Acetate-mevalonate pathway

It is well known that the steroid hormones in mammals are biosynthesized from cholesterol. This compound is derived from the acetate-mevalonate pathway through the monoterpene geranyl pyrophosphate, which undergoes several enzymatic reactions to form the triterpene squalene. 

Until 1993, all terpenes were considered to be derived from the classical acetate/mevalonate pathway involving the condensation of three units of acetyl CoA to 3-hydroxy-3-methylglutaryl CoA, reduction of this intermediate to mevalonic acid and the conversion of the latter to the essential, biological isoprenoid unit, isopentenyl diphosphate (IPP) [17,18,15]. Recently, a totally different IPP biosynthesis was found to operate in certain eubacteria, green algae and higher plants. In this new pathway glyceradehyde-3-phosphate (GAP) and pyruvate are precursurs of isopentenyl diphosphate, but not acetyl-CoA and mevalonate [19,20]. So, an isoprene unit is derived from isopentenyl diphosphate, and can be formed via two alternative pathways, the mevalonate pathway (in eukaryotes) and the deoxyxylulose pathway in prokaryotes and plant plastids [16,19]. 

There are diffent pathways by which all phenolic compounds are synthesized [6,7]. The shikimate/arogenate pathway leads, through phenylalanine, to the majority of plant phenolics, and therefore we shall centre the present revision on the detailed description of this pathway. The acetate/malonate pathway leads to some plant quinones but also to various side-chain-elongated phenylpropanoids (e.g. the group of flavonoids). Finally, the acetate/mevalonate pathway leads by dehydrogenation reactions to some aromatic terpenoids. 

Generally, terpenoids have been believed to be biosynthesized via acetate-mevalonate pathway. Aphidicolin, a tetracyclic diterpenoid isolated from moulds, Cephalosporium aphidicola [47] and Nigrospora sphaerica [48], was also proved to be biosynthesized from mevanonic acid [49]. In this pathway, isopentenyl pyrophosphate (IPP), geranylgeranyl diphosphate (GGPP), labdane-type and pimarane-type diterpenoids were proposed to be intermediate precursors of aphidicolin [50]. 

The first specific precursor for terpenoids in the cytoplasma is the Cg molecule mevalonic acid (MVA), which is built via the classical acetate/mevalonate pathway and converted by a series of phosphorylating and decarboxylation reactions into C5 isopentenyldiphosphate (IPP), the universal building block for chain elongation up to C20. In the chloroplasts, the biosynthesis of IPP starts from glyceraldehyde-3-phosphate and pyruvate to give l-deoxy-D-xylulose-5-phosphate (DOXP) via the non-mevalonate pathway as a recently detected alternative IPP route [19]. The reaction is catalyzed by the enzyme DOXP synthase and can be inhibited by a breakdown product of the herbicide clomazone [12]. 

The initiation step consists in the formation of IPP (12), and its isomer DMAPP (13). The conventional metabolic pathway to form these two molecules is called the acetate/mevalonate pathway (MVA pathway) in which three molecules of acetyl-CoA (3) condense successively to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) (5), which leads to a key intermediate molecule, namely mevalonic acid (MVA) (6). The latter is further phosphorylated and decarboxylated to form the IPP molecule (12). In Hevea brasiliensis, this cytosolic pathway was described by Lynen and Lebras" " in the early 1960s and reviewed more recently by Kekwick and Ohya." Most experimental validations were obtained by observing the incorporation of radioactive tracers, such as [2- C] MVA and [3- C]HMG-CoA. The incorporation of [ ClIPP into rubber was found to be much faster than that of [2- C] MVA. This was assumed to be due to slow conversion of MVA into IPP." Another explanation might be that the MVA pathway was not exclusive for IPP biosynthesis. Indeed less than 10 years ago, a new, mevalonate-independent, IPP biosynthesis pathway was discovered by Rohmer." This plastidic DXP-MEP pathway initiates with a... 

However, failing incoporations of C-labeled aeetate and sueeessful ones of Relabeled glycerol as well as pyruvate in hopanes and ubiquinones showed isopen-tenyldiphosphate (IPP) to originate not only from the acetate mevalonate pathway, but also from activated acetaldehyde (C2, by reaction of pyruvate and thiamine diphosphate) and glyceraldehyde-3-phosphate (C3) R. In this way, 1-deoxy-pentulose-5-phosphate is generated as the first unbranched C5 preeursor of IPP. 

Fig. 95.1 Terpene biosynthesis pathways and their subcellular localization in the plants. Different classes of terpenes are respectively formed in the cytosol or the plastid by two independent pathways in the plants, that is, acetate-mevalonate pathway (MEV) (cytosol) and methylerythritol 4-phosphate (MEP) or deoxyxylulose 5-phosphate pathway (DXP) (plastid). Mraioterpcmes, diterpenes, and tetraterpenes are derived from IPP and DMAPP Irran the plastidial MEP ot DXP pathway. Sesquiterpenes and triterpenes are biosynthesized from IPP and DMAPP from the cytosol pathway. Black square with a white question mark suggests a possible transport of IPP (isopentenylpyrophosphate) from the plastid to the cytosol. Other metabolites involved in the different steps are DMAPP dimethylallylpyrophosphate, FPP famesylpyrophosphate, GASP D- glyceraldehyde- 3-phosphate, GPP geranylpyrophosphate, GGPP geranylgeranylpyro-phosphate. TPSs in the circle correspond to terpene synthases. Broken arrows show several enzymatic steps (Adapted from Aharoni et al. [8] and Sallaud et al. [154])...

Three different metabolic pathways are known to be involved in the synthesis of different classes of phenolic compounds, namely, (1) (Ce — C3) phenylpropanoid derivatives produced by the shikimate/chorismate pathway (2) side chain elongated phenylpropanoids, flavonoids (Ce - C3 - Cg), and few quinones synthesized by the acetate/malOTiate or polyketide pathway and (3) the aromatic terpenoids synthesized throu the acetate/mevalonate pathway. 

Figure 1. C-labelling pattern of B-carotene, phytol and nona-prenyl chain of plastoquinone-9 from [l- C]glucose as found in Lemna gibba and in two green algae (black circles C-enrichment e.g 3% versus 1% at unlabelled positions new IPP pathway). Open circles This labelling was expected if the compounds would have been formed via the classical acetate/mevalonate pathway of IPP formation.

In Chlorella cells grown on [l- C]glucose the sterol carbon skeleton is not labelled according to the acetate/mevalonate pathway. Chondrillasterol, 22,23-dihydrochondrillasterol and ergost-7-enol of Chlorella were labelled in a different way... 

In contrast to chondrillasterol, in the higher plant Lemna gibba, which was also grown on [l- C]glucose (6), sitosterol was labelled as expected via the acetate/mevalonate pathway (Fig. 1). [1- C]Glucose essentially labelled all carbon positions of sitosterol which correspond to C-2, C-4 and C-5 of IPP (Fig. 2). Some minor but significant C-enrichment was also found at carbon positions which correspond to C-I of IPP. This can be interpreted in the frame of the incorporation of C02 (liberated from [l- C]glucose via the oxidative pentose phosphate cycle) into IPP possibly via the leucine bypass or the mevalonate shunt. 

Acetyl CoA is the starting material for the biosynthesis of the fatty acids. It is used for the synthesis of the fatty acids by the acetate-malonate pathway. With the terpenoids we become acquainted with a second, large group of natural products whose biosynthesis starts from acetyl CoA. The terpenoids are furnished via the acetate-mevalonate pathway. 

The acetate-mevalonate pathway. In principle, we have already discussed this route. It is concerned with the formation of cyclic terpenes which can be dehydrogenated to aromatic systems. An example of such a terpene with aromatic character is thymol. This pathway is relatively unimportant in higher plants. Of the three pathways listed we have still to discuss pathways 1 and 2. 

This completes our discussion of the phenols, the second largest group of secondary plant substances after the terpenoids. Listing the biosynthetic pathways in order of increasing importance for higher plants, phenols are formed by the acetate-mevalonate pathway, the acetate-malo-nate pathway, and, particularly, the shikimic acid pathway (Fig. 112). The cinnamic acids occupy a central position in phenol metabolism, participating as they do in the biosynthesis of all other important phenols. 

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