The mevalonic acid pathway

The identification of the chemical pathway by which living organisms synthesize IPP and DMAPP, and hence the whole terpene family, is a remarkable example of scientific detective 

Chemical structures of the terpene precursors. OPPi represents the pyrophosphate group, 

---

Terpenoid substances are of broad distribution and diverse function in insects. One set, elaborated by the mandibular glands of Acanthomyops claviger, acts both as a defensive secretion and as an alarm releaser. When fed Cu-labeled acetate or mevalonate, laboratory colonies of these ants produce radioactive citronellal and citral, providing unambiguous evidence for de novo synthesis of these terpenes by the ant. The incorporations of these precursors implicate the mevalonic acid pathway as the likely biosynthetic route. 

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. 

The isoprenoid side chains of quinones are biosynthesized mainly by the mevalonic acid pathway from acetyl-CoA. Another pathway to biosynthesizing isoprenoids is the so-called non-mevalonate ronte by which isopentenyldiphosphate (IPP) is formed from glyceraldehyde 3-phosphate and pyrnvate. The key molecule is the famesyl-diphosphate (FPP) that accepts other IPP molecules to form polyprenyl diphosphates. 

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... 

Gershenzon, J. Croteau, R. In Recent Advances in Phytochemistry, Biochemistry of the Mevalonic Acid Pathway to Terpenoids Towers, G. H. N. Stafford, H. A., Eds. Plenum Press New Yoik, 1990. pp.99-159. 

The percentage composition of carotenoids in plants depends on growing conditions. The average weight percent ranges are /3-carotene, 25-40% lutein, 40-60% violaxanthin, 10-20% and neoxanthin, 5-13%. Carotenoids are biosynthesized by condensation of acetyl CoA through the mevalonic acid pathway and the Porter-Lincoln pathway. 

Towers, G.H., and H.A. Stafford Biocke/rustry of the Mevalonic Acid Pathway to Terpenoids, Kluwer Academic Publishers. Nonveil. MA, 1990. 

At present, there is no doubt about the biosynthesis of ABA by the carotenoid pathway via the MEP pathway in plants. If ABA is biosynthesized by the direct pathway, the first cyclized intermediate will be ionylide-neethanol, having a hydroxyl group at C-l derived from farnesol however, ionylideneethanol has not been found in plants, so the direct pathway is not involved in ABA biosynthesis. The mevalonic acid pathway may also be excluded because almost no 13C label was incorporated into the carbons, which would be labeled in the mevalonic acid pathway in a feeding experiment with [l-13C]-D-glucose.640... 

In contrast to plants, it has been shown that fungi biosynthesize ABA via direct pathways from IDP supplied by the mevalonic acid pathway. B. cinerea and Cercospora pini-densiflorae fed with [l-13C]-D-glucose biosynthesized ABA, C-2, C-4, C-6, C-l, C-3, C-5, C-l, C-8, and C-9 of which were labeled with 13C, being coincident with the biosynthesis of IDP by the mevalonic acid pathway (Figure 2 7).640 Fungi produce ABA-related compounds, which are converted to ABA in feeding experiments. l, 4 -tr r-Diol (3) of ABA was found... 

McCaskill, D., and Croteau, R. (1993). Procedures for the isolation and quantification of the intermediates of the mevalonic acid pathway. Anal Biochem 215 142-149. 

Adam, K.P., Thiel, R., Zapp, J. and Becker, H. (1998) Involvement of the mevalonic acid pathway and the glyceraldehyde-pymvate pathway in terpenoid biosynthesis of the liverworts Ricciocarpos natans and Conocephalum conicum. Arch. Biochem. Biophys., 354,181-87. 

Monfar, M., Caelles, C., Balcells, L., Ferrer, A., Hegardt, PC. and Boronat, A. (1990) Molecular cloning and characterization of plant 3-hydroxy-3-methylglutaryl coenzyme A reductase, in Biochemistry of the Mevalonic Acid Pathway to Terpenoids (eds G.H.N. Towers and H.A. Stafford). Plenum, New York, pp. 83-97. 

Many of the enzymes involved in the mevalonic acid pathway have been described. Fig. (6) however, studies on the genetic modifications of these enzymes are scarce in the literature. Here an attempt has been made to present the most relevant data on the terpenoid pathway, the enzymes involved and the genetic engineering of them. 

Isopentenyl diphosphate isomerase (IPI E.C. 5.3.3.2) catalyzes the isomerization of isopentenyl diphosphate (IPP) to dimethylallyl diphosphate (DMADP), a previous and mandatory step to create the electrophilic allylic diphosphates needed for the condensation reaction generating geranyl diphosphate, Fig. (6). Thus, IPI is an essential enzyme in organisms which synthesize IPP through the mevalonic acid pathway as archaea, eukaryota and some Gram-positive bacteria [275, 305]. 

The basic unit in the biosynthesis of terpenes is the isoprene molecule, isopren-fenylpyrophosphate formed from acetate in the mevalonic acid pathway, which can self-condense in various ways usually head to tail , less frequently, tail to tail or head to head . 

Processes affecting the carbon-isotopic compositions of isoprenoid lipids. The isoprene carbon skeleton is indicated schematically in Figure 27. The corresponding biosynthetic reactant—equivalent in its role to acetyl-CoA—is isopentenyl pyrophosphate. As shown in Figure 29, this compound can be made by two different and fully independent pathways. The mevalonic-acid pathway was until recently thought to be the only route to isoprenoids. The deoxyxylulose-phosphate, or methylerythritol-phosphate, pathway was first discovered in Bacteria by Rohmer and coworkers (Flesch and Rohmer... 

Figure 29. Relationships h een the carbon positions in isopentenyl pyrophosphate and their sources. In the mevalonic-acid pathway, all five caibon positions in isopentenyl pyrophosphate derive from acetate and, in turn from the C-1 + C-6 and C-2 + C5 positions of glucose. In the methyierythritol-phosphate pathway, one carbon derives from the C-3 + C-4 position in glucose. Moreover, the mapping of positions from preciu ors into products of the two pathways differs sharply, as indicated by stmctures of acyclic and steroidal carbon skeletons based on the MVA (a, c) and MEP pathways (b, d).

The existence of morphologically identical plants which possess oils that have differing chemical compositions is not a new concept. In fact, the existence of infraspecific differences is widespread in the Labiatae and Compositae families, but it is not limited to them. A lew years ago Lawrence (2) showed that Ocimnm basilicum L. can contain oils that possess a variety of compositions. It was also found (hat oils contained constituents that were biosynthesized either via the shikimic acid pathway, or the mevalonic acid pathway, or both (Figure 11). A summary of the data obtained during the analysis of more than 200 separate O. basilicum plants revealed that they possessed oils that, not only contained components from single pathways or dual pathways, but also within these groupings a wide quantitative variation of constituents was also observed. A summary of these data can be seen in Tables X and XI. 

---