Fosmidomycin

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.

KUZUYAMA, T., SHIMIZU, T., TAKAHASHI, S., SETO, H., Fosmidomycin, a specific inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase in the nonmevalonate pathway for terpenoid biosynthesis, Tetrahedron Lett., 1998, 39, 7913-7916. 

ZEIDLER, J., SCHWENDER, J., MULLER, C WIESNER, J., WEIDEMEYER, C., BECK, E., JOMAA, H., LICHTENTHALER, H.K., Inhibition of the non-mevalonate 1-deoxy-D-xylulose 5-phosphate pathway of plant isoprenoid biosynthesis by fosmidomycin, Z. Naturforsch., 1998,53c, 980-986. 

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. 

Figure 12 Mevalonate pathway and nonmevalonate pathway. Antibiotic fosmidomycin inhibits 1-deoxy-D-xylulose 5-phosphate (DXP) reductoisomerase.

Fosmidomycin, initially discovered as a product of Strepto-myces lavendulae with antibacterial and herbicide activity, was recently shovm to act via the inhibition of IspC protein that catalyzes the first committed step in the nonmevalonate pathway of isoprenoid biosynthesis that is absent in humans (43 90, Fig. 11). Based on these findings, the compound is now under clinical evaluation as an antimalarial drug (78). 

Figure 4 Deoxyxylulose phosphate isomero-reductase (DXR) catalyzed conversion of DXP 11 into MEP 12 (a) a-ketol rearrangement, (b) retro-aldol/aldol reaction. Fosmidomycin 19, a DXR inhibitor.

Fosmidomycin 19 (Fig. 4) and its analogs are strong inhibitors of the MEP pathway, and they inhibit strongly the DXR. According to the X-ray structure of the E. coli DXR, which crystallizes in the presence of fosmidomycin, the antibiotic acts as an analog of the DXP substrate rather than as an analog of the intermediate methylerythrose phosphate (9). 

The MEP pathway is the only pathway involved in the biosynthesis of essential isoprenoids in pathogenic bacteria and in parasites, and it is absent in animals and in humans. Therefore, any enzyme of this pathway is a potential target for a novel type of antimicrobial drugs (16, 17). This concept has been validated by the mode of action of fosmidomycin, a natural antibiotic that inhibits the second step of the MEP pathway catalyzed by the deoxyxylulose phosphate reducto-isomerase (DXR). 

Finally, the dichotomy between the cytoplasmic mevalonate pathway and the plastidial MEP pathway is not strict. An exchange of metabolites occurs between the two compartments at the level of C5, Cio, and C15 prenyl diphosphates. The inhibition of one pathway (e.g., by mevinolin for the MVA pathway or by fosmidomycin for the MEP pathway) can be complemented by the other route either partially, as in most tested plant systems, or even completely, in the case of the tobacco Bright Yellow-2 cell cultures (20). In addition, a regulation of the two pathways... 

Steinbacher S, Kaiser J, Eisenreich W, Huber R, Bacher A, Rohdich F. Structural basis of fosmidomycin action revealed by the complex with 2-C-methyl-D-erythritol 4-phosphate synthase (IspC). J. Biol. Chem. 2003 278 18401-18407. 

Fosmidomycin is an antimicrobial drug that acts by inhibiting 1-deoxy-D-xylulose 5-phosphate reductoisomerase, a key enzjme of the non-mevalonate pathway of isopre-noid biosynthesis. It inhibits the synthesis of isoprenoids by Plasmodium falciparum and suppresses the growth of multidrug-resistant strains in vitro. 

In an open, uncontrolled study, fosmidomycin was administered for 3-5 days (1.2 g every 8 hours) to 27 adults with malaria, of whom 16 reported possibly drug-related adverse events (1). The most frequent adverse events were headache, weakness, myalgia, abdominal pain, and loose stools. There were two cases of raised alanine transaminase activity. 

Missinou MA, Borrmann S, Schindler A, Issifou S, Adegnika AA, Matsiegui PB, Binder R, LeU B, Wiesner J, Baranek T, Jomaa H, Kremsner PG. Fosmidomycin for malaria. Lancet 2002 360(9349) 1941-2. 

Fosmidomycin. Fosmidomycin (Fig. 9-12) was Lso-lated from a Sireplomyces fermentation broth in 1980. Its... 

Ohler, E., and Kanzler, S., Synthesis of phosphonic acids related to the antibiotic fosmidomycin from allylic a- and y-hydroxyphosphonates. Phosphorus, Sulfur Silicon Relat. Elem., 112, 71, 1996. Ohler, E., and Zbiral, E., Valence isomerism between 2,4-dienones and 2//-pyrans with dialkoxyphos-phinyl substituents. First synthesis of dialkyl 2//-pyran-4-ylphosphonates, Chem. Ber, 118, 2917, 1985. 

The enzyme 2-C-methyl-D-erythritol-4-phosphate synthetase appears to catalyse a Bilik reaction (Figure 6.10) the substrate l-deoxyxylulose-5-phosphate is converted to the title compound via an intermediate aldehyde, whose carbonyl derives from C3 of the substrate. The first step is thus a Bilik reaction and the aldehyde is subsequently reduced by the enzyme using NADPH as reductant, The X-ray crystal structure of the Escherichia coli enzyme in complex with the promising antimalarial Fosmidomycin (a hydroxamic acid) reveals a bound Mn " coordinated to oxygens equivalent to the substrate carbonyl and 03. The stereochemistry and regiochemistry follow the normal Bilik course, although the crystallographers favour an alkyl shift rather than a reverse aldol-aldol mechanism. The intermediate aldehyde has been shown to be a catalytically competent intermediate. 

The phosphorus-containing antibiotics represent an interesting and even more specialized group of naturally produced, true organophosphorus compounds many of them are of a peptide nature, the general methods of preparation of which will be considered in more detail in a later section, but fosmidomycin (105) is obtainable from Streptomyces species and currently undergoing clinical trials in human medicine. 

Di and trisubstitued vinylphosphonates (361) have been employed as substrates in iridium-catalyzed asymmetric hydrogenations in synthesis of Fosmidomycin analogues (362) by Andersson and co-workers (Scheme 82). Complete conversions and excellent stereoselectivity (up to and above 99% ee) were observed for a range of substrates with both aromatic and aliphatic groups at the prochiral carbon. 

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