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  1. NTU Theses and Dissertations Repository
  2. 生命科學院
  3. 生化科學研究所
請用此 Handle URI 來引用此文件: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/33463
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dc.contributor.advisor梁博煌(Po-Huang Liang)
dc.contributor.authorLing-Yuan Chenen
dc.contributor.author陳翎原zh_TW
dc.date.accessioned2021-06-13T04:41:56Z-
dc.date.available2006-07-19
dc.date.copyright2006-07-19
dc.date.issued2006
dc.date.submitted2006-07-18
dc.identifier.citation[1] Liang, P.H., Ko, T.P., and Wang, A.H.-J. (2002) Structure, mechanism and function of prenyltransferases. Eur. J. Biochem. 269: 3339-3354.
[2] Ogura, K., Koyama, T. & Sagami, H. (1997) in Subcellular Biochem (Bittman, R., ed.) Vol. 28, pp 57-88. Plenum, New York
[3] Poulter C. D. & Rilling, H. C. (1981) in Biosynthesis of isoprenoid compounds (Spurgeon, SL, R., ed.) Vol. 1, pp 225-282, John Wiley & Sons, New York
[4] Spurgeon, S. L. and Poulter, C. D. (1981) in Biosynthesis of isoprenoid compounds (Spurgeon, SL, R., ed.) Vol. 2, pp 1-112, John Wiley & Sons, New York
[5] Sinensky, M. (2000) Recent advances in the study of prenylated proteins. Biochim Biophys Acta 1484, 93-106
[6] Gelb, M. H., Scholten, J. D. and Sebolt-Leopold J. S. (1998) Protein prenylation: from discovery to prospects for cancer treatment. Curr Opin Chem Biol. 2, 40-48
[7] Kellogg, B. A. and Poulter C. D. (1997) Chain elongation in the isoprenoid biosynthetic pathway. Curr Opin Chem Biol. 1, 570-578
[8] Ogura, K. and Koyama, T. (1998) Enzymatic aspects of isoprenoid chain elongation. Chemical Reviews 98, 1263-1276.
[9] Ohnuma, S.-I., Suzuki, M. and Nishino, T. (1994) Archaebacterial ether-linked lipid biosynthetic gene. Expression cloning, sequencing and characterization of geranylgeranyl-diphosphate synthase. J. Biol. Chem. 269, 14792-14797.
[10] Chen, A. and Poulter, C. D. (1994) Isolation and characterization of idsA: the gene for the short chain isoprenyl diphosphate synthase from Methanolbacterium thermoautotrophicum. Arch. Biochem. Biophys. 314, 399-404.
[11] Tachibana, A., Yano, Y. Y., Otani, S., Nomura, N., Sako, Y, and Taniguchi, M. (2000) Novel prenyltransferase gene encoding farnesylgeranyl diphosphate synthase from a hyperthermophilic archeon, Aeropyrum pernix. Eur J. Biochem. 267, 321-328.
[12] Ashby, M. N. and Edwards, P. A. (1990) Elucidation of the deficiency in two yeast coenzyme Q mutants. Characterization of the structural gene encoding hexaprenyl pyrophosphate synthetase. J. Biol. Chem. 265, 13157-13164.
[13] Shimizu, N., Koyama, T. and Ogura, K. (1998) Molecular cloning, expression, and characterization of the genes encoding the two essential protein components of Micrococcus luteus B-P 26 hexaprenyl diphosphate synthase. J. Bacteriol. 180, 1578-1581.
[14] Koike-Takeshita, A., Koyama, T., Obata, S. and Ogura, K. (1995) Molecular cloning and nucleotide sequences of the genes for two essential proteins constituting a novel enzyme system for heptaprenyl diphosphate synthesis. J. Biol. Chem. 270, 18396-18400.
[15] Asai, K.-I., Fujisaki, S., Nishimura, Y., Nishino, T., Okada, K., Nakagawa, T., Kawamukai, M. and Matsuda, H. (1994) The identification of Escherichia coli ispB (cel) gene encoding the octaprenyl diphosphate synthase. Biochem. Biophys. Res. Commun. 202, 340-345.
[16] Okada, K., Suzuki, K., Kamiya, Y., Zhu, X., Fujisaki, S., Nishimura, Y., Nishino, T., Nakagawa, T., Kawamukai, M. and Matsuda, H. (1996) Polyprenyl diphosphate synthase essentially defines the length of the side chain of ubiquinone. Biochim. Biophys. Acta 1302, 217-223.
[17] Okada, K., Minehira, M., Zhu, X., Suzuki, K., Nakagawa, T., Matsuda, H. & Kawamukai, M. (1997) The ispB gene encoding octaprenyl diphosphate synthase is essential for growth of Escherichia coli. J. Bacteriol. 179, 3058-3060.
[18] Ohnuma, S.-I., Koyama, T. and Ogura, K. (1992) Chain length distribution of the products formed in solanesyl diphosphate synthase reaction. J. Biochem. (Tokyo) 112, 743-749.
[19] Ohnuma, S.-I., Koyama, T. and Ogura, K. (1991) Purification of solanesyl-diphosphate synthase from Micrococcus luteus. A new class of prenyltransferase. J. Biol. Chem. 266, 23706-23713.
[20] Teclebrhan, H., Olsson, J., Swiezewska, E. and Dallner, G. (1993) Biosynthesis of the side chain of ubiquinone: trans-prenyltransferase in rat liver microsomes. J. Biol. Chem. 268, 23081-23086.
[21] Suzuki, K., Okada, K. Kamiya, Y., Zhu, X. F., Nakagawa, T., Kawamukai, M. and Matsuda, H. (1997) Analysis of the decaprenyl diphosphate synthase (dps) gene in fission yeast suggests a role of ubiquinone as an antioxidant. J. Biochem. (Tokyo) 121, 496-505.
[22] Collin, M. D. and Jones, D. (1981) Distribution of isoprenoid quinone structural types in bacteria and their taxonomic implication. Microbiol. Rev. 45, 316-354.
[23] Robyt, J. (1998) in Essentials of carbohydrate chemistry Chapter 10, pp 305-318, Springer-Verlag, New York
[24] Sutherland, I. W. (1977) in Surface Carbohydrates of the Prokarotic Cell pp 27, Academic Press, London
[25] Nishikawa, S. and Nakano, A. (1993) Identification of a gene required for membrane protein retention in the early secretory pathway. Proc. Natl. Acad. Sci. 90, 8179-8183.
[26] Sato, M., Sato, K., Nishikawa, S.-I., Hirata, A., Kato, J.-I., and Nakano, A. (1999) The yeast RER2 gene, identified by endoplasmic reticulum protein localization mutations, encodes cis-prenyltransferase, a key enzyme in dolichol synthesis. Mol. Cell. Biol. 19, 471-483.
[27] Oh, S. K., Han, K. H., Ryu, S. B. and Kang, H. (2000) Molecular cloning, expression, and functional analysis of a cis-prenyltransferase from Arabidopsis thaliana. J. Biol. Chem. 275, 18482-18488.
[28] Schulbach, M. C., Brennan, P. J. and Crick, D. C. (2000) Identification of a short (C15) chain Z-isoprenyl diphosphate synthase and a homologous long (C50) chain isoprenyl diphosphate synthase in Mycobacterium tuberculosis. J. Biol. Chem. 275, 22876-22881.
[29] Chen, A., Kroon, P. A., and Poulter, C.D. (1994) Isoprenyl diphosphate synthases: protein sequence comparisons, a phylogenetic tree, and predictions of secondary structure. Protein Sci. 3, 600-607.
[30] Shimizu, N., Koyama, T., and Ogura, K. (1998) Molecular cloning, expression, and purification of undecaprenyl diphosphate synthase. No sequence similarity between E- and Z-prenyl diphosphate synthases. J. Biol. Chem. 273, 19476-19481.
[31] Apfel, C.M., Takacs, B., Fountoulakis, M., Stieger, M., and Keck, W. (1999) Use of genomics to identify bacterial undecaprenyl pyrophosphate synthetase: cloning, expression, and characterization of the essential uppS gene. J. Bacteriol. 181, 483-492.
[32] Tarshis, L.C., Yan, M., Poulter, C.D., and Sacchettini, J.C. (1994) Crystal structure of recombinant farnesyl diphosphate synthase at 2.6-Å resolution. Biochemistry 33, 10871-10877.
[33] Fujihashi, M., Zhang, Y.-W., Higuchi, Y., Li, X.-Y., Koyama, T., and Miki, K. (2001) Crystal structure of cis-prenyl chain elongating enzyme, undecaprenyl diphosphate synthase. Proc. Natl. Acad. Sci. U.S.A. 98: 4337-4342.
[34] Ko, T. P., Chen, Y. K., Robinson, H., Tsai, P. C., Gao, Y.-G, Chen, A. P.-C., Wang, A. H.-J. and Liang, P. H. (2001) Mechanism of product chain length determination and the role of a flexible loop in E. coli undecaprenyl pyrophosphate synthase catalysis. J. Biol. Chem. 276, 47474-47482.
[35] Chang, S.Y., Ko, T.P., Liang, P.H., and Wang, A.H.-J. (2003) Catalytic mechanism revealed by the crystal structure of undecaprenyl pyrophosphate synthase in complex with sulfate, magnesium, and triton. J. Biol. Chem. 278, 29298-29307.
[36] Chang, S. Y., Ko, T. P., Chen, A. P.-C., Chang, J. Y., Wang, A. H.-J. and Liang, P. H. (2004) Substrate Binding mode and reaction mechanism of undecaprenyl pyrophosphate synthase deduced from crystallographic studies. Protein Sci. 13, 971-978.
[37] Chen, Y. H., Chen, A. P.-C., Chen, C. T., Wang, A. H.-J. and Liang, P. H. (2002) Probing the conformational change of Escherichia coli undecaprenyl pyrophosphate synthase during catalysis using an inhibitor and tryptophan mutants. J. Biol. Chem. 277, 7369-7376.
[38] Marrero, P.F., Poulter, C.D., and Edwards, P.A. (1992) Effects of site-directed mutagenesis of the highly conserved aspartate residues in domain II of farnesyl diphosphate synthase activity. J. Biol. Chem. 267: 21873-21878.
[39] Joly, A., and Edwards, P.A. (1993) Effect of site-directed mutagenesis of conserved aspartate and arginine residues upon farnesyl diphosphate synthase activity. J. Biol. Chem. 268, 26983-26989.
[40] Song, L., and Poulter, C.D. (1994) Yeast farnesyl-diphosphate synthase: site-directed mutagenesis of residues in highly conserved prenyltransferase domains I and II. Proc. Natl. Acad. Sci. U.S.A. 91, 3044-3048.
[41] Koyama, T., Obata, S., Saito, K., Takeshita-Koike, A., and Ogura, K. (1994) Structural and functional roles of the cysteine residues of Bacillus stearothermophilus farnesyl diphosphate synthase. Biochemistry 33, 12644-12648.
[42] Koyama, T., Tajima, M., Nishino, T., and Ogura, K. (1995) Significance of Phe-220 and Gln-221 in the catalytic mechanism of farnesyl diphosphate synthase of Bacillus stearothermophilus. Biochem. Biophys. Res. Commun. 212, 681-686.
[43] Koyama, T., Tajima, M., Sano, H., Doi, T., Koike-Takeshita, A., Obata, S., Nishino, T., and Ogura, K. (1996) Identification of significant residues in the substrate binding site of Bacillus stearothermophilus farnesyl diphosphate synthase. Biochemistry 35, 9533-9538.
[44] Guo, R. T., Kuo, C. J., Chou, C. C., Ko, T. P., Shr, H. L., Liang, P. H. and Wang, A. H.-J. (2004) Crystal structure of octaprenyl pyrophosphate synthase from hyperthermophilic Thermotoga maritima and mechanism of product chain length determination. J. Biol. Chem. 279, 4903-4912.
[45] Hosfield, D. J., Zhang, Y., Dougan, D. R., Broun, A., Tari, L. W., Swanson, R. V., and Finn, J. (2004) Structural Basis for Bisphosphonate-mediated Inhibition of Isoprenoid Biosynthesis, J. Biol. Chem. 279, 8526-8529.
[46] Kinoshita, K., Sadanami, K., Kidera, A., and Go, N. (1999) Structural motif of phosphate-binding site common to various protein superfamilies: All-against-all structural comparison of protein-mononucleotide complexes. Protein Eng. 12, 11–14.
[47] Paget’s disease, hypercalcemia due to malignancy and potentially for parasitic diseases caused by Toxoplasma gondi
[48] Pan, J.J., Yang, L.W., and Liang, P.H. (2000). Effect of site-directed mutagenesis of the conserved aspartate and glutamate on E. coli undecaprenyl pyrophosphate synthase catalysis. Biochemistry 39, 13856-13861.
[49] Pan, J. J., Chiou, S. T., and Liang, P. H. (2000). Product distribution and pre-steady-state kinetic analysis of Escherichia coli undecaprenyl pyrophosphate synthase reaction. Biochemistry 39, 10936-10942.
[50] Fujii, H., Koyama, T., and Ogura, K. (1982) Efficient enzymatic hydrolysis of polyprenyl pyrophosphates. Biochim. Biophys. Acta 712, 716-718.
[51] Chen, A. P.-C., Chang, S. Y., Lin, Y. C., Sun, Y. S., Chen, C. T., Wang, A. H.-J., and Liang, P. H. (2005) Substrate and product specificities of cis-type undecaprenyl pyrophosphate synthase. Biochem J. 386, 169-176.
[52] Chen, A. P.-C., Chen, Y. H., Liu, H. P., Li, Y. C., Chen, C. T., and Liang, P. H. (2002) Synthesis and application of a fluorescent substrate analogue to study ligand interactions for undecaprenyl pyrophosphate synthase. J. Am. Chem. Soc. 124, 15217-15224.
[53] Pan, J. J., Kuo, T. H., Chen, Y. K., Yang, L. W. and Liang, P. H. (2002) Insight into the activation mechanism of Escherichia coli octaprenyl pyrophosphate synthase derived from pre-steady-state kinetic analysis. Biochim. Biophys. Acta, 1594, 64-73.
[54] Kuo, T. H., and Liang, P. H. (2002) Reaction kinetic pathway of the recombinant octaprenyl pyrophosphate synthase from Thermotoga maritima: how is it different from that of the mesophilic enzyme. Biochim. Biophys. Acta, 1594, 64-73.
[55] Poulter, C.D., Argyle, J.C., and Mash, E.A. (1977) Letter: Prenyltransferase. New evidence for an ionization-condensation-elimination mechanism with 2-fluorogeranyl pyrophosphate. J. Am. Chem. Soc. 99: 957-959.
[56] Chang, S.Y., Chen, Y.K., Wang, A.H.-J., and Liang, P.H. (2003). Identification of the active conformation and the importance of length of the flexible loop 72-83 in regulating the conformational change of undecaprenyl pyrophosphate synthase. Biochemistry 42, 14452-14459.
[57] Fersht, A. (1985) in Enzyme structure and mechanism. Chapter 5. The pH dependence of enzyme catalysis. pp 156. W. H. Freeman and Co., New York.
dc.identifier.urihttp://tdr.lib.ntu.edu.tw/jspui/handle/123456789/33463-
dc.description.abstract類異戊二烯族化合物廣泛分布於自然界是由異戊二烯焦磷酸構成的聚合物。此類化合物的生合成是由一類異戊二烯轉移酵素所催化。這類酵素通常催化多個含5個碳異戊二烯焦磷酸和含15個碳的全反式法呢基焦磷酸結合生成長鏈產物。在一般細菌中,十一異戊二烯焦磷酸合成酵素產生的55個碳的產物可攜帶醣質以合成細菌胞壁peptidoglycan,因此酵素的活性抑制劑可作為抗生素藥物。然而在肺結核桿菌中,存在一新奇短順式法呢焦磷酸合成酶,可催化含10 個碳geranyl焦磷酸和異戊二烯焦磷酸結合生成含一順式雙鍵的法呢焦磷酸並以此為原料使用十異戊二烯焦磷酸合成酶來合成含50個碳的十異戊二烯焦磷酸。 本篇論文研究此二酵素反應機制及動力學,進而使用電腦模擬尋求發展抑制其活性的小分子。zh_TW
dc.description.abstractIsoprenoids are widely distributed natural polymers containing isopentenyl pyrophosphate (IPP) as building block. The biosyntheses of isoprenoids are carried out by a group of enzymes called prenyltransferases which catalyze the head to tail condensation between IPP and farnesyl pyrophosphate (FPP) to make linear long-chain products. In bacteria, by using all-trans FPP, the C55 undecaprenyl pyrophosphate (UPP) generated by UPP synthase (UPPs) serves as a lipid carrier to transport lipid II across the bacterial cell membrane for peptidoglycan synthesis of the cell wall. However, in M. tuberculosis, a novel short-chain FPP synthase (FPPs) was found to catalyze the condensation between 10-carbon geranyl pyrophosphate and IPP to form a cis double bond. From this ω,E,Z-FPP, a C50 long-chain decaprenyl pyrophosphate (DPP) is synthesized by the decaprenyl pyrophosphate synthase (DPPs) as the lipid carrier in M. tuberculosis. In this thesis, I describe the mechanistic and kinetic caracterization of this novel FPPs as well as the DPPs. For developing anti- M. tuberculosis drug, we used the crystal structure of UPPs as a template and performed computer screening to search for the small molecule inhibitors of the M. tuberculosis FPPs and DPPs.en
dc.description.provenanceMade available in DSpace on 2021-06-13T04:41:56Z (GMT). No. of bitstreams: 1
ntu-95-R93b46025-1.pdf: 1031298 bytes, checksum: 9252cf387cb653897fdacd06344b7154 (MD5)
Previous issue date: 2006
en
dc.description.tableofcontentsABSTRACT………………………………………………………………………….. 4
ABBREVIATIONS……………………………………………………………………6
INTRODUCTION ………...…………………………………………………………. 7
MATERIALS AND METHODS ………...…………………………………………..12
RESULTS ………...………………………………………………………………….26
DISCUSSION ………..……………………………………………………………...36
TABLES ………..……………………………………………………………………40
FIGURES …………………………………………………………………………....43
REFERENCES ………...…………………………………………………………….65
dc.language.isoen
dc.subject結核桿菌zh_TW
dc.subject異戊二烯焦磷酸轉移&#37238zh_TW
dc.subjectDPPsen
dc.subjectFPPsen
dc.subjectcis-type prenyltransferasesen
dc.title結核桿菌短及長順式異戊二烯焦磷酸轉移酶的反應機制、動力學,及抑制劑研究zh_TW
dc.titleMechanistic, kinetic and inhibitory studies of a short-chain and a long-chain cis-type prenyltransferases from M. tuberculosis.en
dc.typeThesis
dc.date.schoolyear94-2
dc.description.degree碩士
dc.contributor.oralexamcommittee孟子青(Tzu-Ching Meng),邱繼輝(Kay-Hooi Khoo)
dc.subject.keyword結核桿菌,異戊二烯焦磷酸轉移&#37238,zh_TW
dc.subject.keywordcis-type prenyltransferases,FPPs,DPPs,en
dc.relation.page74
dc.rights.note有償授權
dc.date.accepted2006-07-19
dc.contributor.author-college生命科學院zh_TW
dc.contributor.author-dept生化科學研究所zh_TW
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