biosynthesis of the ergot alkaloids involves condensation of dimethyl-allyl pyrophosphate (derived from mevalonic acid) with tryptophan. Closure of the C- and D-rings of the alkaloid involves specific hydroxylations by cytochrome P450-dependent oxidases and rearrangements. Further modifications involve N-methylation in the presence of S-adenosyl methionine and/or condensation with amino acids and peptides. Coupling of lysergyl CoA with certain peptides forms the peptide alkaloids which are the most bioactive of the ergot alkaloids. 

Methyl vinyl ketone, 31-32, 225, 676, 697-703, 887, 970, 974,1112 Methyl a- and /5-xylopyranoside, 834 DL-Mevalonic acid 5-phosphate, 811 Mevalonolactone, 146, 809-810 (R and S), 809 Michael reaction, 1069 Mitomycin, 941 Mobay, 1171 Molecular rotations, 297 Molecular sieves, 333, 431, 703-705, 739 Mondur TD-80,1171 Monobromopentaerythritol, 450 Monochlorourea, 1107,1267 Monoethylamme-borane, 16 Monoethyl raalonate, 523 Monomethylamine-borane, 16 Monoperoxytucdnic acid, an Penuodnlc acid... 

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