Isoprenoid intermediates

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

The antimicrobial action of ethambutol, like that of isoniazid, is specific for mycobacteria, suggesting a target in the unique components of the mycobacterial cell wall. Cells treated with ethambutol accumulate an isoprenoid intermediate, decaprenyl-arabinose which is the source ofarabinose in the arabinogalactan polymer. This suggests that ethambutol blocks assembly of the arabinogalactan through inhibition of an arabinosyl transferase enzyme. 

In the next segment of the pathway, mevalonate is converted to squalene, which is cyclized to form lanosterol. The first stage in this sequence of reactions is the synthesis of the five-carbon isoprenoid intermediates, isopentenyl pyro-... 

In recent years, there has been great interest in the pleiotropic effects of statins (Table 3). Many of these effects have been attributed to HMG-CoA reductase inhibition and the subsequent impairment in the synthesis of isoprenoid intermediates, which are downstream products of the cholesterol biosynthetic pathway. As a consequence, isoprenylation of proteins involved in intracellular signaling may be prevented, resulting in a variety of effects, such as an increase in bioavailability of endothelium-derived nitric oxide (53). 

Figure 6.4 De novo synthesis of cholesterol. Pathway of cholesterol biosynthesis. Synthesis begins with the transport of acetyl-CoA from the mitochondrion to the cytosol. The rate-limiting step occurs at the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase catalysed step. The phosphorylation reactions are required to solubilise the isoprenoid intermediates in the pathway. Intermediates in the pathway are used for the synthesis of prenylated proteins, dolichol, coenzyme Q and the side chain of haem a.

Ethambutol is thought to block assembly of the arabinogalactan polysaccharide by inhibition of an arabinotransferase enzyme. Cells treated with ethambutol accumulate the isoprenoid intermediate decaprenylarabinose, which supplies arabinose units for assembly in the arabinogalactan polymer. 

Cholesterol is synthesized mainly in the liver by a three-stage process. All 27 carbon atoms in the cholesterol molecule are derived from acetyl-CoA. The first stage is the synthesis of the activated five-carbon isoprene unit, isopentenyl pyrophosphate. Six molecules of isopentenyl pyrophosphate then condense to form squalene in a sequence of reactions that also synthesize isoprenoid intermediates that are important in protein isoprenylation modifications. The characteristic four-ring structure of cholesterol is then formed by cycUzing of the linear squalene molecule. Several demethylations, the reduction of a double bond, and the migration of another double bond result in the formation of cholesterol. Figure 34-1 provides an overview of cholesterol biosynthesis. 

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

The precise mechanism for the antiproliferative property of tocotrienols is imcertain, but it may lie in its prenylated side chain involved in the prodnction of isoprenoid intermediates from the mevalonate biosynthetic pathwayThese intermediates are thought to be involved in the prenylation of several signal-transduction proteins, including the Ras protein, essential for normal cell growth. 

The steps required to convert mevalonic acid to the active-isoprenoid intermediate have been worked out with some assurance. The initial step involves the phosphorylation of mevalonic acid to mevalonic acid-5-phosphate by an enzyme called mevalonic kinase. This enzyme was found in yeast by Tchen (1958). The properties of the mevalonic kinase of liver have been described in detail by Levy and PopjAK (1960). The kinase is inhibited by p-chloromercuribenzoate but not by iodoacetamide. The enzyme requires Mg++, Mn++, or Ca++ and ATP or inosine triphosphate. The kinase is specific for the (+) form of mevalonic acid. Mevalonic acid-5-phosphate is phosphorylated further to give mevalonic acid-5-pyrophos-phate (de Waard and Popjak, 1959 Henning et al. 1959). The purified enzyme (Bloch et al., 1959) requires a divalent metal ion for activity (Mg++ is preferable) and has no pronounced pH optimum. Mevalonic acid pyrophosphate then undergoes simultaneous dehydration and decarboxylation to yield isopentenylpyro-phosphate (Lynen et al., 1958 Chaykin et al., 1958). The enzyme concerned with the dehydration and decarboxylation has been purified (Bloch et al., 1959) and shown to have a pH optimum between 5.5 and 7.4 and to require a divalent metal ion (Mg++, Mn++, Fe++ or Co++). The series of reactions in which mevalonate is converted to isopentenylpyrophosphate is outlined in Figure 6. Brodie et al. (1963) have established a new pathway for the biosynthesis of mevalonic acid from malonyl CoA. The importance of this particular pathway in the synthesis of sterols is still unknown. 

Bonner and Arreguin (1949) had suggested an acetate isoprenoid intermediate step in the biosynthetic pathway for rubber (Fig. 3). It now became evident that the pathway of cholesterol biosynthesis must include a compound which could be derived from acetate and converted to an isoprenoid intermediate. 

ON THE ORIGIN OF ISOPRENOID INTERMEDIATES FOR THE SYNTHESIS OF PLASTOQUINONE-9 AND B-CAROTENE IN DEVELOPING CHLOROPLASTS... 

Cross-talk is also evident in the biosynthesis of certain sesquiterpenes and diterpenes. In chamomile flowers (see Section 3.5.1) it is thought that export of isoprenoid intermediates formed by the 1-DXP pathway takes place into a cellular space which has access to IPP derived from both 1-DXP and mevalonate pathways (Adam etal. 1999). 

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