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.
. Protein targets for structure-based anti-Mycobacterium tuberculosis drug discovery[J]. Protein & Cell, 2010, 1(5): 435-442.
Zhiyong Lou, Xiaoxue Zhang. Protein targets for structure-based anti-Mycobacterium tuberculosis drug discovery. Prot Cell, 2010, 1(5): 435-442.
Andries, K., Verhasselt, P., Guillemont, J., Gohlmann, H.W., Neefs, J.M., Winkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., . (2005). A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223-227 .
2
Bhatt, A., Molle, V., Besra, G.S., Jacobs, W.R., Jr., and Kremer, L. (2007). The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development. Mol Microbiol 64, 1442-1454 . doi: 10.1111/j.1365-2958.2007.05761.x
3
Bocchino, M., Sanduzzi, A., and Bariffi, F. (2000). Mycobacterium tuberculosis and HIV co-infection in the lung: synergic immune dysregulation leading to disease progression. Monaldi Arch Chest Dis 55, 381-388 .
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., . (1998). Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr 54, 905-921 . doi: 10.1107/S0907444998003254
5
Carroll, P., Pashley, C.A., and Parish, T. (2008). Functional analysis of GlnE, an essential adenylyl transferase in Mycobacterium tuberculosis. J Bacteriol 190, 4894-4902 . doi: 10.1128/JB.00166-08
6
Chatterjee, D. (1997). The mycobacterial cell wall: structure, biosynthesis and sites of drug action. Curr Opin Chem Biol 1, 579-588 . doi: 10.1016/S1367-5931(97)80055-5
7
Chaudhuri, B.N., Sawaya, M.R., Kim, C.Y., Waldo, G.S., Park, M.S., Terwilliger, T.C., and Yeates, T.O. (2003). The crystal structure of the first enzyme in the pantothenate biosynthetic pathway, ketopantoate hydroxymethyltransferase, from M tuberculosis. Structure 11, 753-764 . doi: 10.1016/S0969-2126(03)00106-0
8
Chetnani, B., Das, S., Kumar, P., Surolia, A., and Vijayan, M. (2009). Mycobacterium tuberculosis pantothenate kinase: possible changes in location of ligands during enzyme action. Acta Crystallogr D Biol Crystallogr 65, 312-325 . doi: 10.1107/S0907444909002170
9
Cohen-Gonsaud, M., Ducasse, S., Hoh, F., Zerbib, D., Labesse, G., and Quemard, A. (2002). Crystal structure of MabA from Mycobacterium tuberculosis, a reductase involved in long-chain fatty acid biosynthesis. J Mol Biol 320, 249-261 . doi: 10.1016/S0022-2836(02)00463-1
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., . (2001). Massive gene decay in the leprosy bacillus. Nature 409, 1007-1011 . doi: 10.1038/35059006
11
Deckers-Hebestreit, G., and Altendorf, K. (1996). The F0F1-type ATP synthases of bacteria: structure and function of the F0 complex. Annu Rev Microbiol 50, 791-824 . doi: 10.1146/annurev.micro.50.1.791
12
Dessen, A., Quemard, A., Blanchard, J.S., Jacobs, W.R., Jr., and Sacchettini, J.C. (1995). Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science 267, 1638-1641 . doi: 10.1126/science.7886450
Ducasse-Cabanot, S., Cohen-Gonsaud, M., Marrakchi, H., Nguyen, M., Zerbib, D., Bernadou, J., Daffe, M., Labesse, G., and Quemard, A. (2004). In vitro inhibition of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein reductase MabA by isoniazid. Antimicrob Agents Chemother 48, 242-249 . doi: 10.1128/AAC.48.1.242-249.2004
15
Feng, Z., and Barletta, R.G. (2003). 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 47, 283-291 . doi: 10.1128/AAC.47.1.283-291.2003
16
Fioravanti, E., Adam, V., Munier-Lehmann, H., and Bourgeois, D. (2005). The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3'-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition. Biochemistry 44, 130-137 . doi: 10.1021/bi0484163
17
Fioravanti, E., Haouz, A., Ursby, T., Munier-Lehmann, H., Delarue, M., and Bourgeois, D. (2003). Mycobacterium tuberculosis thymidylate kinase: structural studies of intermediates along the reaction pathway. J Mol Biol 327, 1077-1092 . doi: 10.1016/S0022-2836(03)00202-X
18
Fontecave, M., Nordlund, P., Eklund, H., and Reichard, P. (1992). The redox centers of ribonucleotide reductase of Escherichia coli. Adv Enzymol Relat Areas Mol Biol 65, 147-183 .
19
Georgieva, E.R., Narvaez, A.J., Hedin, N., and Graslund, A. (2008). Secondary structure conversions of Mycobacterium tuberculosis ribonucleotide reductase protein R2 under varying pH and temperature conditions. Biophys Chem 137, 43-48 . doi: 10.1016/j.bpc.2008.06.009
20
Godreuil, S., Renaud, F., Van de Perre, P., Carriere, C., Torrea, G., and Banuls, A.L. (2007). Genetic diversity and population structure of Mycobacterium tuberculosis in HIV-1-infected compared with uninfected individuals in Burkina Faso. Aids 21, 248-250 . doi: 10.1097/QAD.0b013e328011ec64
21
Gong, C., Martins, A., Bongiorno, P., Glickman, M., and Shuman, S. (2004). Biochemical and genetic analysis of the four DNA ligases of mycobacteria. J Biol Chem 279, 20594-20606 . doi: 10.1074/jbc.M401841200
22
Gould, T.A., van de Langemheen, H., Munoz-Elias, E.J., McKinney, J.D., and Sacchettini, J.C. (2006). Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis. Mol Microbiol 61, 940-947 . doi: 10.1111/j.1365-2958.2006.05297.x
23
Gourley, D.G., Shrive, A.K., Polikarpov, I., Krell, T., Coggins, J.R., Hawkins, A.R., Isaacs, N.W., and Sawyer, L. (1999). The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction. Nat Struct Biol 6, 521-525 . doi: 10.1038/9287
24
Haouz, A., Vanheusden, V., Munier-Lehmann, H., Froeyen, M., Herdewijn, P., Van Calenbergh, S., and Delarue, M. (2003). Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism. J Biol Chem 278, 4963-4971 . doi: 10.1074/jbc.M209630200
25
Hasan, S., Daugelat, S., Rao, P.S., and Schreiber, M. (2006). Prioritizing genomic drug targets in pathogens: application to Mycobacterium tuberculosis. PLoS Comput Biol 2, e61. doi: 10.1371/journal.pcbi.0020061
26
He, X., and Reynolds, K.A. (2002). Purification, characterization, and identification of novel inhibitors of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus. Antimicrob Agents Chemother 46, 1310-1318 . doi: 10.1128/AAC.46.5.1310-1318.2002
27
Huang, H., Scherman, M.S., D'Haeze, W., Vereecke, D., Holsters, M., Crick, D.C., and McNeil, M.R. (2005). 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 280, 24539-24543 . doi: 10.1074/jbc.M504068200
28
Jordan, A., Pontis, E., Aslund, F., Hellman, U., Gibert, I., and Reichard, P. (1996). The ribonucleotide reductase system of Lactococcus lactis. Characterization of an NrdEF enzyme and a new electron transport protein. J Biol Chem 271, 8779-8785 .
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., . (2001). Galactan biosynthesis in Mycobacterium tuberculosis. Identification of a bifunctional UDP-galactofuranosyltransferase. J Biol Chem 276, 26430-26440 . doi: 10.1074/jbc.M102022200
30
Kurth, D.G., Gago, G.M., de la Iglesia, A., Bazet Lyonnet, B., Lin, T.W., Morbidoni, H.R., Tsai, S.C., and Gramajo, H. (2009). ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria. Microbiology 155, 2664-2675 .
31
Lederer, E., Adam, A., Ciorbaru, R., Petit, J.F., and Wietzerbin, J. (1975). Cell walls of Mycobacteria and related organisms; chemistry and immunostimulant properties. Mol Cell Biochem 7, 87-104 . doi: 10.1007/BF01792076
32
Leger, M., Gavalda, S., Guillet, V., van der Rest, B., Slama, N., Montrozier, H., Mourey, L., Quemard, A., Daffe, M., and Marrakchi, H. (2009). The dual function of the Mycobacterium tuberculosis FadD32 required for mycolic acid biosynthesis. Chem Biol 16, 510-519 . doi: 10.1016/j.chembiol.2009.03.012
33
LeMagueres, P., Im, H., Ebalunode, J., Strych, U., Benedik, M.J., Briggs, J.M., Kohn, H., and Krause, K.L. (2005). The 1.9 ? crystal structure of alanine racemase from Mycobacterium tuberculosis contains a conserved entryway into the active site. Biochemistry 44, 1471-1481 . doi: 10.1021/bi0486583
34
Li de la Sierra, I., Munier-Lehmann, H., Gilles, A.M., Barzu, O., and Delarue, M. (2001). X-ray structure of TMP kinase from Mycobacterium tuberculosis complexed with TMP at 1.95 ? resolution. J Mol Biol 311, 87-100 . doi: 10.1006/jmbi.2001.4843
35
Li, W., Xin, Y., McNeil, M.R., and Ma, Y. (2006). rmlB and rmlC genes are essential for growth of mycobacteria. Biochem Biophys Res Commun 342, 170-178 . doi: 10.1016/j.bbrc.2006.01.130
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., and McNeil, M.R. (2001). 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 45, 1407-1416 . doi: 10.1128/AAC.45.5.1407-1416.2001
37
Maier, T., Jenni, S., and Ban, N. (2006). Architecture of mammalian fatty acid synthase at 4.5 ? resolution. Science 311, 1258-1262 . doi: 10.1126/science.1123248
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., . (2008). Deciphering the proteomic profile of Mycobacterium leprae cell envelope. Proteomics 8, 2477-2491 .
Mdluli, K., and Spigelman, M. (2006). Novel targets for tuberculosis drug discovery. Curr Opin Pharmacol 6, 459-467 . doi: 10.1016/j.coph.2006.06.004
41
Meganathan, R. (2001). Biosynthesis of menaquinone (vitamin K2) and ubiquinone (coenzyme Q): a perspective on enzymatic mechanisms. Vitam Horm 61, 173-218 . doi: 10.1016/S0083-6729(01)61006-9
42
Mowa, M.B., Warner, D.F., Kaplan, G., Kana, B.D., and Mizrahi, V. (2009). Function and regulation of class I ribonucleotide reductase-encoding genes in mycobacteria. J Bacteriol 191, 985-995 . doi: 10.1128/JB.01409-08
43
Munoz-Elias, E.J., and McKinney, J.D. (2005). Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat Med 11, 638-644 . doi: 10.1038/nm1252
44
Munoz-Elias, E.J., Upton, A.M., Cherian, J., and McKinney, J.D. (2006). Role of the methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth, and virulence. Mol Microbiol 60, 1109-1122 . doi: 10.1111/j.1365-2958.2006.05155.x
45
Musayev, F., Sachdeva, S., Scarsdale, J.N., Reynolds, K.A., and Wright, H.T. (2005). Crystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A. J Mol Biol 346, 1313-1321 . doi: 10.1016/j.jmb.2004.12.044
46
Nakano, Y., Suzuki, N., Yoshida, Y., Nezu, T., Yamashita, Y., and Koga, T. (2000). Thymidine diphosphate-6-deoxy-L-lyxo-4-hexulose reductase synthesizing dTDP-6-deoxy-L-talose from Actinobacillus actinomycetemcomitans. J Biol Chem 275, 6806-6812 . doi: 10.1074/jbc.275.10.6806
47
Nunn, C.M., Djordjevic, S., Hillas, P.J., Nishida, C.R., and Ortiz de Montellano, P.R. (2002). The crystal structure of Mycobacterium tuberculosis alkylhydroperoxidase AhpD, a potential target for antitubercular drug design. J Biol Chem 277, 20033-20040 . doi: 10.1074/jbc.M200864200
48
Oliveira, J.S., Pereira, J.H., Canduri, F., Rodrigues, N.C., de Souza, O.N., de Azevedo, W.F., Jr., Basso, L.A., and Santos, D.S. (2006). 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 359, 646-666 . doi: 10.1016/j.jmb.2006.03.055
49
Portevin, D., de Sousa-D'Auria, C., Montrozier, H., Houssin, C., Stella, A., Laneelle, M.A., Bardou, F., Guilhot, C., and Daffe, M. (2005). 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 280, 8862-8874 . doi: 10.1074/jbc.M408578200
50
Qureshi, H., Arif, A., Alam, E., and Qadir, N. (2010). Integration of informal medical practitioners in DOTS implementation to improve case detection rate. J Pak Med Assoc 60, 33-37 .
51
Raman, K., Rajagopalan, P., and Chandra, N. (2005). Flux balance analysis of mycolic acid pathway: targets for anti-tubercular drugs. PLoS Comput Biol 1, e46. doi: 10.1371/journal.pcbi.0010046
52
Rivers, E.C., and Mancera, R.L. (2008a). New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discov Today 13, 1090-1098 . doi: 10.1016/j.drudis.2008.09.004
53
Rivers, E.C., and Mancera, R.L. (2008b). New anti-tuberculosis drugs with novel mechanisms of action. Curr Med Chem 15, 1956-1967 . doi: 10.2174/092986708785132906
54
Rodriguez-Concepcion, M. (2004). The MEP pathway: a new target for the development of herbicides, antibiotics and antimalarial drugs. Curr Pharm Des 10, 2391-2400 . doi: 10.2174/1381612043384006
55
Sambandamurthy, V.K., Wang, X., Chen, B., Russell, R.G., Derrick, S., Collins, F.M., Morris, S.L., and Jacobs, W.R., Jr. (2002). A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis. Nat Med 8, 1171-1174 . doi: 10.1038/nm765
56
Scarsdale, J.N., Kazanina, G., He, X., Reynolds, K.A., and Wright, H.T. (2001). Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III. J Biol Chem 276, 20516-20522 .
57
Sharma, V., Grubmeyer, C., and Sacchettini, J.C. (1998). Crystal structure of quinolinic acid phosphoribosyltransferase from Mmycobacterium tuberculosis: a potential TB drug target. Structure 6, 1587-1599 . doi: 10.1016/S0969-2126(98)00156-7
58
Sharma, V., Sharma, S., Hoener zu Bentrup, K., McKinney, J.D., Russell, D.G., Jacobs, W.R., Jr., and Sacchettini, J.C. (2000). Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis. Nat Struct Biol 7, 663-668 . doi: 10.1038/77964
59
Sjoberg, B.M., Reichard, P., Graslund, A., and Ehrenberg, A. (1978). The tyrosine free radical in ribonucleotide reductase from Escherichia coli. J Biol Chem 253, 6863-6865 .
60
Srivastava, S.K., Dube, D., Kukshal, V., Jha, A.K., Hajela, K., and Ramachandran, R. (2007). NAD+-dependent DNA ligase (Rv3014c) from Mycobacterium tuberculosis: novel structure-function relationship and identification of a specific inhibitor. Proteins 69, 97-111 . doi: 10.1002/prot.21457
61
Srivastava, S.K., Tripathi, R.P., and Ramachandran, R. (2005). NAD+-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors. J Biol Chem 280, 30273-30281 . doi: 10.1074/jbc.M503780200
62
Takayama, K., Wang, C., and Besra, G.S. (2005). Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev 18, 81-101 . doi: 10.1128/CMR.18.1.81-101.2005
63
Tang, Y., Kim, C.Y., Mathews, II, Cane, D.E., and Khosla, C. (2006). 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 103, 11124-11129 . doi: 10.1073/pnas.0601924103
64
Teh, J.S., Yano, T., and Rubin, H. (2007). Type II NADH: menaquinone oxidoreductase of Mycobacterium tuberculosis. Infect Disord Drug Targets 7, 169-181 . doi: 10.2174/187152607781001781
65
Trivedi, O.A., Arora, P., Sridharan, V., Tickoo, R., Mohanty, D., and Gokhale, R.S. (2004). Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature 428, 441-445 . doi: 10.1038/nature02384
66
Uppsten, M., Davis, J., Rubin, H., and Uhlin, U. (2004). Crystal structure of the biologically active form of class Ib ribonucleotide reductase small subunit from Mycobacterium tuberculosis. FEBS Lett 569, 117-122 . doi: 10.1016/j.febslet.2004.05.059
67
Vanheusden, V., Munier-Lehmann, H., Froeyen, M., Busson, R., Rozenski, J., Herdewijn, P., and Van Calenbergh, S. (2004). Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. J Med Chem 47, 6187-6194 . doi: 10.1021/jm040847w
68
Vanheusden, V., Munier-Lehmann, H., Froeyen, M., Dugue, L., Heyerick, A., De Keukeleire, D., Pochet, S., Busson, R., Herdewijn, P., and Van Calenbergh, S. (2003). 3'-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. J Med Chem 46, 3811-3821 . doi: 10.1021/jm021108n
69
Visca, P., Fabozzi, G., Milani, M., Bolognesi, M., and Ascenzi, P. (2002). Nitric oxide and Mycobacterium leprae pathogenicity. IUBMB Life 54, 95-99 . doi: 10.1080/15216540214542
70
Vispe, S., and Satoh, M.S. (2000). DNA repair patch-mediated double strand DNA break formation in human cells. J Biol Chem 275, 27386-27392 .
71
Wang, S., and Eisenberg, D. (2003). Crystal structures of a pantothenate synthetase from M. tuberculosis and its complexes with substrates and a reaction intermediate. Protein Sci 12, 1097-1108 . doi: 10.1110/ps.0241803
72
Wang, S., and Eisenberg, D. (2006). Crystal structure of the pantothenate synthetase from Mycobacterium tuberculosis, snapshots of the enzyme in action. Biochemistry 45, 1554-1561 . doi: 10.1021/bi051873e
73
Weinstein, E.A., Yano, T., Li, L.S., Avarbock, D., Avarbock, A., Helm, D., McColm, A.A., Duncan, K., Lonsdale, J.T., and Rubin, H. (2005). Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci U S A 102, 4548-4553 . doi: 10.1073/pnas.0500469102
74
Yano, T., Li, L.S., Weinstein, E., Teh, J.S., and Rubin, H. (2006). Steady-state kinetics and inhibitory action of antitubercular phenothiazines on mycobacterium tuberculosis type-II NADH-menaquinone oxidoreductase (NDH-2). J Biol Chem 281, 11456-11463 . doi: 10.1074/jbc.M508844200
75
Yuan, Y., Crane, D.C., Musser, J.M., Sreevatsan, S., and Barry, C.E., 3rd (1997). MMAS-1, the branch point between cis- and trans-cyclopropane-containing oxygenated mycolates in Mycobacterium tuberculosis. J Biol Chem 272, 10041-10049 . doi: 10.1074/jbc.272.15.10041
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: 10.1016/j.jmb.2009.12.033
