Data processing: structural design – modeling – simulation – and em – Simulating nonelectrical device or system – Biological or biochemical
Reexamination Certificate
2007-10-23
2007-10-23
Steadman, David J. (Department: 1656)
Data processing: structural design, modeling, simulation, and em
Simulating nonelectrical device or system
Biological or biochemical
C435S183000
Reexamination Certificate
active
10240636
ABSTRACT:
The present invention provides the structure of the enzyme 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME) synthase, a member of the cytidyltransferase family of enzymes fromEscherichia coli. CDP-ME is a critical intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis in a number of prokaryotic organisms, in algae, in the plastids of plants, and in the malaria parasite. Since vertebrates synthesize isoprenoid precursors using a mevalonate pathway, CDP-ME synthase and other enzymes of the mevalonate-independent pathway for isoprenoid production represent attractive targets for the structure-based design of selective antibacterial, herbicidal, and antimalarial drugs. Accordingly, the present invention provides methods for screening for compounds that inhibit enzymes of the mevalonate-independent pathway and pharmaceutical compositions and antibacterial formulations thereof. Further provided are methods of inhibiting the enzymes of the pathway and bacterial terpenoid synthesis and methods for treating a subject suffering from a bacterial infection.
REFERENCES:
patent: 5579250 (1996-11-01), Balaji et al.
patent: 5642292 (1997-06-01), Itai et al.
H. Jomaa et al. (1999) “Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs,” Science vol. 285, pp. 1573-1576.
Eisenreich et al.Cell Mol Life Sci. Jun. 2004;61(12):1401-26.
Sprenger et al., Proc. Natl. Acad. Sci. USA vol. 94, pp. 12857-12862, 1997.
Takahashi et al., Prroc. Natl. Acad. Sci. USA, vol. 95, pp. 9879-9884, 1998.
Seeman et al. Angew. Chem. Int. Ed. vol. 41, pp. 4337-4339, 2002.
Rohdich et al. Proc. Natl. Acad. Sci. USA, vol. 100, pp. 1586-1591, 2003.
“Encyclopedia of Molecular Biology” (Creighton, T., John Wiley and Sons, Inc. New York, 1999).
Kierzek et al., Biophys. Chem., vol. 91, pp. 1-20, 2001.
Wiencek, Annu. Rev. Biomed. Eng., vol. 1, pp. 505-534, 1999.
Ke & Doudna, Methods, vol. 34, pp. 408-414, 2004.
Derewenda et al. Acta Crystallogr. D., vol. 62, pp. 116-124, 2006.
Buts et al. (Acta Crystallogr. D., vol. 61, pp. 1149-1159, 2005).
Skarzynski et al. (Acta Crystallogr. D., vol. 62, pp. 102-107, 2006.
Ridley, Science, vol. 285, pp. 1502-1503, 1999.
McPherson, A. Current Approaches to Macromolecular Crystallization. European Journal of Biochemistry. 1990. vol. 189, pp. 1-23.
International Search Report for PCT Application No. PCT/US01/14371.
Bork, et al., “The cytidylyltransferase superfamily: Identification of the nucleotide-binding site and fold prediction.”Proteins, 22:259-266, (1995).
Herz, et al., “Biosynthesis of terpenoids: YgbB protein converts 4-diphosphocytidyl-2C-methyl-D-erythritol 2-phosphate to 2C-methyl-D-erythritol 2,4-cyclodiphosphate,”PNAS, 97:2486-2490, (2000).
Jelakovic, et al., “The three-dimensional structure of capsule-specific CMP: 2-keto-3-deoxy-manno-octonic acid synthetase fromEscherichia coli,”FEBS Lett., 391:157-161, (1996).
Jomaa et al., “Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs.”Science, 285:1573-1576, (1999).
Koppisch, et al., “Synthesis of 2-C-Methyl-D-erythritol 4-phosphate: The first pathway-specific intermediate in the methylerythritol phosphate route to isoprenoids.”Org. Lett., 2:215-17, (2000).
Kuzuyama, et al., “Formation of 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol from 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase, a new enzyme in the nonmevalonate pathway.”Tet. Lett., 41:703-6, (2000).
Kuzuyama et al., “Fosmidomycin, a specific inhibnitor of 1-Deoxy-D-Xylulose 5-phosphate reductoisomerase in the nonmevalonate pathway for terpenoid biosynthesis.” Tetrahedron Letters, 39: 7913-7916, (1998).
Luttgen, et al., “Biosynthesis of terpenoids, YchB protein ofEscherichia coliphosphorylates the 2-hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol.”PNSA, 97:1062-7, (2000).
Park, et al., “Identification of functional conserved residues of CTP:glycerol-3-phosphate Cytidylyltransferase.”J. Biol. Chem., 272:15161-6, (1997).
Rohdich, et al., Cytidine 5'-triphosphate-dependent biosynthesis of isoprenoids: YgbP protein ofEscherichia colicatalyzes the formation of 4-diphosphocytidyl-2-C-methylerythritol.PNSA, 96:11758-63, (1999).
Rohdich, et al., “Biosynthesis of terpenoids: 4-Diphosphocytidyl-2-C-methyl-D-erythritol kinase from tomato.”PNAS, 97:8251-6, (2000).
Takagi, et al., “Studies on the nonmevalonate pathway: formation of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate from 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol.”Tetr. Lett., 41:3395-8, (2000).
Veitch, et al. “The role of histidine residues in the HXGH site of CTP:phosphocholine cytidylytransferase in CTP binding and catalysis.”Eur. J. Biochem., 255:227-34, (1998).
Veitch, et al., “Substitution of serine for glycine-91 in the HXGH motif of CTP: Phosphocholine cytidylyltransferase implicates this motif in CTP binding.”Biochemistry, 35: 10743-10750, (1996).
Weber, et al., “A prototypical cytidylyltransferase: CTP:glycerol-3-phosphate cytidylyltransferase fromBacillus subtilis.”Structure. Fold. Des., 7:1113-24, (1999).
Bowman Marianne E.
Noel Joseph P.
Richard Stéphane
Foley & Lardner LLP
Noakes Suzanne M.
Reiter Stephen E.
Steadman David J.
The Salk Institute for Biological Studies
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