Bacteria isoprenoids

Isoprenoids represent the largest family of natural products, with an exceptional structural diversity. Isoprenoids are present in all living organisms. This group includes essential metabolites, such as sterols 27 (Fig. 6) of the eukaryotic plasma membranes, prenyl chains of the quinones 22 and 23 from electron transport chains, and carotenoids 25 from the photosynthetic apparatus in the plant chloroplasts, or in the phototrophic bacteria. Isoprenoids also include secondary metabolites of a more restricted distribution and with a less obvious physiologic significance. Their carbon skeleton can be derived from the combination of C5 subunits with the branched skeleton of isoprene. 

Rohmer, M., The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants, Nat. Prod. Rep., 16, 565, 1999. 

Lichtenthaler, H.K. et al., The non-mevalonate isoprenoid biosynthesis of plants as a test system for new herbicides and drugs against pathogenic bacteria and the malaria parasite, Z. Naturforsch. C 55, 305, 2000. 

ROHMER, M., KNANI, M., SIMONIN, P., SUTTER, B., SAHM, H., Isoprenoid biosynthesis in bacteria a novel pathway for the early steps leading to isopentenyl diphosphate, Biochem. J., 1993,295, 517-524. 

C-methyl-D-erythritol 2,4-cyclodiphosphate synthase catalyses the conversion of 4-diphospho-cytidyl-2-C-methyl-D-erythritol 2-phosphate to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECDP) (Equation (7)). This reaction is part of the isoprenoid biosynthesis pathway in many plants and bacteria. The structure of the E. coli enzyme bound to Mn, cytosine monophosphate, and 2-C-methyl-D-erythritol 2,4-cyclodiphosphate has been determined. The enzyme in the crystal and probably in solution is trimeric, three monomers are packed in a circular assembly with three-fold symmetry. The active site is at the interface of two adjacent monomers all the ligands bound to the Mn + come from one monomer and a MECDP molecule. The structure of this active site is shown in Figure 29 ... 

Chemistry.—The chemical structures of several bacterial menaquinones (MKs) with partly saturated isoprenoid side-chains have been studied. Spectroscopic (u.v., i.r., m.s., and H n.m.r.) and chromatographic data have been recorded for the tetrahydro-MK8 and -MK9 mixture of some nocardioform and coryneform bacteria.The main component tetrahydro-MK9 has the second and third iso-prene residues from the quinone ring saturated, i.e. has structure (159), 2-... 

Although far less numerous than the terpenoid/isoprenoid or polyketide NPs, the alkaloids (with an estimated 20,000 different structures) have a special place in NP research because a few are of great value to humans—for example, morphine, theobromine, caffeine, vincristine, quinine, codeine, cocaine, nicotine and strychnine. These often complex chemicals are found in about 20% of vascular plants and a smaller number of fungi, marine invertebrates and a few bacteria. ... 

From the many enzymes that are known to make and break C-C bonds, we first chose the two transferases, transketolase (TKT) and transaldolase (TAL), both from the Gram-negative bacterium Escherichia coli. While project B21 evolved, we learned that this microorganism holds other and so far unknown enzymes which are of interest for asymmetric syntheses. One transketolase-like enzyme, 1-deoxy-D-xylulose 5-phosphate synthase (DXS), turned out to be the first enzyme of a novel biosynthetic pathway leading to isoprenoids in bacteria, algae, and plants. The other, fructose 6-phosphate aldolase (ESA) - while similar to transaldolase - allows the direct use of the inexpensive dihydroxyacetone in aldol condensations. 

It has been established that DXS catalyzes the first step in a novel biosynthetic pathway leading to isoprenoids in bacteria, algae, plant chloroplasts, and in the malaria parasite, Plasmodium falciparum. DXS is therefore a novel target for antibiotics, herbicides, or anti-malarials. Our work has contributed to an understanding of the novel biosynthetic pathway and could further open new perspectives on how to inhibit the pathway in pathogenic bacteria, protists, or weeds. 

The mevalonate-independent pathway is present in most bacteria and all phototropic organisms. In higher plants and most algae both pathways run independently. The mevalonate pathway is located in the cytoplasm and is responsible for the biosynthesis of most sesquiterpenoids. The mevalonate-independent pathway, in contrast, is restricted to the chloroplasts where plastid-related isoprenoids such as monoterpenes and diterpenes are biosynthesised via this pathway [43-45]. Figure 4.2 illustrates the interrelationships of both biosynthetic pathways connected to Fig. 4.1 [46]. 

In addition to NAD and flavoproteins, three other types of electron-carrying molecules function in the respiratory chain a hydrophobic quinone (ubiquinone) and two different types of iron-containing proteins (cytochromes and iron-sulfur proteins). Ubiquinone (also called coenzyme Q, or simply Q) is a lipid-soluble ben-zoquinone with a long isoprenoid side chain (Fig. 19-2). The closely related compounds plastoquinone (of plant chloroplasts) and menaquinone (of bacteria) play roles analogous to that of ubiquinone, carrying electrons in membrane-associated electron-transfer chains. Ubiquinone can accept one electron to become the semi-quinone radical ( QH) or two electrons to form ubiquinol (QH2) (Fig. 19-2) and, like flavoprotein carriers, it can act at the junction between a two-electron donor and a one-electron acceptor. Because ubiquinone is both small and hydrophobic, it is freely diffusible within the lipid bilayer of the inner mitochondrial membrane and can shuttle reducing equivalents between other, less mobile electron carriers in the membrane. And because it carries both electrons and protons, it plays a central role in coupling electron flow to proton movement. 

In 1955, R. A. Morton and associates in Liverpool announced the isolation of a quinone which they named ubiquinone for its ubiquitous occurrence.484 485 It was characterized as a derivative of benzoquinone attached to an unsaturated polyprenyl (isoprenoid) side chain (Fig. 15-24). In fact, there is a family of ubiquinones that from bacteria typically contains six prenyl units in its side chain, while most ubiquinones from mammalian mitochondria contain ten. Ubiquinone was also isolated by F. L. Crane and associates using isooctane extraction of mitochondria. These workers proposed that the new quinone, which they called coenzyme Q, might participate in electron transport. As is described in Chapter 18, this function has been fully established. Both the name ubiquinone and the abbreviation Q are in general use. A subscript indicates the number of prenyl units, e.g., Q10. Ubiquinones can be reversibly reduced to the hydro-quinone forms (Fig. 15-24), providing a basis for their function in electron transport within mitochondria and chloroplasts.486 490... 

The pathway also operates in some bacteria and apparently is the sole source of isoprenoid compounds for the unicellular alga Scenedesmus.28 The pathway is outlined in Fig. 22-2. Pyruvate is decarboxylated by a thiamin diphosphate-dependent enzyme,29 and the resulting enamine is condensed with D-glyceraldehyde 3-phosphate to form 1-deoxyxylulose 5-phosphate.28, i0 31a The latter undergoes an isomeroreductase rearrange-... 

Collins, M.D. and Jones, D. (1 981) Distribution of isoprenoid quinone structural types in bacteria and their taxonomic implication. Microbiological Reviews 45, 31 6-354. 

A mevalonate-independent isoprenoid biosynthetic pathway occurring only among bacteria, algae, and plants was also identified in/ falciparum and Tgondii.Fosmidomycin, known to inhibit 1-deoxy-D-xylulose-5-phosphate isomerase in this pathway, was found to also inhibit in vitro growth of P falciparum and to cure P vinckei infection in mice. However, the same questions about whether the pathway plays an indispensable role in this parasitic organism and whether fosmidomycin inhibits the parasites by inhibiting the particular enzyme remain to be answered. 

Risatti, J.B., Rowland, S.J., Yon, D., and Maxwell, J.R. (1984) Sterochemical studies of acyclic isoprenoids—XII. Lipids of methanogenic bacteria and possible contributions to sediments. In Advances in Organic Geochemistry (Schenck, P.A., and de Leeuw, J.W., eds.), pp. 93-103, Pergamon Press, Oxford, UK. 

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