Skip to main content
Protein & Cell logoLink to Protein & Cell
. 2010 Jun 4;1(5):435–442. doi: 10.1007/s13238-010-0057-3

Protein targets for structure-based anti-Mycobacterium tuberculosis drug discovery

Zhiyong Lou 1,, Xiaoxue Zhang 2
PMCID: PMC4875134  PMID: 21203958

Abstract

Mycobacterium tuberculosis, which belongs to the genus Mycobacterium, is the pathogenic agent for most tuberculosis (TB). As TB remains one of the most rampant infectious diseases, causing morbidity and death with emergence of multi-drug-resistant and extensively-drug-resistant forms, it is urgent to identify new drugs with novel targets to ensure future therapeutic success. In this regards, the structural genomics of M. tuberculosis provides important information to identify potential targets, perform biochemical assays, determine crystal structures in complex with potential inhibitor(s), reveal the key sites/residues for biological activity, and thus validate drug targets and discover novel drugs. In this review, we will discuss the recent progress on novel targets for structure-based anti-M. tuberculosis drug discovery.

Keywords: Mycobacterium tuberculosis, crystal structure, drug discovery, target

References

  1. Andries K., Verhasselt P., Guillemont J., Gohlmann H.W., Neefs J. M., Winkler H., Van Gestel J., Timmerman P., Zhu M., Lee E., et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307:223–227. doi: 10.1126/science.1106753. [DOI] [PubMed] [Google Scholar]
  2. Bhatt A., Molle V., Besra G.S., Jacobs W.R., Jr., Kremer L. The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development. Mol Microbiol. 2007;64:1442–1454. doi: 10.1111/j.1365-2958.2007.05761.x. [DOI] [PubMed] [Google Scholar]
  3. Bocchino M., Sanduzzi A., Bariffi F. Mycobacterium tuberculosis and HIV co-infection in the lung: synergic immune dysregulation leading to disease progression. Monaldi Arch Chest Dis. 2000;55:381–388. [PubMed] [Google Scholar]
  4. Brunger A.T., Adams P.D., Clore G.M., DeLano W.L., Gros P., Grosse-Kunstleve R.W., Jiang J.S., Kuszewski J., Nilges M., Pannu N.S., et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998;54:905–921. doi: 10.1107/S0907444998003254. [DOI] [PubMed] [Google Scholar]
  5. Carroll P., Pashley C.A., Parish T. Functional analysis of GlnE, an essential adenylyl transferase in Mycobacterium tuberculosis. J Bacteriol. 2008;190:4894–4902. doi: 10.1128/JB.00166-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chatterjee D. The mycobacterial cell wall: structure, biosynthesis and sites of drug action. Curr Opin Chem Biol. 1997;1:579–588. doi: 10.1016/S1367-5931(97)80055-5. [DOI] [PubMed] [Google Scholar]
  7. Chaudhuri B.N., Sawaya M.R., Kim C.Y., Waldo G.S., Park M.S., Terwilliger T.C., Yeates T.O. The crystal structure of the first enzyme in the pantothenate biosynthetic pathway, ketopantoate hydroxymethyltransferase, from M tuberculosis. Structure. 2003;11:753–764. doi: 10.1016/S0969-2126(03)00106-0. [DOI] [PubMed] [Google Scholar]
  8. Chetnani B., Das S., Kumar P., Surolia A., Vijayan M. Mycobacterium tuberculosis pantothenate kinase: possible changes in location of ligands during enzyme action. Acta Crystallogr D Biol Crystallogr. 2009;65:312–325. doi: 10.1107/S0907444909002170. [DOI] [PubMed] [Google Scholar]
  9. Cohen-Gonsaud M., Ducasse S., Hoh F., Zerbib D., Labesse G., Quemard A. Crystal structure of MabA from Mycobacterium tuberculosis, a reductase involved in long-chain fatty acid biosynthesis. J Mol Biol. 2002;320:249–261. doi: 10.1016/S0022-2836(02)00463-1. [DOI] [PubMed] [Google Scholar]
  10. Cole S.T., Eiglmeier K., Parkhill J., James K.D., Thomson N.R., Wheeler P.R., Honore N., Garnier T., Churcher C., Harris D., et al. Massive gene decay in the leprosy bacillus. Nature. 2001;409:1007–1011. doi: 10.1038/35059006. [DOI] [PubMed] [Google Scholar]
  11. Deckers-Hebestreit G., Altendorf K. The F0F1-type ATP synthases of bacteria: structure and function of the F0 complex. Annu Rev Microbiol. 1996;50:791–824. doi: 10.1146/annurev.micro.50.1.791. [DOI] [PubMed] [Google Scholar]
  12. Dessen A., Quemard A., Blanchard J.S., Jacobs W.R., Jr., Sacchettini J.C. Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science. 1995;267:1638–1641. doi: 10.1126/science.7886450. [DOI] [PubMed] [Google Scholar]
  13. Dias M.V., Borges J.C., Ely F., Pereira J.H., Canduri F., Ramos C. H., Frazzon J., Palma M.S., Basso L.A., Santos D.S., et al. Structure of chorismate synthase from Mycobacterium tuberculosis. J Struct Biol. 2006;154:130–143. doi: 10.1016/j.jsb.2005.12.008. [DOI] [PubMed] [Google Scholar]
  14. Ducasse-Cabanot S., Cohen-Gonsaud M., Marrakchi H., Nguyen M., Zerbib D., Bernadou J., Daffe M., Labesse G., Quemard A. In vitro inhibition of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein reductase MabA by isoniazid. Antimicrob Agents Chemother. 2004;48:242–249. doi: 10.1128/AAC.48.1.242-249.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Feng Z., Barletta R.G. Roles of Mycobacterium smegmatis D-alanine:D-alanine ligase and D-alanine racemase in the mechanisms of action of and resistance to the peptidoglycan inhibitor D-cycloserine. Antimicrob Agents Chemother. 2003;47:283–291. doi: 10.1128/AAC.47.1.283-291.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fioravanti E., Adam V., Munier-Lehmann H., Bourgeois D. The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3′-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition. Biochemistry. 2005;44:130–137. doi: 10.1021/bi0484163. [DOI] [PubMed] [Google Scholar]
  17. Fioravanti E., Haouz A., Ursby T., Munier-Lehmann H., Delarue M., Bourgeois D. Mycobacterium tuberculosis thymidylate kinase: structural studies of intermediates along the reaction pathway. J Mol Biol. 2003;327:1077–1092. doi: 10.1016/S0022-2836(03)00202-X. [DOI] [PubMed] [Google Scholar]
  18. Fontecave M., Nordlund P., Eklund H., Reichard P. The redox centers of ribonucleotide reductase of Escherichia coli. Adv Enzymol Relat Areas Mol Biol. 1992;65:147–183. doi: 10.1002/9780470123119.ch4. [DOI] [PubMed] [Google Scholar]
  19. Georgieva E.R., Narvaez A.J., Hedin N., Graslund A. Secondary structure conversions of Mycobacterium tuberculosis ribonucleotide reductase protein R2 under varying pH and temperature conditions. Biophys Chem. 2008;137:43–48. doi: 10.1016/j.bpc.2008.06.009. [DOI] [PubMed] [Google Scholar]
  20. Godreuil S., Renaud F., Van de Perre P., Carriere C., Torrea G., Banuls A.L. Genetic diversity and population structure of Mycobacterium tuberculosis in HIV-1-infected compared with uninfected individuals in Burkina Faso. Aids. 2007;21:248–250. doi: 10.1097/QAD.0b013e328011ec64. [DOI] [PubMed] [Google Scholar]
  21. Gong C., Martins A., Bongiorno P., Glickman M., Shuman S. Biochemical and genetic analysis of the four DNA ligases of mycobacteria. J Biol Chem. 2004;279:20594–20606. doi: 10.1074/jbc.M401841200. [DOI] [PubMed] [Google Scholar]
  22. Gould T.A., van de Langemheen H., Munoz-Elias E.J., McKinney J. D., Sacchettini J.C. Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis. Mol Microbiol. 2006;61:940–947. doi: 10.1111/j.1365-2958.2006.05297.x. [DOI] [PubMed] [Google Scholar]
  23. Gourley D.G., Shrive A.K., Polikarpov I., Krell T., Coggins J.R., Hawkins A.R., Isaacs N.W., Sawyer L. The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction. Nat Struct Biol. 1999;6:521–525. doi: 10.1038/9287. [DOI] [PubMed] [Google Scholar]
  24. Haouz A., Vanheusden V., Munier-Lehmann H., Froeyen M., Herdewijn P., Van Calenbergh S., Delarue M. Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism. J Biol Chem. 2003;278:4963–4971. doi: 10.1074/jbc.M209630200. [DOI] [PubMed] [Google Scholar]
  25. Hasan S., Daugelat S., Rao P.S., Schreiber M. Prioritizing genomic drug targets in pathogens: application to Mycobacterium tuberculosis. PLoS Comput Biol. 2006;2:e61. doi: 10.1371/journal.pcbi.0020061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. He X., Reynolds K.A. Purification, characterization, and identification of novel inhibitors of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus. Antimicrob Agents Chemother. 2002;46:1310–1318. doi: 10.1128/AAC.46.5.1310-1318.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Huang H., Scherman M.S., D’Haeze W., Vereecke D., Holsters M., Crick D.C., McNeil M.R. Identification and active expression of the Mycobacterium tuberculosis gene encoding 5-phospho-“alpha”-d-ribose-1-diphosphate: decaprenyl-phosphate 5-phosphoribosyltransferase, the first enzyme committed to decaprenylphosphoryl-d-arabinose synthesis. J Biol Chem. 2005;280:24539–24543. doi: 10.1074/jbc.M504068200. [DOI] [PubMed] [Google Scholar]
  28. Jordan A., Pontis E., Aslund F., Hellman U., Gibert I., Reichard P. The ribonucleotide reductase system of Lactococcus lactis. Characterization of an NrdEF enzyme and a new electron transport protein. J Biol Chem. 1996;271:8779–8785. doi: 10.1074/jbc.271.15.8779. [DOI] [PubMed] [Google Scholar]
  29. Kremer L., Dover L.G., Morehouse C., Hitchin P., Everett M., Morris H.R., Dell A., Brennan P.J., McNeil M.R., Flaherty C., et al. Galactan biosynthesis in Mycobacterium tuberculosis. Identification of a bifunctional UDP-galactofuranosyltransferase. J Biol Chem. 2001;276:26430–26440. doi: 10.1074/jbc.M102022200. [DOI] [PubMed] [Google Scholar]
  30. Kurth D.G., Gago G.M., de la Iglesia A., Bazet Lyonnet B., Lin T. W., Morbidoni H.R., Tsai S.C., Gramajo H. ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria. Microbiology. 2009;155:2664–2675. doi: 10.1099/mic.0.027714-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lederer E., Adam A., Ciorbaru R., Petit J.F., Wietzerbin J. Cell walls of Mycobacteria and related organisms; chemistry and immunostimulant properties. Mol Cell Biochem. 1975;7:87–104. doi: 10.1007/BF01792076. [DOI] [PubMed] [Google Scholar]
  32. Leger M., Gavalda S., Guillet V., van der Rest B., Slama N., Montrozier H., Mourey L., Quemard A., Daffe M., Marrakchi H. The dual function of the Mycobacterium tuberculosis FadD32 required for mycolic acid biosynthesis. Chem Biol. 2009;16:510–519. doi: 10.1016/j.chembiol.2009.03.012. [DOI] [PubMed] [Google Scholar]
  33. LeMagueres P., Im H., Ebalunode J., Strych U., Benedik M.J., Briggs J.M., Kohn H., Krause K.L. The 1.9 Å crystal structure of alanine racemase from Mycobacterium tuberculosis contains a conserved entryway into the active site. Biochemistry. 2005;44:1471–1481. doi: 10.1021/bi0486583. [DOI] [PubMed] [Google Scholar]
  34. Li de la Sierra I., Munier-Lehmann H., Gilles A.M., Barzu O., Delarue M. X-ray structure of TMP kinase from Mycobacterium tuberculosis complexed with TMP at 1.95 Å resolution. J Mol Biol. 2001;311:87–100. doi: 10.1006/jmbi.2001.4843. [DOI] [PubMed] [Google Scholar]
  35. Li W., Xin Y., McNeil M.R., Ma Y. rmlB and rmlC genes are essential for growth of mycobacteria. Biochem Biophys Res Commun. 2006;342:170–178. doi: 10.1016/j.bbrc.2006.01.130. [DOI] [PubMed] [Google Scholar]
  36. Ma Y., Stern R.J., Scherman M.S., Vissa V.D., Yan W., Jones V.C., Zhang F., Franzblau S.G., Lewis W.H., McNeil M.R. Drug targeting Mycobacterium tuberculosis cell wall synthesis: genetics of dTDP-rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dTDP-glucose to dTDP-rhamnose. Antimicrob Agents Chemother. 2001;45:1407–1416. doi: 10.1128/AAC.45.5.1407-1416.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Maier T., Jenni S., Ban N. Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science. 2006;311:1258–1262. doi: 10.1126/science.1123248. [DOI] [PubMed] [Google Scholar]
  38. Marques M.A., Neves-Ferreira A.G., da Silveira E.K., Valente R.H., Chapeaurouge A., Perales J., da Silva Bernardes R., Dobos K. M., Spencer J.S., Brennan P.J., et al. Deciphering the proteomic profile of Mycobacterium leprae cell envelope. Proteomics. 2008;8:2477–2491. doi: 10.1002/pmic.200700971. [DOI] [PubMed] [Google Scholar]
  39. McCoy A.J., Grosse-Kunstleve R.W., Adams P.D., Winn M.D., Storoni L.C., Read R.J. Phaser crystallographic software. J Appl Crystallogr. 2007;40:658–674. doi: 10.1107/S0021889807021206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Mdluli K., Spigelman M. Novel targets for tuberculosis drug discovery. Curr Opin Pharmacol. 2006;6:459–467. doi: 10.1016/j.coph.2006.06.004. [DOI] [PubMed] [Google Scholar]
  41. Meganathan R. Biosynthesis of menaquinone (vitamin K2) and ubiquinone (coenzyme Q): a perspective on enzymatic mechanisms. Vitam Horm. 2001;61:173–218. doi: 10.1016/S0083-6729(01)61006-9. [DOI] [PubMed] [Google Scholar]
  42. Mowa M.B., Warner D.F., Kaplan G., Kana B.D., Mizrahi V. Function and regulation of class I ribonucleotide reductase-encoding genes in mycobacteria. J Bacteriol. 2009;191:985–995. doi: 10.1128/JB.01409-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Munoz-Elias E.J., McKinney J.D. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat Med. 2005;11:638–644. doi: 10.1038/nm1252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Munoz-Elias E.J., Upton A.M., Cherian J., McKinney J.D. Role of the methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth, and virulence. Mol Microbiol. 2006;60:1109–1122. doi: 10.1111/j.1365-2958.2006.05155.x. [DOI] [PubMed] [Google Scholar]
  45. Musayev F., Sachdeva S., Scarsdale J.N., Reynolds K.A., Wright H.T. Crystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A. J Mol Biol. 2005;346:1313–1321. doi: 10.1016/j.jmb.2004.12.044. [DOI] [PubMed] [Google Scholar]
  46. Nakano Y., Suzuki N., Yoshida Y., Nezu T., Yamashita Y., Koga T. Thymidine diphosphate-6-deoxy-L-lyxo-4-hexulose reductase synthesizing dTDP-6-deoxy-L-talose from Actinobacillus actinomycetemcomitans. J Biol Chem. 2000;275:6806–6812. doi: 10.1074/jbc.275.10.6806. [DOI] [PubMed] [Google Scholar]
  47. Nunn C.M., Djordjevic S., Hillas P.J., Nishida C.R., Ortiz de Montellano P.R. The crystal structure of Mycobacterium tuberculosis alkylhydroperoxidase AhpD, a potential target for antitubercular drug design. J Biol Chem. 2002;277:20033–20040. doi: 10.1074/jbc.M200864200. [DOI] [PubMed] [Google Scholar]
  48. Oliveira J.S., Pereira J.H., Canduri F., Rodrigues N.C., de Souza O.N., de Azevedo W.F., Jr., Basso L.A., Santos D.S. Crystallographic and pre-steady-state kinetics studies on binding of NADH to wild-type and isoniazid-resistant enoyl-ACP (CoA) reductase enzymes from Mycobacterium tuberculosis. J Mol Biol. 2006;359:646–666. doi: 10.1016/j.jmb.2006.03.055. [DOI] [PubMed] [Google Scholar]
  49. Portevin D., de Sousa-D’Auria C., Montrozier H., Houssin C., Stella A., Laneelle M.A., Bardou F., Guilhot C., Daffe M. The acyl-AMP ligase FadD32 and AccD4-containing acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for mycobacterial growth: identification of the carboxylation product and determination of the acyl-CoA carboxylase components. J Biol Chem. 2005;280:8862–8874. doi: 10.1074/jbc.M408578200. [DOI] [PubMed] [Google Scholar]
  50. Qureshi H., Arif A., Alam E., Qadir N. Integration of informal medical practitioners in DOTS implementation to improve case detection rate. J Pak Med Assoc. 2010;60:33–37. [PubMed] [Google Scholar]
  51. Raman K., Rajagopalan P., Chandra N. Flux balance analysis of mycolic acid pathway: targets for anti-tubercular drugs. PLoS Comput Biol. 2005;1:e46. doi: 10.1371/journal.pcbi.0010046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Rivers E.C., Mancera R.L. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discov Today. 2008;13:1090–1098. doi: 10.1016/j.drudis.2008.09.004. [DOI] [PubMed] [Google Scholar]
  53. Rivers E.C., Mancera R.L. New anti-tuberculosis drugs with novel mechanisms of action. Curr Med Chem. 2008;15:1956–1967. doi: 10.2174/092986708785132906. [DOI] [PubMed] [Google Scholar]
  54. Rodriguez-Concepcion M. The MEP pathway: a new target for the development of herbicides, antibiotics and antimalarial drugs. Curr Pharm Des. 2004;10:2391–2400. doi: 10.2174/1381612043384006. [DOI] [PubMed] [Google Scholar]
  55. Sambandamurthy V.K., Wang X., Chen B., Russell R.G., Derrick S., Collins F.M., Morris S.L., Jacobs W.R., Jr A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis. Nat Med. 2002;8:1171–1174. doi: 10.1038/nm765. [DOI] [PubMed] [Google Scholar]
  56. Scarsdale J.N., Kazanina G., He X., Reynolds K.A., Wright H. T. Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III. J Biol Chem. 2001;276:20516–20522. doi: 10.1074/jbc.M010762200. [DOI] [PubMed] [Google Scholar]
  57. Sharma V., Grubmeyer C., Sacchettini J.C. Crystal structure of quinolinic acid phosphoribosyltransferase from Mmycobacterium tuberculosis: a potential TB drug target. Structure. 1998;6:1587–1599. doi: 10.1016/S0969-2126(98)00156-7. [DOI] [PubMed] [Google Scholar]
  58. Sharma V., Sharma S., Hoener zu Bentrup K., McKinney J.D., Russell D.G., Jacobs W.R., Jr., Sacchettini J.C. Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis. Nat Struct Biol. 2000;7:663–668. doi: 10.1038/77964. [DOI] [PubMed] [Google Scholar]
  59. Sjoberg B.M., Reichard P., Graslund A., Ehrenberg A. The tyrosine free radical in ribonucleotide reductase from Escherichia coli. J Biol Chem. 1978;253:6863–6865. [PubMed] [Google Scholar]
  60. Srivastava S.K., Dube D., Kukshal V., Jha A.K., Hajela K., Ramachandran R. NAD+-dependent DNA ligase (Rv3014c) from Mycobacterium tuberculosis: novel structurefunction relationship and identification of a specific inhibitor. Proteins. 2007;69:97–111. doi: 10.1002/prot.21457. [DOI] [PubMed] [Google Scholar]
  61. Srivastava S.K., Tripathi R.P., Ramachandran R. NAD+-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors. J Biol Chem. 2005;280:30273–30281. doi: 10.1074/jbc.M503780200. [DOI] [PubMed] [Google Scholar]
  62. Takayama K., Wang C., Besra G.S. Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev. 2005;18:81–101. doi: 10.1128/CMR.18.1.81-101.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Tang Y., Kim C.Y., Mathews I.I., Cane D.E., Khosla C. The 2.7-Angstrom crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase. Proc Natl Acad Sci U S A. 2006;103:11124–11129. doi: 10.1073/pnas.0601924103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Teh J.S., Yano T., Rubin H. Type II NADH: menaquinone oxidoreductase of Mycobacterium tuberculosis. Infect Disord Drug Targets. 2007;7:169–181. doi: 10.2174/187152607781001781. [DOI] [PubMed] [Google Scholar]
  65. Trivedi O.A., Arora P., Sridharan V., Tickoo R., Mohanty D., Gokhale R.S. Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature. 2004;428:441–445. doi: 10.1038/nature02384. [DOI] [PubMed] [Google Scholar]
  66. Uppsten M., Davis J., Rubin H., Uhlin U. Crystal structure of the biologically active form of class Ib ribonucleotide reductase small subunit from Mycobacterium tuberculosis. FEBS Lett. 2004;569:117–122. doi: 10.1016/j.febslet.2004.05.059. [DOI] [PubMed] [Google Scholar]
  67. Vanheusden V., Munier-Lehmann H., Froeyen M., Busson R., Rozenski J., Herdewijn P., Van Calenbergh S. Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. J Med Chem. 2004;47:6187–6194. doi: 10.1021/jm040847w. [DOI] [PubMed] [Google Scholar]
  68. Vanheusden V., Munier-Lehmann H., Froeyen M., Dugue L., Heyerick A., De Keukeleire D., Pochet S., Busson R., Herdewijn P., Van Calenbergh S. 3′-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. J Med Chem. 2003;46:3811–3821. doi: 10.1021/jm021108n. [DOI] [PubMed] [Google Scholar]
  69. Visca P., Fabozzi G., Milani M., Bolognesi M., Ascenzi P. Nitric oxide and Mycobacterium leprae pathogenicity. IUBMB Life. 2002;54:95–99. doi: 10.1080/15216540214542. [DOI] [PubMed] [Google Scholar]
  70. Vispe S., Satoh M.S. DNA repair patch-mediated double strand DNA break formation in human cells. J Biol Chem. 2000;275:27386–27392. doi: 10.1074/jbc.M003126200. [DOI] [PubMed] [Google Scholar]
  71. Wang S., Eisenberg D. Crystal structures of a pantothenate synthetase from M. tuberculosis and its complexes with substrates and a reaction intermediate. Protein Sci. 2003;12:1097–1108. doi: 10.1110/ps.0241803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Wang S., Eisenberg D. Crystal structure of the pantothenate synthetase from Mycobacterium tuberculosis, snapshots of the enzyme in action. Biochemistry. 2006;45:1554–1561. doi: 10.1021/bi051873e. [DOI] [PubMed] [Google Scholar]
  73. Weinstein E.A., Yano T., Li L.S., Avarbock D., Avarbock A., Helm D., McColm A.A., Duncan K., Lonsdale J.T., Rubin H. Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci U S A. 2005;102:4548–4553. doi: 10.1073/pnas.0500469102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Yano T., Li L.S., Weinstein E., Teh J.S., Rubin H. Steady-state kinetics and inhibitory action of antitubercular phenothiazines on mycobacterium tuberculosis type-II NADH-menaquinone oxidoreductase (NDH-2) J Biol Chem. 2006;281:11456–11463. doi: 10.1074/jbc.M508844200. [DOI] [PubMed] [Google Scholar]
  75. Yuan Y., Crane D.C., Musser J.M., Sreevatsan S., Barry C.E., 3rd MMAS-1, the branch point between cis- and transcyclopropane-containing oxygenated mycolates in Mycobacterium tuberculosis. J Biol Chem. 1997;272:10041–10049. doi: 10.1074/jbc.272.15.10041. [DOI] [PubMed] [Google Scholar]
  76. Zhou, X., Lou, Z., Fu, S., Yang, A., Shen, H., Li, Z., Feng, Y., Bartlam, M., Wang, H., and Rao, Z. Crystal structure of ArgP from Mycobacterium tuberculosis confirms two distinct conformations of full-length LysR transcriptional regulators and reveals its function in DNA binding and transcriptional regulation. J Mol Biol 396, 1012–1024. [DOI] [PubMed]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES