Skip to main content Accessibility help
×
Home

Inhibitors of imidazoleglycerolphosphate dehydratase as herbicides

  • Daisaku Ohta (a1), Ichiro Mori (a2) and Eric Ward (a3)

Abstract

An enzyme-directed approach has led to finding specific inhibitors of imidazoleglycerolphosphate dehydratase (IGPD), which catalyzes a dehydration reaction of imidazoleglycerol phosphate (IGP) to form imidazoleacetol phosphate in the biosynthesis of histidine. These newly synthesized IGPD inhibitors showed wide-spectrum, postemergence herbicidal activity at application rates ranging from 0.05 to 2 kg ai ha−1. IGPD from wheat germ was purified to apparent homogeneity and characterized, and IGPD cDNAs were isolated from Arabidopsis and wheat cDNA libraries. Both the purified plant enzyme and the recombinant enzymes, which have been prepared by expressing the isolated IGPD cDNAs in the baculovirus/insect cell system, were used for establishment of an in vitro enzyme assay for inhibitor evaluation. Enzyme inhibitors were designed and synthesized by considering the structure of the substrate, IGP, and the inhibition activities were enhanced by a systematic structure—activity relationship study in vitro. Three triazole phosphonates, IRL 1695, IRL 1803, and IRL 1856, inhibited the reaction of the enzyme with Ki values of 40 ± 6.5 nM, 10 ± 1.6 nM, and 8.5 ± 1.4 nM, respectively, and were highly cytotoxic to cultured plant cells. Plant cell growth inhibition was completely reversed only by l-histidine, proving that the cytotoxicity was primarily caused by the inhibition of histidine biosynthesis. These new IGPD inhibitors have demonstrated that the specific inhibition of plant IGPD is lethal to plants. Further, treatment of Arabidopsis with IRL 1803 affected gene expression of eight enzymes involved in the biosynthesis of aromatic amino acids, histidine, lysine, and purines. These effects were reversed by the addition of l-histidine, indicating that the changes in gene expression were caused by the inhibition of l-histidine biosynthesis. These results indicate that higher plants, like microorganisms, are capable of cross-pathway metabolic regulation.

Copyright

Corresponding author

References

Hide All
Alifano, P., Fani, R., Lio, P., Lazcano, A., Bazzicalupo, M., Carlomagno, M. S., Bruni, C. B. 1996. Histidine biosynthetic pathway and genes: structure, regulation and evolution. Microbiol. Rev. 60: 4469.
Ames, B. N. 1957. The biosynthesis of histidine: d-erythro-imidazoleglycerol phosphate dehydratase. J. Biol Chem. 228: 131143.
Ames, B. N. and Mitchell, H. K. 1955. The biosynthesis of histidine: imidazoleglycerol phosphate, imidazoleacetol phosphate and histidinol phosphate. J. Biol. Chem. 212: 687697.
Berlyn, M. B. 1967. Gene-enzyme relationships in histidine biosynthesis in Aspergillus nidulans . Genetics 57: 561570.
Bond, T. J. and Akers, J. 1961. Mechanism of growth inhibition of Escherichia coli by 3-amino 1,2,4-triazole. J. Bacteriol. 81: 327328.
Brady, D. R. and Houston, L. L. 1973. Some properties of the catalytic sites of imidazoleglycerol phosphate dehydratase–histidinol phosphate phosphatase, a bifunctional enzyme from Salmonella typhimurium . J. Biol. Chem. 248: 25882592.
Burns, E. R., Buchanan, G. A., and Carter, M. C. 1971. Inhibition of carotenoid synthesis as a mechanism of action of amitrole, dichlormate and pyriclor. Plant Physiol. 47: 144148.
Carlomagno, M. S., Chiariotti, L., Alifano, P., Nappo, A. G., and Bruni, C. B. 1988. Structure and function of the Salmonella typhimurium and Escherichia coli K-12 histidine operons. J. Mol. Biol. 203: 585606.
Carsiotis, M. and Jones, R. F. 1974. Cross pathway regulation: tryptophanemediated control of histidine and arginine biosynthetic enzymes in Neurospora crassa . J. Bacteriol. 119: 889892.
Chiariotti, L., Nappo, A. G., Carlomagno, M. S., and Bruni, C. B. 1986. Gene structure in the histidine operon of Escherichia coli: identification and nucleotide sequence of the hisB gene. Mol. Gen. Genet. 202: 4247.
Duggleby, R. G. 1988. Determination of inhibition constants, I 50 values and the type of inhibition for enzyme-catalyzed reactions. Biochem. Med. Metab. Biol. 40: 204212.
Duke, S. O. 1990. Overview of herbicide mechanisms of action. Environ. Health Perspect. 87: 263271.
Ebbole, D. J., Paluh, J. L., Plamann, M., Sachs, M. S., and Yanofsky, C. 1991. cpc-1, the general regulatory gene for genes of amino acid biosynthesis in Neurospora crassa, is differentially expressed during the asexual life cycle. Mol. Cell Biol. 11: 928934.
Fink, G. R. 1964. Gene-enzyme relations in histidine biosynthesis in yeast. Science 146: 525527.
Flint, D., Emptage, M. H., Finnegan, M. G., Fu, W., and Johnson, M. K. 1993. The role and properties of the iron-sulfur cluster in Escherichia coli dihydroxy-acid dehydratase. J. Biol. Chem. 268: 1473214742.
Glaser, R. D. and Houston, L. L. 1974. Subunit structure and photooxidation of yeast imidazoleglycerolphosphate dehydratase. Biochemistry 13: 51455152.
Gottesman, S. 1984. Bacterial regulation: global regulatory networks. Annu. Rev. Genet. 18: 415441.
Guyer, D., Patton, D., and Ward, E. 1995. Evidence for cross-pathway regulation of metabolic gene expression in plants. Proc. Natl. Acad. Sci. USA 92: 49975000.
Hawkes, T. R., Cox, J. M., Barnes, N. J., et al. 1993. Imidazole glycerol phosphate dehydratase: a herbicidal target. in Proceedings of the Brighton Crop Protection Conference—Weeds. Farnham, Great Britain: British Crop Protection Council, pp. 739744.
Haworth, P. and Siehl, D. L. 1990. Design of enzyme-targeted agrochemicals. J. Agric. Food Chem. 38: 12711273.
Heim, D. R. and Larrinua, I. M. 1989. Primary site of action of amitrole in Arabidopsis thaliana involves inhibition of root elongation but not of histidine or pigment biosynthesis. Plant Physiol. 91: 12261231.
Hilton, J. L. 1969. Inhibitions of growth and metabolism by 3-amino-1,2,4-triazole (amitrole). J. Agric. Food. Chem. 17: 182198.
Hilton, J. L., Kearney, P. C., and Ames, B. N. 1965. Mode of action of the herbicide, 3-amino-1,2,4-triazole (amitrole): inhibition of an enzyme of histidine biosynthesis. Arch. Biochem. Biophys. 112: 544547.
Hinnebusch, A. G. 1992. The molecular and cellular biology of the yeast Saccharomyces . In Jones, E. W., Pringle, J. R., and Broach, J. R., eds. Gene Expression. Volume II. Plainview, NY: Cold Spring Harbor Laboratory Press, pp. 319411.
Johnston, H. M. and Roth, J. R. 1979. Histidine mutants requiring adenine: selection of mutations with reduced hisG expression in Salmonella typhimurium . Genetics. 92: 115.
Kishore, G. M. and Shah, D. M. 1988. Amino acid biosynthesis inhibitors as herbicides. Annu. Rev. Biochem. 57: 627663.
Lam, P.Y.S., Jadhav, P. K., Eyermann, C. J., et al. 1994. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 263: 380384.
Lauble, H., Kennedy, M. C., Beinert, H., and Stout, C. D. 1992. Crystal structures of aconitase with isocitrate and nitroisocitrate bound. Biochemistry 31: 27352748.
Legerton, T. L. and Yanofsky, C. 1985. Cloning and characterization of the multifunctional his3 gene of Neurospora crassa . Gene 39: 129140.
Loper, J. C. 1961. Enzyme complementation in mixed extracts of mutants from Salmonella histidine B locus. Proc. Natl. Acad. Sci. USA 46: 14401450.
Mano, J., Hatano, M., Koizumi, S., Tada, S., Hashimoto, M., and Scheidegger, A. 1993. Purification and properties of a monofunctional imidazoleglycerol–phosphate dehydratase from wheat. Plant Physiol. 103: 733739.
Matringe, M., Camadro, J.-M., Labbe, P., and Scalla, R. 1989. Protoporphyrinogen oxidase as molecular site for diphenyl ether herbicides. Biochem. J. 260: 232235.
Mauer, W., Gerber, H. R., and Rufener, J. 1987. CGA 136&872: a new post-emergence herbicide for the selective control of Sorghum spp. and Ecymus repens in Maize. in Proceedings of Brighton Crop Protection Conference—Weeds. Volume 1. Farnham, Great Britain: British Crop Protection Council, pp. 4148.
Miflin, B. J. 1980. Histidine biosynthesis. in Miflin, B. J., ed. The Biochemistry of Plants. Volume 5. Amino Acids and Derivatives. New York: Academic Press, pp. 533539.
Moore, J. F., Parker, A. R., Davisson, V. J., and Schwab, J. M. 1993. Stereochemical course of the Escherichia coli imidazoleglycerol phosphate dehydrogenase reaction. J. Am. Chem. Soc. 115: 33383339.
Morgaliash, E., Novogrodsky, A., and Schefter, A. 1960. Irreversible reaction of 3-amino-1,2,4-triazole and related inhibitors with the protein catalase. Biochem. J. 74: 339350.
Mori, I., Fonné-Pfister, R., Matsunaga, S., et al. 1995a. A novel class of herbicide: specific inhibitors of imidazoleglycerol phosphate dehydratase. Plant Physiol. 107: 719723.
Mori, I., Iwasaki, G., Kimura, Y., et al. 1995b. Synthesis of inhibitors of imidazoleglycerol phosphate dehydratase. J. Am. Chem. Soc. 117: 44114412.
Nagai, A., Suzuki, K., Ward, E., Moyer, M., Hashimoto, M., Mano, J., Ohta, D., and Scheidegger, A. 1992a. Overexpression of plant histidinol dehydrogenase using a baculovirus vector system. Arch. Biochem. Biophys. 295: 235239.
Nagai, A., Suzuki, K., Ward, E., et al. 1992b. Histidinol dehydrogenase in higher plants. Purification, cloning and expression. in Research in Photosynthesis. Volume IV. Dordrecht, The Netherlands: Kluwer Academic Publishers, pp. 9598.
Niederberger, P., Miozzari, G., and Huetter, R. 1981. Biological role of the general control of amino acid biosynthesis in Saccharomyces cerevisiae . Mol. Cell. Biol. 1: 584593.
Parker, A. R., Moore, T., Edman, J., Schwab, J. M., and Davisson, V. J. 1994. Cloning, sequence analysis and expression of the gene encoding imidazoleglycerol phosphate dehydratase in Cryptococcus neoformans . Gene 145: 135138.
Patil, S. S., Kolattukudy, P. E., and Dimond, A. E. 1970. Inhibition of ornitine carbamyl transferase from bean plants by the toxin of Pseudomonas phaseolicola . Plant Physiol. 46: 752753.
Pillmoor, J. B., Wright, K., and Lindell, S. D. 1991. Herbicide discovery through rational design: some experiences. in Proceedings of the Brighton Crop Protection Conference—Weeds. Farnham, Great Britain: British Crop Protection Council, pp. 857866.
Pinto, J.E.B.P., Dyer, W. E., Weller, S. C., and Herrmann, K. M. 1988. Glyphosate induces 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase in potato (Solanum tuberosum L.) cells grown in suspension culture. Plant Physiol. 87: 891893.
Rudiger, W. and Benz, J. 1979. Influence of aminotriazole on the biosynthesis of chlorophyll and phytol. Z. Naturforsch. 34C: 10551057.
Saika, H., Früh, T., Iwasaki, G., Koizumi, S., Mori, I., and Hayakawa, K. 1993. Synthesis of (2R, 3R)-, (2S, 3S) (2R, 3S)-, and (2S, 3R)-imidazole glycerol phosphates (IGP): substrates for IGP-dehydratase (IGPD). Bioorg. Med. Chem. Lett. 3: 21292134.
Shaner, D. L. and Singh, B. K. 1992. How does inhibition of amino acid biosynthesis kill plants? in Singh, B. K., Flores, H. E., and Shannon, J. C., eds. Biosynthesis and Molecular Regulation of Amino Acids in Plants. Rockville, MD: American Society of Plant Physiologists, pp. 174183.
Siehl, D. L. 1992. Considerations in selecting a target site for herbicide design. in Singh, B. K., Flores, H. E., and Shannon, J. C., eds. Biosynthesis and Molecular Regulation of Amino Acids in Plants. Rockville, MD: American Society of Plant Physiologists, pp. 146162.
Sinden, S. L. and Durbon, R. D. 1968. Glutamate synthetase inhibition: possible mode of action of wildfire toxin from Pseudomonas tabaci . Nature (London) 219: 379380.
Smith, I. K. 1985. Stimulation of glutathione synthesis in photorespirating plants by catalase inhibitors. Plant Physiol. 79: 10441047.
Staples, M. A. and Houston, L. L. 1979. Proteolytic degradation of imidazoleglycerol phosphate dehydratase–histidinol phosphatase from Salmonella typhymurium and the isolation of a resistant bifunctional core enzyme. J. Biol. Chem. 254: 13951401.
Steinruecken, H. and Amrhein, N. 1980. The herbicide glyphosate is a potent inhibitor of 5-enolpyruvyl-shikimic acid 3-phosphate synthase. Biochem. Biophys. Res. Commun. 94: 12071212.
Struhl, K. 1985. Nucleotide sequence and transcriptional mapping of the yeast pet56-his3-ded1 gene region. Nucleic Acids Res. 13: 85878601.
Struhl, K., Cameron, J. R., and Davis, R. W. 1976. Functional genetic expression of eukaryotic DNA in Escherichia coli . Proc. Natl. Acad. Sci. USA 73: 14711475.
Struhl, K. and Davis, R. W. 1977. Production of a functional eukaryotic enzyme in Escherichia coli: cloning and expression of the yeast structural gene for imidazoleglycerol phosphate dehydratase (his3). Proc. Natl. Acad. Sci. USA 74: 52555259.
Struhl, K. and Davis, R. W. 1981. Transcription of the his3 gene region in Saccharomyces cerevisiae . J. Mol. Biol. 152: 535552.
Tada, S., Hatano, M., Nakayama, Y., Volrath, S., Guyer, D., Ward, E., and Ohta, D. 1995. Insect cell expression of recombinant imidazoleglycerol phosphate dehydratase of Arabidopsis and wheat and inhibition by triazole herbicides. Plant Physiol. 109: 153159.
Tada, S., Volrath, S., Guyer, D., Scheidegger, A., Ryals, J., Ohta, D., and Ward, E. 1994. Isolation and characterization of cDNAs encoding imidazoleglycerolphosphate dehydratase from Arabidopsis thaliana . Plant Physiol. 105: 579583.
von Heijne, G. and Nishikawa, K. 1991. Chloroplast transit peptides: the perfect random coil? FEBS Lett. 278: 13.
von Itzstein, M., Wu, W. Y., Kok, G. B., et al. 1993. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature (London) 363: 418423.
Walsh, C. 1979. Enzymatic reaction mechanisms. New York: W. H. Freeman, p. 542.
Ward, E., Volrath, S., Koizumi, S., Tada, S., Mori, I., and Iwasaki, G., inventors; Ciba-Geigy Corp., assignee. 1994 Apr 29. Herbicide resistant transgenic plants and their preparation. WO 9426909.
Wei, T. P., Ramasubramanian, T. S., Pu, F., and Golden, J. W. 1993. Anabaena sp. strain PCC 7120 bifA gene encoding a sequence specific DNA binding protein cloned by in vivo transcriptional interference selection. J. Bacteriol. 175: 40254035.
Wiater, A., Hulanicka, D., and Klopotowski, T. 1971a. Structural requirements for inhibition of yeast imidazoleglycerol phosphate dehydratase by triazole and anion inhibitors. Acta. Biochim. Pol. 18: 289297.
Wiater, A., Klopotowski, T., and Bagdasarian, G. 1971b. Synergistic inhibition of plant imidazoleglycerol phosphate dehydratase by aminotriazole and phosphate. Acta. Biochim. Pol. 18: 309314.
Wiater, A., Krajewska-Grynkiewicz, K., and Klopotowski, T. 1971c. Histidine biosynthesis and its regulation in plants. Acta. Biochim. Pol. 18: 299307.
Winkler, M. E. 1987. Biosynthesis of histidine. In Escherichia coli and Salmonella typhimurium . In Neidhardt, F. C., Ingraham, J. L., Low, K. B., Magasanik, B., Schaechter, M., and Umbarger, H. E., eds. Cellular and Molecular Biology. Volume I. Washington, DC: American Society of Microbiology, pp. 395411.
Wolfner, M., Yep, D., Messenguy, F., and Fink, G. R. 1975. Integration of amino acid biosynthesis into the cell cycle of Saccharomyces cerevisiae . J. Mol. Biol. 96: 273290.

Keywords

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed