Isoprenoid diphosphate synthases

Evidence for de novo synthesis of pheromone components was obtained by showing that labeled acetate and mevalonate were incorporated into ipsdienol by male Ips pini [103,104]. Similarly, labeled acetate and other labeled intermediates were shown to be incorporated into frontalin in a number of Dendroctonus species [105]. Possible precursors to frontalin include 6-methyl-6-hep-ten-2-one, which was incorporated into frontalin by D. ruffipennis [106]. The precursor 6-methyl-6-hepten-2-one also was shown to be converted to bre-vicomin in the bark beetle, Dendroctonus ponderosae [107]. In addition, the expression patterns of HMG-CoA reductase and HMG-CoA synthase are tightly correlated with frontalin production in Dendroctonus jeffreyi [108, 109]. A geranyl diphosphate synthase cDNA from I. pini was also isolated, functionally expressed, and modeled [110]. These data indicate that the de novo isoprenoid biosynthetic pathway is present in bark beetles. A variety of other monoterpene alcohols such as myrcenol, pityol, and sulcitol are probably synthesized through similar pathways [111]... 

Mevalonate kinase deficiency. Mevalonate kinase and farnesyl-diphosphate synthase are localized in the peroxisome and are involved in the synthesis of isoprenoids. Mevalonate kinase deficiency causes severe developmental delay, dysmorphic features and early death. Mevalonate deficiency has also been observed in the hyperimmuno-globulinemia-and periodic fever syndrome. 

Prenylation, the key step in terpene biosynthesis, is catalyzed by prenyltransferases. These enzymes are responsible for the condensation of isopentenyl pyrophosphate (IPP) with an allyl pyrophosphate, thus yielding isoprenoids. Numerous studies have been performed with fluorinated substrates in order to determine the mechanism of the reactions that involve these enzymes prenyltransferases, farnesyl diphosphate synthase (FDPSase), famesyltransferase (PFTase), and IPP isomerase. These studies are based on the potential ability of fluorine atoms to destabilize cationic intermediates, and then slow down S l type processes in these reactions. 

Longer chain isoprenoids are synthesized via two other isoprenyl diphosphate enzyme systems in mammals [21]. Long E-isoprenyl diphosphate synthase (IDS) produces the side chains of ubiquinone. The length of the side chain varies amongst species, and in humans a C50 synthase has been identified [22]. Dehydrodolichyl diphosphate synthase, the only Z-IDS found in mammals, is responsible for the synthesis of the sugar carriers dohchol and dolichyl phosphate [23]. Plants have additional Z-IDS which can catalyze the production of very long isoprene species, such as natural... 

Wiemer, A.J., Yu, J.S., Lamb, K.M., Hohl, R.J., and Wiemer, D.F. (2008). Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors. Bioorg Med Chem 16 390-399. 

Bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically for treatment of bone diseases. Many of their effects may be mediated by depletion of geranylgeranyl diphosphate, and Wiemer and coworkers have discovered a number of novel pivaloyloxymethyl-modified isoprenoid bisphosphonates (251) that selectively inhibited geranylgeranyl diphosphate synthase. They found that addition of pivaloyloxymethyl moieties to isoprenoid bisphosphonates increased their potency towards cellular geranylgeranylation even though this modification decreased their in vitro inhibition of geranylgeranyl diphosphate synthase. Moreover, pivaloyloxymethyl modifications more effectively increased the cellular activity of the more polar isoprenoid bisphosphonates. 

FIGURE 1.4 Proposed biosynthetic route for the biosynthesis of (A) squalene oxide (squalene-2,3-oxide) via the isoprenoid pathway and (B) triterpene saponins of the dammarane-type and oleanane-type from squalene oxide. PP, diphosphate group GPS, geranyl phosphate synthase FPS, farnesyl phosphate synthase NADPH, nicotinamide adenine dinucleotide phosphate. 

The terpenes, carotenoids, steroids, and many other compounds arise in a direct way from the prenyl group of isopentenyl diphosphate (Fig. 22-1).16a Biosynthesis of this five-carbon branched unit from mevalonate has been discussed previously (Chapter 17, Fig. 17-19) and is briefly recapitulated in Fig. 22-1. Distinct isoenzymes of 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) in the liver produce HMG-CoA destined for formation of ketone bodies (Eq. 17-5) or mevalonate.7 8 A similar cytosolic enzyme is active in plants which, collectively, make more than 30,000 different isoprenoid compounds.910 However, many of these are formed by an alternative pathway that does not utilize mevalonate but starts with a thiamin diphosphate-dependent condensation of glyceraldehyde 3-phosphate with pyruvate (Figs. 22-1,22-2). 

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