A subsystems-based approach to the identification of drug targets in bacterial pathogens

  • Andrei L. Osterman
  • Tadhg P. Begley
Part of the Progress in Drug Research book series (PDR, volume 64)


This chapter describes a three-stage approach to target identification based upon subsystem analysis. Subsystems analysis focuses on related metabolic pathways as a unit and is a biochemically-informed approach to target selection. The process involves three stages of analysis; the first stage, selection of the target subsystem, is guided by information about its essentiality and on the predicted vulnerability of the targeted pathway or enzyme to inhibition. The second stage involves analysis of the target subsystem by means of comparative genomics, including genome context analysis and metabolic reconstruction. The third stage evaluates the selection of the specific target genes within the subsystem by target prioritization and validation. The whole process allows for a careful consideration of spectrum, drugability, biological rationale and the metabolic role of the specific target within the context of an integrated circuit within a specific metabolic pathway.


Drug Target Bacterial Pathogen Subsystem Analysis Glutamine Amidotransferase Metabolic Subsystem 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Overbeek R, Begley T, Butler RM, Choudhuri JV, Chuang HY, Cohoon M, de Crecy-Lagard V, Diaz N, Disz T, Edwards R et al (2005) The subsystems approach to genome annotation and its use in the project to annotate 1000 genomes. Nucleic Acids Res 33: 5691–5702PubMedCrossRefGoogle Scholar
  2. 2.
    Ye Y, Osterman A, Overbeek R, Godzik A (2005) Automatic detection of subsystem/pathway variants in genome analysis. Bioinformatics 21: i1–i9CrossRefGoogle Scholar
  3. 3.
    Schmid MB, Kapur N, Isaacson DR, Lindroos P, Sharpe C (1989) Genetic analysis of temperature-sensitive lethal mutants of Salmonella typhimurium. Genetics 123: 625–633PubMedGoogle Scholar
  4. 4.
    Moir DT, Shaw KJ, Hare RS, Vovis GF (1999) Genomics and antimicrobial drug discovery. Antimicrob Agents Chemother 43: 439–446PubMedGoogle Scholar
  5. 5.
    Galperin MY, Koonin EV (1999) Searching for drug targets in microbial genomes. Curr Opin Biotechnol 10: 571–578PubMedCrossRefGoogle Scholar
  6. 6.
    Read TD, Gill SR, Tettelin H, Dougherty BA (2001) Finding drug targets in microbial genomes. Drug Discovery Today 6: 887–892PubMedCrossRefGoogle Scholar
  7. 7.
    Ji Y (2002) The role of genomics in the discovery of novel targets for antibiotic therapy. Pharmacogenomics 3: 315–323PubMedCrossRefGoogle Scholar
  8. 8.
    Lehoux DE, Sanschagrin F, Levesque RC (2001) Discovering essential and infection-related genes. Curr Opin Microbiol 4: 515–519PubMedCrossRefGoogle Scholar
  9. 9.
    Yin D, Fox B, Lonetto ML, Etherton MR, Payne DJ, Holmes DJ, Rosenberg M, Ji Y (2004) Identification of antimicrobial targets using a comprehensive genomic approach. Pharmacogenomics 5: 101–113PubMedCrossRefGoogle Scholar
  10. 10.
    Osterman A, Overbeek R (2003) Missing genes in metabolic pathways: a comparative genomics approach. Curr Opin Chem Biol 7: 238–251PubMedCrossRefGoogle Scholar
  11. 11.
    Koonin EV, Mushegian AR, Bork P (1996) Non-orthologous gene displacement. Trends Genet 12: 334–336PubMedCrossRefGoogle Scholar
  12. 12.
    Galperin MY, Koonin EV (2001) Chapter 15: Comparative Genome Analysis. In: A Baxevanis, F Ouellette (eds): Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins. Second Edition. Wiley-Liss Inc. pp 359–392Google Scholar
  13. 13.
    Kremer LS, Besra GS (2002) Current status and future development of antitubercular chemotherapy. Expert Opin Investig Drugs 11: 1033–1049PubMedCrossRefGoogle Scholar
  14. 14.
    Palsson BO, Price ND, Papin JA (2003) Development of network-based pathway definitions: the need to analyze real metabolic networks. Trends Biotechnol 21: 195–198PubMedCrossRefGoogle Scholar
  15. 15.
    Burgard AP, Nikolaev EV, Schilling CH, Maranas CD (2004) Flux coupling analysis of genome-scale metabolic network reconstructions. Genome Res 14(2): 301–312PubMedCrossRefGoogle Scholar
  16. 16.
    Edwards JS, Palsson BO (2000) Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions. BMC Bioinformatics 1: 1PubMedCrossRefGoogle Scholar
  17. 17.
    Thiele I, Vo TD, Price ND, Palsson BO (2005) Expanded metabolic reconstruction of Helicobacter pylori (iIT341 GSM/GPR): an in silico genome-scale characterization of single-and double-deletion mutants. J Bacteriol 187: 5818–5830PubMedCrossRefGoogle Scholar
  18. 18.
    Becker SA, Palsson BO (2005) Genome-scale reconstruction of the metabolic network in Staphylococcus aureus N315: an initial draft to the two-dimensional annotation. BMC Microbiol 5: 8PubMedCrossRefGoogle Scholar
  19. 19.
    Forster J, Famili I, Palsson BO, Nielsen J (2003) Large-scale evaluation of in silico gene deletions in Saccharomyces cerevisiae. Omics 7: 193–202PubMedCrossRefGoogle Scholar
  20. 20.
    Haft DH, Selengut JD, Brinkac LM, Zafar N, White O (2005) Genome Properties: a system for the investigation of prokaryotic genetic content for microbiology, genome annotation and comparative genomics. Bioinformatics 21: 293–306PubMedCrossRefGoogle Scholar
  21. 21.
    Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M (2004) The KEGG resource for deciphering the genome. Nucleic Acids Res 32 Database issue: D277–280PubMedCrossRefGoogle Scholar
  22. 22.
    (2005) Get ready to GO! A biologist’s guide to the Gene Ontology. Brief Bioinform 6: 298–304Google Scholar
  23. 23.
    Krieger CJ, Zhang P, Mueller LA, Wang A, Paley S, Arnaud M, Pick J, Rhee SY, Karp PD (2004) MetaCyc: a multiorganism database of metabolic pathways and enzymes. Nucleic Acids Res 32: D438–442PubMedCrossRefGoogle Scholar
  24. 24.
    Arigoni F, Talabot F, Peitsch M, Edgerton MD, Meldrum E, Allet E, Fish R, Jamotte T, Curchod ML, Loferer H (1998) A genome-based approach for the identification of essential bacterial genes. Nat Biotechnol 16: 851–856PubMedCrossRefGoogle Scholar
  25. 25.
    Ji Y, Zhang B, Van SF, Horn, Warren P, Woodnutt G, Burnham MK, Rosenberg M (2001) Identification of critical staphylococcal genes using conditional phenotypes generated by antisense RNA. Science 293: 2266–2269PubMedCrossRefGoogle Scholar
  26. 26.
    Thanassi JA, Hartman-Neumann SL, Dougherty TJ, Dougherty BA, Pucci MJ (2002) Identification of 113 conserved essential genes using a high-throughput gene disruption system in Streptococcus pneumoniae. Nucleic Acids Res 30: 3152–3162PubMedCrossRefGoogle Scholar
  27. 27.
    Forsyth RA, Haselbeck RJ, Ohlsen KL, Yamamoto RT, Xu H, Trawick JD, Wall D, Wang L, Brown-Driver V, Froelich JM et al (2002) A genome-wide strategy for the identification of essential genes in Staphylococcus aureus. Mol Microbiol 43: 1387–1400PubMedCrossRefGoogle Scholar
  28. 28.
    Sassetti CM, Boyd DH, Rubin EJ (2003) Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol 48: 77–84PubMedCrossRefGoogle Scholar
  29. 29.
    Mushegian AR, Koonin EV (1996) A minimal gene set for cellular life derived by comparison of complete bacterial genomes. Proc Natl Acad Sci USA 93: 10268–10273PubMedCrossRefGoogle Scholar
  30. 30.
    Fleischmann RD, Adams MD, White O, Clayton RA, Kirkness EF, Kerlavage AR, Bult CJ, Tomb JF, Dougherty BA, Merrick JM et al (1995) Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269: 496–512PubMedCrossRefGoogle Scholar
  31. 31.
    Fraser CM, Gocayne JD, White O, Adams MD, Clayton RA, Fleischmann RD, Bult CJ, Kerlavage AR, Sutton G, Kelley GM et al (1995) The minimal gene complement of Mycoplasma genitalium. Science 270: 397–403PubMedCrossRefGoogle Scholar
  32. 32.
    Hutchison CA, Peterson SN, Gill SR, Cline RT, White O, Fraser CM, Smith HO, Venter JC (1999) Global transposon mutagenesis and a minimal Mycoplasma genome. Science 286: 2165–2169PubMedCrossRefGoogle Scholar
  33. 33.
    Ross-Macdonald P, Coelho PS, Roemer T, Agarwal S, Kumar A, Jansen R, Cheung KH, Sheehan A, Symoniatis D, Umansky L et al (1999) Large-scale analysis of the yeast genome by transposon tagging and gene disruption. Nature 402: 413–418PubMedCrossRefGoogle Scholar
  34. 34.
    Winzeler EA, Shoemaker DD, Astromoff A, Liang H, Anderson K, Andre B, Bangham R, Benito R, Boeke JD, Bussey H et al (1999) Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285: 901–906PubMedCrossRefGoogle Scholar
  35. 35.
    Akerley BJ, Rubin EJ, Novick VL, Amaya K, Judson N, Mekalanos JJ (2002) A genome-scale analysis for identification of genes required for growth or survival of Haemophilus influenzae. Proc Nat Acad Sci USA 99: 966–971PubMedCrossRefGoogle Scholar
  36. 36.
    Kobayashi K, Ehrlich SD, Albertini A, Amati G, Andersen KK, Arnaud M, Asai K, Ashikaga S, Aymerich S, Bessieres P et al (2003) Essential Bacillus subtilis genes. Proc Natl Acad Sci USA 100: 4678–4683PubMedCrossRefGoogle Scholar
  37. 37.
    Gerdes SY, Scholle MD, Campbell JW, Balazsi G, Ravasz E, Daugherty MD, Somera AL, Kyrpides NC, Anderson I, Gelfand MS et al (2003) Experimental determination and system level analysis of essential genes in Escherichia coli MG1655. J Bacteriol 185: 5673–5684PubMedCrossRefGoogle Scholar
  38. 38.
    Jacobs MA, Alwood A, Thaipisuttikul I, Spencer D, Haugen E, Ernst S, Willo, Kaul R, Raymond C, Levy R et al (2003) Comprehensive transposon mutant library of Pseudomonas aeruginosa. Proc Nat Acad Sci USA 100: 14339–14344PubMedCrossRefGoogle Scholar
  39. 39.
    Sassetti CM, Rubin EJ (2003) Genetic requirements for mycobacterial survival during infection. Proc Nat Acad Sci USA 100: 12989–12994PubMedCrossRefGoogle Scholar
  40. 40.
    Potvin E, Lehoux DE, Kukavica-Ibrulj I, Richard KL, Sanschagrin F, Lau GW, Levesque RW (2003) In vivo functional genomics of Pseudomonas aeruginosa for high-throughput screening of new virulence factors and antibacterial targets. Environ Microbiol 5: 1294–1308PubMedCrossRefGoogle Scholar
  41. 41.
    Herbert MA, Hayes S, Deadman ME, Tang CM, Hood DW, Moxon ER (2002) Signature tagged mutagenesis of Haemophilus influenzae identifies genes required for in vivo survival. Microb Pathog 33: 211–223PubMedCrossRefGoogle Scholar
  42. 42.
    Schmid MB (1998) Novel approaches to the discovery of antimicrobial agents. Curr Opin Chem Biol 2: 529–534PubMedCrossRefGoogle Scholar
  43. 43.
    Yin D, Ji Y (2002) Genomic analysis using conditional phenotypes generated by antisense RNA. Curr Opin Microbiol 5: 330–333PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang R, Ou HY, Zhang CT (2004) DEG: a database of essential genes. Nucleic Acids Res 32 Database issue: D271–272PubMedCrossRefGoogle Scholar
  45. 45.
    Jordan IK, Rogozin IB, Wolf YI, Koonin EV (2002) Essential genes are more evolutionarily conserved than are nonessential genes in bacteria. Genome Res 12: 962–968PubMedCrossRefGoogle Scholar
  46. 46.
    Koonin EV (2003) Comparative genomics, minimal gene-sets and the last universal common ancestor. Nature Rev Microbiol 1: 127–136CrossRefGoogle Scholar
  47. 47.
    Gil R, Silva FJ, Pereto J, Moya A (2004) Determination of the core of a minimal bacterial gene set. Microbiol Mol Biol Rev 68: 518–537, table of contentsPubMedCrossRefGoogle Scholar
  48. 48.
    Gerdes SY, Scholle MD, D’Souza M, Bernal A, Baev MV, Farrell M, Kurnasov OV, Daugherty MD, Mseeh F, Polanuyer BM et al (2002) From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways. J Bacteriol 184: 4555–4572PubMedCrossRefGoogle Scholar
  49. 49.
    Michal G (1999) Biochemical pathways: An atlas of biochemistry and molecular biology. John Wiley & Sons, Inc. New York, USAGoogle Scholar
  50. 50.
    Tatusov RL, Natale DA, Garkavtsev IV, Tatusova TA, Shankavaram UT, Rao BS, Kiryutin B, Galperin MY, Fedorova ND, Koonin EV (2001) The COG database: new developments in phylogenetic classification of proteins from complete genomes. Nucleic Acids Res 29: 22–28PubMedCrossRefGoogle Scholar
  51. 51.
    Selkov E, Maltsev N, Olsen GJ, Overbeek R, Whitman WB (1997) A reconstruction of the metabolism of Methanococcus jannaschii from sequence data. Gene 197: GC11–26PubMedCrossRefGoogle Scholar
  52. 52.
    Bono H, Ogata H, Goto S, Kanehisa M (1998) Reconstruction of amino acid biosynthesis pathways from the complete genome sequence. Genome Res 8: 203–210PubMedGoogle Scholar
  53. 53.
    Galperin MY (2004) The Molecular Biology Database Collection: 2004 update. Nucleic Acids Res 32 Database issue: D3–22PubMedCrossRefGoogle Scholar
  54. 54.
    Green ML, Karp PD (2004) A Bayesian method for identifying missing enzymes in predicted metabolic pathway databases. BMC Bioinformatics 5: 76PubMedCrossRefGoogle Scholar
  55. 55.
    Haferkamp I, Schmitz-Esser S, Linka N, Urbany C, Collingro A, Wagner M, Horn M, Neuhaus HE (2004) A candidate NAD+ transporter in an intracellular bacterial symbiont related to Chlamydiae. Nature 432: 622–625PubMedCrossRefGoogle Scholar
  56. 56.
    Bieganowski P, Pace HC, Brenner C (2003) Eukaryotic NAD+ synthetase Qns1 contains an essential, obligate intramolecular thiol glutamine amidotransferase domain related to nitrilase. J Biol Chem 278: 33049–33055PubMedCrossRefGoogle Scholar
  57. 57.
    Bellinzoni M, Buroni S, Pasca MR, Guglierame P, Arcesi F, De Rossi E, Riccardi G (2005) Glutamine amidotransferase activity of NAD+ synthetase from Mycobacterium tuberculosis depends on an amino-terminal nitrilase domain. Res Microbiol 156: 173–177PubMedGoogle Scholar
  58. 58.
    Willison JC, Tissot G (1994) The Escherichia coli efg gene and the Rhodobacter capsulatus adgA gene code for NH3-dependent NAD synthetase. J Bacteriol 176: 3400–3402PubMedGoogle Scholar
  59. 59.
    Bieganowski P, Brenner C (2003) The reported human NADsyn2 is ammonia-dependent NAD synthetase from a pseudomonad. J Biol Chem 278: 33056–33059PubMedCrossRefGoogle Scholar
  60. 60.
    Rizzi M, Nessi C, Mattevi A, Coda A, Bolognesi M, Galizzi A (1996) Crystal structure of NH3-dependent NAD+ synthetase from Bacillus subtilis. Embo J 15: 5125–5134PubMedGoogle Scholar
  61. 61.
    Kang GB, Kim YS, Im YJ, Rho SH, Lee JH, Eom SH (2005) Crystal structure of NH3-dependent NAD+ synthetase from Helicobacter pylori. Proteins 58: 985–988PubMedCrossRefGoogle Scholar
  62. 62.
    Kurnasov O, Goral V, Colabroy K, Gerdes S, Anantha S, Osterman A, Begley TP (2003) NAD biosynthesis: identification of the tryptophan to quinolinate pathway in bacteria. Chem Biol 10: 1195–1204PubMedCrossRefGoogle Scholar
  63. 63.
    Colabroy KL, Zhai H, Li T, Ge Y, Zhang Y, Liu A, Ealick SE, McLafferty FW, Begley TP (2005) The mechanism of inactivation of 3-Hydroxyanthranilate-3,4-dioxygenase by 4-Chloro-3-hydroxyanthranilate. Biochemistry 44: 7623–7631PubMedCrossRefGoogle Scholar
  64. 64.
    Kurnasov O, Jablonski L, Polanuyer B, Dorrestein P, Begley T, Osterman A (2003) Aerobic tryptophan degradation pathway in bacteria: novel kynurenine formamidase. FEMS Microbiol Lett 227: 219–227PubMedCrossRefGoogle Scholar
  65. 65.
    Ravasz E, Somera AL, Mongru DA, Oltvai ZN, Barabasi AL (2002) Hierarchical organization of modularity in metabolic networks. Science 297: 1551–1555PubMedCrossRefGoogle Scholar
  66. 66.
    von Mering C, Zdobnov EM, Tsoka S, Ciccarelli FD, Pereira-Leal JB, Ouzounis CA, Bork P (2003) Genome evolution reveals biochemical networks and functional modules. Proc Natl Acad Sci USA 100: 15428–15433CrossRefGoogle Scholar
  67. 67.
    Huynen MA, Snel B, von Mering C, Bork P (2003) Function prediction and protein networks. Curr Opin Cell Biol 15: 191–198PubMedCrossRefGoogle Scholar
  68. 68.
    Dandekar T, Sauerborn R (2002) Comparative genome analysis and pathway reconstruction. Pharmacogenomics 3: 245–256PubMedCrossRefGoogle Scholar
  69. 69.
    Koonin EV, Galperin MY (2002) SEQUENCE — EVOLUTION — FUNCTION. Computational approaches in comparative genomics. Kluwer Academic Publishers, Boston, USAGoogle Scholar
  70. 70.
    Penfound T, Foster JW (1996) Biosynthesis and Recycling of NAD. In: Neihardt (ed.): Escherichia Coli and Salmonella. ASM pp 721–730Google Scholar
  71. 71.
    Mehl RA, Kinsland C, Begley TP (2000) Identification of the Escherichia coli nicotinic acid mononucleotide adenylyltransferase gene. J Bacteriol 182: 4372–4374PubMedCrossRefGoogle Scholar
  72. 72.
    Overbeek R, Fonstein M, D’Souza M, Pusch GD, Maltsev N (1999) The use of gene clusters to infer functional coupling. Proc Natl Acad Sci USA 96: 2896–2901PubMedCrossRefGoogle Scholar
  73. 73.
    Overbeek R, Fonstein M, D’Souza M, Pusch GD, Maltsev N (1999) Use of contiguity on the chromosome to predict functional coupling. In Silico Biol 1: 93–108PubMedGoogle Scholar
  74. 74.
    Zhang X, Kurnasov OV, Karthikeyan S, Grishin NV, Osterman AL, Zhang H (2003) Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis. J Biol Chem 278: 13503–13511PubMedCrossRefGoogle Scholar
  75. 75.
    Zhou T, Kurnasov O, Tomchick DR, Binns DD, Grishin NV, Marquez VE, Osterman AL, Zhang H (2002) Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase. Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin. J Biol Chem 277: 13148–13154PubMedCrossRefGoogle Scholar
  76. 76.
    Berger F, Lau C, Dahlmann M, Ziegler M (2005) Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem 280(43): 36334–36341PubMedCrossRefGoogle Scholar
  77. 77.
    Garavaglia S, D’Angelo I, Emanuelli M, Carnevali F, Pierella F, Magni G, Rizzi M (2002) Structure of human NMN adenylyltransferase. A key nuclear enzyme for NAD homeostasis. J Biol Chem 277: 8524–8530PubMedCrossRefGoogle Scholar
  78. 78.
    Raffaelli N, Sorci L, Amici A, Emanuelli M, Mazzola F, Magni G (2002) Identification of a novel human nicotinamide mononucleotide adenylyltransferase. Biochem Biophys Res Commun 297: 835–840PubMedCrossRefGoogle Scholar
  79. 79.
    Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S (2004) Structure and function of nicotinamide mononucleotide adenylyltransferase. Curr Med Chem 11: 873–885PubMedCrossRefGoogle Scholar
  80. 80.
    Marcotte EM, Pellegrini M, Ng HL, Rice DW, Yeates TO, Eisenberg D (1999) Detecting protein function and protein-protein interactions from genome sequences. Science 285: 751–753PubMedCrossRefGoogle Scholar
  81. 81.
    Kurnasov OV, Polanuyer BM, Ananta S, Sloutsky R, Tam A, Gerdes SY, Osterman AL (2002) Ribosylnicotinamide kinase domain of NadR protein: Identification and implications in NAD biosynthesis. J Bacteriol 184: 6906–6917PubMedCrossRefGoogle Scholar
  82. 82.
    Kemmer G, Reilly TJ, Schmidt-Brauns J, Zlotnik GW, Green BA, Fiske MJ, Herbert M, Kraiss A, Schlor S, Smith A et al (2001) NadN and e (P4) are essential for utilization of NAD and nicotinamide mononucleotide but not nicotinamide riboside in Haemophilus influenzae. J Bacteriol 183: 3974–3981PubMedCrossRefGoogle Scholar
  83. 83.
    Zhu N, Roth JR (1991) The nadI region of Salmonella typhimurium encodes a bifunctional regulatory protein. J Bacteriol 173: 1302–1310PubMedGoogle Scholar
  84. 84.
    Raffaelli N, Lorenzi T, Mariani PL, Emanuelli M, Amici A, Ruggieri S, Magni G (1999) The Escherichia coli NadR regulator is endowed with nicotinamide mononucleotide adenylyltransferase activity. J Bacteriol 181: 5509–5511PubMedGoogle Scholar
  85. 85.
    Merdanovic M, Sauer E, Reidl J (2005) Coupling of NAD + biosynthesis and nicotinamide ribosyl transport: Characterization of NadR ribonucleotide kinase mutants of Haemophilus influenzae. J Bacteriol 187: 4410–4420PubMedCrossRefGoogle Scholar
  86. 86.
    Sauer E, Merdanovic M, Mortimer AP, Bringmann G, Reidl J (2004) PnuC and the utilization of the nicotinamide riboside analog 3-aminopyridine in Haemophilus influenzae. Antimicrob Agents Chemother 48: 4532–4541PubMedCrossRefGoogle Scholar
  87. 87.
    Martin PR, Shea RJ, Mulks MH (2001) Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence. J Bacteriol 183: 1168–1174PubMedCrossRefGoogle Scholar
  88. 88.
    Singh SK, Kurnasov OV, Chen B, Robinson H, Grishin NV, Osterman AL, Zhang H (2002) Crystal structure of Haemophilus influenzae NadR protein. A bifunctional enzyme endowed with NMN adenyltransferase and ribosylnicotinimide kinase activities. J Biol Chem277: 33291–33299PubMedCrossRefGoogle Scholar
  89. 89.
    Geerlof A, Lewendon A, Shaw WV (1999) Purification and characterization of phosphopantetheine adenylyltransferase from Escherichia coli. J Biol Chem 274: 27105–27111PubMedCrossRefGoogle Scholar
  90. 90.
    Strauss E, Kinsland C, Ge Y, McLafferty FW, Begley TP (2001) Phosphopantothenoylcysteine synthetase from Escherichia coli. Identification and characterization of the last unidentified coenzyme A biosynthetic enzyme in bacteria. J Biol Chem 276: 13513–13516PubMedCrossRefGoogle Scholar
  91. 91.
    Mishra P, Park PK, Drueckhammer DG (2001) Identification of yacE (coaE) as the structural gene for dephosphocoenzyme A kinase in Escherichia coli K-12. J Bacteriol 183: 2774–2778PubMedCrossRefGoogle Scholar
  92. 92.
    Daugherty M, Polanuyer B, Farrell M, Scholle M, Lykidis A, de Crecy-Lagard V, Osterman A (2002) Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J Biol Chem 277: 21431–21439PubMedCrossRefGoogle Scholar
  93. 93.
    Heath RJ, Rock CO (2000) A triclosan-resistant bacterial enzyme. Nature 406: 145–146PubMedCrossRefGoogle Scholar
  94. 94.
    Zhang YM, Frank MW, Virga KG, Lee RE, Rock CO, Jackowski S (2004) Acyl carrier protein is a cellular target for the antibacterial action of the pantothenamide class of pantothenate antimetabolites. J Biol Chem 279: 50969–50975PubMedCrossRefGoogle Scholar
  95. 95.
    Olland AM, Underwood KW, Czerwinski RM, Lo MC, Aulabaugh A, Bard J, Stahl ML, Somers WS, Sullivan FX, Chopra R (2002) Identification, characterization, and crystal structure of Bacillus subtilis nicotinic acid mononucleotide adenylyltransferase. J Biol Chem 277: 3698–3707PubMedCrossRefGoogle Scholar
  96. 96.
    Jayaram HN, Cooney DA, Grusch M, Krupitza G (1999) Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis. Curr Med Chem 6: 561–574PubMedGoogle Scholar
  97. 97.
    Clifton G, Bryant SR, Skinner CG (1970) N’-(substituted) pantothenamides, antimetabolites of pantothenic acid. Arch Biochem Biophys 137: 523–528PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag 2007

Authors and Affiliations

  • Andrei L. Osterman
    • 1
    • 2
  • Tadhg P. Begley
    • 3
  1. 1.Disease CenterBurnham Institute for Medical Research, Infectious and InflammatoryLa JollaUSA
  2. 2.Fellowship for Interpretation of Genomes (FIG)Burr RidgeUSA
  3. 3.Cornell UniversityIthacaUSA

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