Mevalonic acid early pathway

Since carotenoids are isoprenoids, they share a common early pathway with other biologically important isoprenoids such as sterols, gibberellins, phytol and the terpenoid quinones (Fig. 13.3). In all cases, these compounds are derived from the C5 isoprenoid, isopentenyl diphosphate (IPP). Until a few years ago it was believed that a single pathway from the Cg precursor mevalonic acid (MVA) formed IPP, which itself was synthesised from hydroxymethylglutaryl coenzyme A (HMG CoA) by the action of HMG... 

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). 

The early steps in the ergot alkaloid biosynthetic pathway are outlined in Fig. 1. The first determinant and rate-limiting step is the prenylation of tryptophan to 4-(y,y-dimethylallyl)tryptophan (DMAT), catalyzed by dimethy-lallyl-diphosphate L-tryptophan dimethylallyltransferase (DMAT synthase EC 2.5.1.34) (Heinstein et al., 1971 Gebler and Poulter, 1992). The prenyl group for the DMAT synthase reaction is provided in the form of dimethylallyl diphosphate (DMAPP), which is derived from mevalonic acid. After the formation of DMAT, the free amino group of this intermediate is N-methylated with a methyl group donated by S-adenosylmethionine (AdoMet). The N-methylated DMAT is then converted into chanoclavine I by closure of the... 

The gibberellin biosynthetic pathway can be divided into two major sections, the early pathway, from mevalonic acid (MVA) to GAi2 aldehyde (a single pathway), and the pathways subsequent to least four at this time). 

The isoprenoids are derived from mevalonic acid (MVA), which is formed from three molecules of acetyl-CoA (Fig. 3). Two molecules of acetyl-CoA are condensed, yielding acetoacetyl-CoA. Subsequently, this product is coupled with another molecule of acetyl-CoA to yield 35-hydroxy-3-methylglutaryl-CoA (HMG-CoA). By reduction of HMG-CoA MVA is obtained. MVA is further converted in some steps to yield the Cs-unit isopentenyl diphosphate (IPP), which is then isomerized to dimethy-lallyl diphosphate (DMAPP), the starter molecule of the isoprenoid pathway. Coupling of DMAPP with one or more IPP molecules yields the basic structures which form the backbone of terpenoid biosynthesis. A number of reviews on the early steps in the terpenoid biosynthesis have been published (70-77). 

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... 

Phinney, B. O. and C. R. Spray, Plant hormones and the biosynthesis of gibberellins The early-13-hydroxylation pathway leading to GAi, in Biochemistry of the Mevalonic Acid Pathway to Terpenoids (G. H. N. Towers and H. A. Stafford, eds.). Recent Advances in Phytochemistry Vol. 24, 203-218, Plenum Press, New York, 1990. 

A (HMG-CoA) reductase inhibitors that block the HMG-CoA reductase (HMGR) conversion of HMG-CoA into mevalonic acid, an early and rate-limiting step in de novo cholesterol biosynthesis. The lactone ring of the statin molecule is reversibly converted to an open acid that resembles the HGM portion of HMG-CoA (Figure 8.2), the substrate of the reaction catalyzed by the HMGR enzyme (Endo, 2004). The mechanism by which statins lower cholesterol is an important factor in its success. Previous attempts to reduce cholesterol biosynthesis, such as the Triparanol compound that blocks a late step in the pathway, were ultimately unsuccessful due to accumulation of potentially toxic precursors and adverse effects. 

However, there are other changes. There is an increase in sterol (chiefly ergosterol) and a shift in the relative proportions of carotenoids (8). These effects are prevented by the protein synthesis inhibitor cycloheximide (9). Since carotenoids and sterols share a common biosynthesis to farnesyl pyrc hosphate, the hormones must act by derepressing the synthesis of enzjnnes early in this pathway. Preliminary experiments have shown that mevalonate kinase activities are unaffected by trisporic acid, indicating that this is Unlikely to be the limiting enzjnae a more likely candidate is 3-hydroxy-3 ethylglutaryl CoA reductase. 

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