Plants HMG-CoA

Isoprenoid biosynthetic pathways produce an astonishing variety of products in different cell types and different species. Despite this diversity, the beginning of isoprenoid biosynthesis appears to be identical in most of the species investigated (e.g., yeast, mammals, and plants). (HMG-CoA = / -hydroxy-/3-methylglutaryl-CoA)... 

Further research activities have included the partial characterization of the plant HMG-CoA reductase and the study of the interrelationship between the cytoplasmic and organelle me-valonate pathways. He has also showed that mitochondrial biomembranes of most plants simultaneously contain two or more homoiogues of ubiquinones as electron carriers. More recently his research has been concerned with the de novo fatty acid and lipid biosynthesis as affected by xenobiotics. Here Hartmut LIchtenthaier has presented evidence that the plastidic acetyl-CoA carboxylase is the target for various classes of new herbicides. 

Bach TJ, Wettstein A, Boronat A, Ferrer A, Enjuto M, Gruissem W, Narita JO. Properties and molecular cloning of plant HMG-CoA reductase. In Patterson GW, Nes WD, editors. Physiology and Biochemistry of Sterols, American Oils Chemists Sociandy, Champaign, Illinois, 1991 29-49 ... 

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). 

One of the best therapeutic approaches may be to prevent absorption of cholesterol from the intestines by inclusion of a higher fiber content in the diet.66 Supplementation with a cholesterol-binding resin may provide additional protection. Plant sterols also interfere with cholesterol absorption. Incorporation of esters of sitostanol into margarine provides an easy method of administration. Supplemental vitamin E may also be of value.q Another effective approach is to decrease the rate of cholesterol synthesis by administration of drugs that inhibit the synthesis of cholesterol. Inhibitors of HMG-CoA reductase,s hh (e.g., vaLostatin) iso-pentenyl-PP isomerase, squalene synthase (e.g.,... 

Plant sterols inhibit the intestinal absorption of cholesterol and so have a useful hypocholesterolemic action. They also inhibit endogenous synthesis of cholesterol, by inhibiting and repressing the regulatory enzyme of cholesterol synthesis, hydroxymethylglutaryl (HMG)-CoA reductase. Other compounds synthesized from mevalonate also inhibit and repress HMG-CoA reductase and have a hypocholesterolemic action, including squalene (found in relatively large amounts in olive oil), ubiquinone (Section 14.6), and the tocotrienols (Section 4.1). 

The IBP and its products are displayed in Figure 12.1. HMG-CoA, ultimately derived from acetyl-CoA is converted to mevalonate via the enzyme HMG-CoA reductase (HMGR) [8]. This reaction is the rate-limiting step in the pathway. Mevalonate is then phosphorylated via mevalonate kinase (MK) to yield 5-phosphomevalonate [9]. IPP is formed following additional phosphorylation and decarboxylation steps [10]. Isomerization of IPP via the enzyme IPP isomerase yields DMAPP [11]. In mammals, the enzyme farnesyl pyrophosphate synthase (FDPS) catalyzes the synthesis of both GPP and FPP [12]. In plants, a separate GPP synthase has been identified [13]. GPP is a key intermediate in plants as it serves as the precursor for all monoterpenes. In animals, however, GPP appears to serve only as an intermediate in the synthesis of FPP. Very low basal levels of GPP have been measured in cell culture, although cellular GPP levels can become markedly increased in the setting of FDPS inhibition [14]. 

The classic route for the formation of the C5 building blocks of terpenoid bios)mthesis in plants is via the reactions of the mevaionate pathway, first demonstrated in yeast and mammals. This well-characterized sequence (Fig. 5.3) involves the stepwise condensation of three molecules of acetyl coenz)mie A (AcCoA) to form the branched C6 compound, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Following the reduction of HMG-CoA to mevalonic acid, two successive phosphorylations and a decarboxylationelimination yield the C5 compound, IFF. 

Korth, K.L., Stermer, B.A., Bhattacharyya, M.K. and Dixon, R.A. (1997) HMG-CoA reductase gene families that differentially accumulate transcripts in potato tubers are developmentally expressed in floral tissues. Plant Mol Biol, 33, 545-51. 

Rlat, J. and Mensink, R.R., Effects of plant stanol esters on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase mRNA expression in mononuclear blood cells of healthy men and women, EASES J., 16, 258, 2002. 

Fig. 6), led to the discovery of the mevalonate pathway leading to IPP 7 and DMAPP 8 (Fig. 1). In this pathway, isoprene units are derived, like fatty acids, from acetyl-coenzyme A 1. The key intermediate is mevalonate 4, which results from the reduction of hydroxymethylglutaryl-coenzyme A 3 catalyzed by the HMG-CoA reductase, and represents the committed step of the pathway. Confirmation of this pathway was obtained for the biosynthesis of plant sterols, triterpenes, and sesquiterpenes. 

The biosynthesis of cholesterol, related steroids, and phytosterols is dealt with in this section whereas the further metabolism of these classes and the remaining nonsteroidal triterpenoids are covered in the following two sections. Reviews have appeared on the biosynthesis of sterols and higher terpenoids, the in vivo metabolism of steroids in primates" and in plant tissue culture," and dietary feedback control of cholesterol synthesis." The latter contains a reasoned defence of the hypothesis that HMG-CoA reductase is controlled by alterations to its supporting microsomal membrane. Abstracts of a symposium on all aspects of steroid biosynthesis have appeared." ... 

HMG-CoA reductase activity has been detected in mammals, birds, insects, reptiles, fish, higher plants, moulds, yeast and bacteria [112]. HMG-CoA reductase probably is present in any life form capable of synthesizing isoprenoids. In mammals, HMG-CoA reductase activity has been detected in many tissues (Table 3). The highest quantities are present in liver and intestine, which together provide 2/3-3/4... 

Other medically important polyketides include the antibiotics doxorubicin (14-hydroxydaunomycin Fig. 5-23), rifamycin (Box 28-and the antifimgal pimaricin, griseofulvin, and amphotericin (Fig. 21-10), the HMG-CoA reductase inhibitor lovastatin, the 2-butanyl-4-methylthreonine of cyclosporin A (Box 9-F), and other immunosuppressants such as rapamycin. Many characteristic plant products, including stilbenes and chalcones (Box 21-E), are polyketides. A variety of different polyketides serve as phytoalexins. Some such as aflatoxin are dangerous toxins. Ants and ladybird beetles make toxic polyamine alkaloids using a polyketide pathway. ... 

A basic question in which our laboratory has been interested over the last few years revolves around the problem of MVA synthesis and the flow of this compound to the major isopentenoid compounds in the plant cell. The pathway for the biosynthesis of polyisoprenoids and the position of the key-resulatins enzyme HMG-CoA reductase is summarized in Figure 1. Our studies and those of other groups have revealed that the regulatory role of HMG-CoA reductase does not seem to be confined only to mammals (1-8). but can also be extended to plants (9-22) and fungi (23-27). 

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