Isoprenoid biosynthesis inhibitors

Table 9.2 Incorporation rate of [2-14C]-pyruvate into monoterpenes of isolated peppermint oil gland secretory cells in the presence of fosmidomycin, a specific inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an enzyme of the mevalonate-independent pathway of isoprenoid biosynthesis.

H Jomaa, J Wiester, S Sanderbrand, B Altincicek, C Weidemeyer, M Hintz, I Tur-bachova, M Eberl, J Zeidler, HK Lichtenthaler, D Soldati, E Beck. Inhibitors of nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285 1573-1576, 1999. 

Lichtenthaler, H.K. (2000) Non-mevalonate isoprenoid biosynthesis enzymes, genes and inhibitors. Biochem. Soc. Trans., 28, 785-9. 

Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Tiirbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 1999 285 1573-1576. 

A second pathway based upon small molecule diphosphates, isoprenoid biosynthesis, may rival the importance of nucleotide metabolism in the treatment of human disease [201]. Because isoprenoids have important roles in heart disease, bone disease, and cancer, various groups have investigated ways to elevate the concentration and target the delivery of isoprenoid pathway inhibitors using prodrug strategies. 

Mevinolin has been described [1] as a potent and specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the formation of MVA, the first committed step in isoprenoid biosynthesis. Assuming that ABA is synthesized from a larger precursor, one would expect mevinolin to be without effect on short-term ABA biosynthesis. However, as shown in Table 1, mevinolin strongly inhibited ABA accumulation in water-stressed Xanthium leaves, 50% inhibition being caused by approximately 0.4 mM mevinolin. Attempts to reverse the inhibition with prior or simultaneous MVA applications failed (Table 2). This indicates that HMG-CoA reductase is not the critical step in ABA biosynthesis that is blocked by mevinolin. It must be assumed, therefore, that mevinolin inhibits other reactions in the ABA biosynthetic pathway. Although reversal of mevinolin inhibition of growth by MVA has been observed in plants [3], failure to obtain reversal has been observed with the accumulation of sesquiterpenoid phytoalexins in potato [21] and tobacco [6]. 

Mevalonate kinase [E.C.2.7.1.36 (5) -> (6)] preparations from several plants are inhibited by geranyl, geranylgeranyl, farnesyl, and phytyl pyrophosphates, the most potent inhibitors being the latter two compounds.This enzyme may, therefore, be a control point of isoprenoid biosynthesis in plants. A cell-free system for conversion of mevalonic acid (5) into mevalonic acid S-pyro-phosphate (7) has been prepared from the sapogenin-producing plant Agave americana. ... 

HMG-CoA reductase mediates the first committed step in sterol biosynthesis. The active forms of the reductase inhibitors are structural analogs of the HMG-CoA intermediate (Figure 35-3) that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme and thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins. It is not known whether this has biologic significance. 

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 statins have achieved major importance as inhibitors of cholesterol biosynthesis and they are used in humans for the treatment of coronary disease. These compounds block isoprenoid formation by inhibiting the key enzyme, hydroxymethylglutaryl co-enzyme A reductase (HMGCoA reductase). This pathway is described in Chapter 5. The active form of the statins, in which the lactone ring is opened, has a formal resemblance to HMGCoA. This inhibition... 

On the other hand, HMG-CoA reductase inhibitors have also been shown to decrease the biosynthesis of other biologically important isoprenoid compounds derived from mevalonate. Thus, there has been continued interest in developing hypolipidemic agents that inhibit the enzymes involved specifically in the later stages of cholesterol biosynthesis. Zaragozic acid derivatives were isolated from several microbial species and they exhibited dose-dependent inhibition of cholesterol biosynthesis as potent squalene synthase inhibitors. Viridiofungins, bisabosquals, macrolactins, CJ-15,183, CJ-13,981 and CJ-13,982 were also isolated as mammalian squalene synthase inhibitors of microbial origin. 

Some plant growth retardants can inhibit ABA biosynthesis in the fungus Cerco-spora rosicola [22]. The most effective were paclobutrazol, ancymidol and decylimidazole [21]. CCC, Alar and paclobutrazol also act as inhibitors of GA biosynthesis and both ABA and GA are synthesized via the isoprenoid pathway. However, different growth inhibitors act at different points on the pathway and thus may inhibit either or both ABA and GA biosynthesis. 

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