20 The Role of Mycobacterial Kinases and Phosphatases in Growth, Pathogenesis, and Cell Wall Metabolism

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

20 The Role of Mycobacterial Kinases and Phosphatases in Growth, Pathogenesis, and Cell Wall Metabolism, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815783/9781555814687_Chap20-1.gif /docserver/preview/fulltext/10.1128/9781555815783/9781555814687_Chap20-2.gif


This chapter summarizes studies on the role of mycobacterial kinases and phosphatases (i) in the growth and pathogenesis of mycobacterium and (ii) in the cell wall metabolism of the pathogen. Earlier, the two-component systems (TCSs) involving a histidine kinase (HK) and a response regulator (RR) were considered to play a key role in phosphotransfer mechanism for signal transduction in bacteria, whereas serine/threonine protein kinases (STPKs) and their associated phosphatases were more relevant to signal transduction pathways in eukaryotes. However, with the inflow of bacterial genome sequences, it is now known that these eukaryotic-like protein kinases and phosphatases are present in prokaryotes also and play an important role in bacterial metabolism and pathogenesis. Transposon-insertion mutagenesis experiments carried out to identify the genes required for optimal in vitro mycobacterial growth resulted in the identification of only three out of the 11 mycobacterial kinases, namely PknA, PknB, and PknG. In view of the unique cell wall structure of mycobacteria and the presence of a large repertoire of polyketides and complex lipids, kinases and phosphatases are bound to play an important role in the regulation of the cell wall metabolism of this pathogen. Future work will expose the mechanistic details and proteins used by this pathogen to downregulate the host signaling pathways. Structural analysis of complexes of these signaling proteins may provide the key to designing molecules for selective disruption of signal transduction.

Citation: Tyagi A, Singh R, Gupta V. 2008. 20 The Role of Mycobacterial Kinases and Phosphatases in Growth, Pathogenesis, and Cell Wall Metabolism, p 323-343. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch20

Key Concept Ranking

Two-Component Signal Transduction Systems
Bacterial Cellular Processes
Bacterial Proteins
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1.
Figure 1.

Two-component signal transduction. Two-component signal transduction systems are a mechanism that bacteria use to sense and respond to their environment. These modular and conserved systems are typically composed of a histidine kinase (HK) generally anchored in the cell membrane and a cytoplasmic response regulator (RR). Both proteins harbor two functional important domains (HK comprises sensor and kinase transmitter domains, whereas RR comprises receiver and effector domains). The HK detects a specific environmental stimulus through its sensor domain leading to ATP-dependent autophosphorylation of a histidine residue in the cytoplasmic kinase transmitter domain. The phosphoryl group from the activated transmitter domain is then transferred to an aspartic acid residue in the receiver domain of its cognate RR, resulting in the activation of the effector domain that mediates the cellular response (changes in gene expression or protein function).

Citation: Tyagi A, Singh R, Gupta V. 2008. 20 The Role of Mycobacterial Kinases and Phosphatases in Growth, Pathogenesis, and Cell Wall Metabolism, p 323-343. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2.
Figure 2.

Phosphorylation of FHA-domain proteins by serine/threonine protein kinases (STPKs) in vitro. FHA domains are ubiquitous phosphothreonine peptide recognition motifs that play diverse roles in STPK signal transduction. PknF senses extracellular signals and regulates transport of solutes across the cellular membrane through phosphorylation of Rv1747 (ABC transporter). Rv1747 has two FHA domains, one of which is phosphorylated by PknB, PknD, PknE, and PknF, whereas the other domain is more restrictively phosphorylated. The above-mentioned STPKs also phosphorylate GarA, a regulator of glycogen degradation during cell growth. PknB and PknF have also been shown to phosphorylate Rv0020c in vitro. PknH, PknB, and PknA phosphorylates the FHA-containing protein EmbR, which, in turn, induces transcription from the operon, leading to a higher LAM/LM ratio. LAM is known to be an important determinant of virulence and modulator of host immune responses.

Citation: Tyagi A, Singh R, Gupta V. 2008. 20 The Role of Mycobacterial Kinases and Phosphatases in Growth, Pathogenesis, and Cell Wall Metabolism, p 323-343. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3.
Figure 3.

Role of kinases and phosphatases in cell wall metabolism of mycobacteria. In response to various environmental cues, STPKs become autophosphorylated (double arrow) and, in turn, phosphorylate their target proteins, enabling them to carry out their respective functions in the cell. Of the many target proteins of STPKs, only those known to be involved in cell wall metabolism are shown in the figure. PstP (a Ser/Thr phosphatase) in response to environmental cues dephosphorylates (dashed arrows) phosphorylated STPKs and some of the phosphorylated target proteins such as EmbR and PbpA, thus rendering them inactive. The PhoP-PhoR two-component system is involved in the biosynthesis of polyketide derived lipids, which are important constituents of the cell wall. ? indicates that the pathway is proposed but not experimentally validated.

Citation: Tyagi A, Singh R, Gupta V. 2008. 20 The Role of Mycobacterial Kinases and Phosphatases in Growth, Pathogenesis, and Cell Wall Metabolism, p 323-343. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4.
Figure 4.

Structures and IC values (µM) of various compounds that have been identified as inhibitors of mycobacterial tyrosine phosphatases. (A and B) 3′ substituted indolizine-1-carbonitrile derivatives have been identified as inhibitors of mycobacterial tyrosine phosphatase B (MptpB) having IC values of 22.0 and 7.5 µM, respectively. Roseophilin and prodigiosin represent a new class of natural products and have been shown to inhibit tyrosine phosphatases. An analogue of roseophilin (C) has been shown to inhibit mycobacterial tyrosine phosphatase A (MptpA) with an IC value of 9.4 µM. Compound D, a prodigiosin derivative, inhibited the enzymatic activity of MptpA with an IC value of 28.7 µM. In an alternative approach 2-dimethylpyrrol-1-yl benzoic acid derivatives (E and F) have been identified as MptpA inhibitors from the rationally assorted fragment based FMP library. Compounds E and F had IC values of 1.9 and 1.6 µM, respectively.

Citation: Tyagi A, Singh R, Gupta V. 2008. 20 The Role of Mycobacterial Kinases and Phosphatases in Growth, Pathogenesis, and Cell Wall Metabolism, p 323-343. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Alex, L. A., and, M. I. Simon. 1994. Protein histidine kinases and signal transduction in prokaryotes and eukaryotes. Trends Genet. 10:133138.
2. Alonso, A.,, J. Sasin,, N. Bottini,, I. Friedberg,, I. Friedberg,, A. Osterman,, A. Godzik,, T. Hunter,, J. Dixon, and, T. Mustelin. 2004. Protein tyrosine phosphatases in the human genome. Cell 117:699711.
3. Av-Gay, Y., and, M. Everett. 2000. The eukaryotic like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol. 8:238244.
4. Av-Gay, Y.,, S. Jamil, and, S. J. Drews. 1999. Expression and characterization of the Mycobacterium tuberculosis serine/threonine protein kinase PknB. Infect. Immun. 67:56765682.
5. Baca, O. G.,, M. J. Roman,, R. H. Glew,, R. F. Christner,, J. E. Buhler, and, A. S. Aragon. 1993. Acid phosphatase activity in Coxiella burnetii: a possible virulence factor. Infect. Immun. 61:42324239.
6. Bakalara, N.,, A. Seyfang,, C. Davis, and, T. Baltz. 1995. Characterization of a life-cycle-stage-regulated membrane protein tyrosine phosphatase in Trypanosoma brucei. Eur. J. Biochem. 234:871877.
7. Belanger, A. E., and, G. F. Hatfull. 1999. Exponential-phase glycogen recycling is essential for growth of Mycobacterium smegmatis. J. Bacteriol. 181:66706678.
8. Betts, J. C.,, P. T. Lukey,, L. C. Robb,, R. A. McAdam, and, K. Duncan. 2002. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol. Microbiol. 43:717731.
9. Bhakta, S.,, G. S. Besra,, A. M. Upton,, T. Parish,, C. Sholto-Douglas-Vernon,, K. J. C. Gibson,, S. Knutton,, S. Gordon,, R. P. daSilva,, M. C. Anderton, and, E. Sim. 2004. Arylamine Nacetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target. J. Exp. Med. 199:11911199.
10. Birck, C.,, Y. Chen,, F. M. Hulett, and, J. P. Samama. 2003. The crystal structure of the phosphorylation domain in PhoP reveals a functional tandem association mediated by an asymmetric interface. J. Bacteriol. 185:254261.
11. Bliska, J. B.,, J. E. Galan, and, S. Falkow. 1993. Signal transduction in the mammalian cell during bacterial attachment and entry. Cell 73:903920.
12. Boitel, B.,, M. Ortiz-Lombardia,, R. Duran,, F. Pompeo,, S. T. Cole,, C. Cervenansky, and, P. M. Alzari. 2003. PknB kinase activity is regulated by phosphorylation in two Thr residues and dephosphorylation by PstP, the cognate phospho-Ser/Thr phosphatase, in Mycobacterium tuberculosis. Mol. Microbiol. 49:14931508.
13. Bork, P.,, N. P. Brown,, H. Hegyi, and, J. Schultz. 1996. The protein phosphatase 2C (PP2C) superfamily: detection of bacterial homologues. Protein Sci. 5:14211425.
14. Bridges, A. 2001. Chemical inhibitors of protein kinases. Chem. Rev. 101:25412572.
15. Camacho, L. R.,, P. Constant,, C. Raynaud,, M. A. Laneelle,, J. A. Triccas,, B. Gicquel,, M. Daffe, and, C. Guilhot. 2001. Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier. J. Biol. Chem. 276:1984519854.
16. Camacho, L. R.,, D. Ensergueix,, E. Perez,, B. Gicquel, and, C. Guilhot. 1999. Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol. Microbiol. 34:257267.
17. Castandet, J.,, J. F. Prost,, P. Peyron,, C. Astarie-Dequeker,, E. Anes,, A. J. Cozzone,, G. Griffiths, and, I. Maridonneau-Parini. 2005. Tyrosine phosphatase MptpA of Mycobacterium tuberculosis inhibits phagocytosis and increases actin polymerization in macrophages. Res. Microbiol. 156:10051013.
18. Chaba, R.,, M. Raje, and, P. K. Chakraborti. 2002. Evidence that a eukaryotic-type serine/threonine protein kinase from Mycobacterium tuberculosis regulates morphological changes associated with cell division. Eur. J. Biochem. 269:10781085.
19. Chatterjee, D., and, K. H. Khoo. 1998. Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan with profound physiological effects. Glycobiology 8:113120.
20. Chopra, P.,, B. Singh,, R. Singh,, R. Vohra,, A. Koul,, L. S. Meena,, H. Koduri,, M. Ghildiyal,, P. Deol,, T. K. Das,, A. K. Tyagi, and, Y. Singh. 2003. Phosphoprotein phosphatase of Mycobacterium tuberculosis dephosphorylates serine-threonine kinases PknA and PknB. Biochem. Biophys. Res. Commun. 311:112120.
21. Cirri, P.,, P. Chiarugi,, G. Camici,, G. Manao,, L. Pazzagli,, A. Caselli,, I. Barghini,, G. Cappugi,, G. Raugei, and, G. Ramponi. 1993. The role of Cys-17 in the pyridoxal 5′-phosphate inhibition of the bovine liver low M(r) phosphotyrosine protein phosphatase. Biochim. Biophys. Acta 1161:216222.
22. Cole, S. T.,, R. Brosch,, J. Parkhill,, T. Garnier,, C. Churcher,, D. Harris,, S. V. Gordon,, K. Eiglmeier,, S. Gas,, C. E. Barry,, F. Tekaia,, K. Badcock,, D. Basham,, D. Brown,, T. Chillingworth,, R. Connor,, R. Davies,, K. Devlin,, T. Feltwell,, S. Gentles,, N. Hamlin,, S. Holroyd,, T. Hornsby,, K. Jagels,, A. Krogh,, J. McLean,, S. Moule,, L. Murphy,, K. Oliver,, J. Osborne,, M. A. Quail,, M. A. Rajandream,, J. Rogers,, S. Rutter,, K. Seeger,, J. Skelton,, R. Squares,, S. Squares,, J. E. Sulston,, K. Taylor,, S. Whitehead, and, B. G. Barrell. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537544.
23. Coombes, B. K.,, Y. Valdez, and, B. B. Finlay. 2004. Evasive maneuvers by secreted bacterial proteins to avoid innate immune responses. Curr. Biol. 14:R856R867.
24. Cosma, C. L.,, D. R. Sherman, and, L. Ramakrishnan. 2003. The secret lives of the pathogenic mycobacteria. Annu. Rev. Microbiol. 57:641676.
25. Cowley, S. C.,, R. Babakaif, and, Y. Av-Gay. 2002. Expression and localization of the Mycobacterium tuberculosis protein tyrosine phosphatase, PtpA. Res. Microbiol. 153:233241.
26. Cowley, S.,, M. Ko,, N. Pick,, R. Chow,, K. J. Downing,, B. G. Gordhan,, J. C. Betts,, V. Mizrahi,, D. A. Smith,, R. W. Stokes, and, Y. Av-Gay. 2004. The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo. Mol. Microbiol. 52:16911702.
27. Cox, J. S.,, B. Chen,, M. McNeil, and, W. R. Jacobs, Jr. 1999. Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 402:7983.
28. Cozzone, A. J. 2005. Role of protein phosphorylation on serine/threonine and tyrosine in the virulence of bacterial pathogens. J. Mol. Microbiol. Biotechnol. 9:198213.
29. Cozzone, A. J. 1993. ATP-dependent protein kinases in bacteria. J. Cell. Biochem. 51:713.
30. Curry, J. M.,, R. Whalan,, D. M. Hunt,, K. Gohil,, M. Strom,, L. Rickman,, M. J. Colston,, S. J. Smerdon, and, R. S. Buxton. 2005. An ABC transporter containing a forkhead-associated domain interacts with a serine-threonine protein kinase and is required for growth of Mycobacterium tuberculosis in mice. Infect. Immun. 73:44714477.
31. Daffe, M., and, P. Draper. 1998. The envelope layers of mycobacteria with reference to their pathogenicity. Adv. Microb. Physiol. 39:131203.
32. Dannenberg, A. M. Jr. 1991. Delayed type hypersensitivity and cell mediated immunity in the pathogenesis of tuberculosis. Immunol. Today 12:228233.
33. Dar, A. C.,, T. E. Dever, and, F. Sicheri. 2005. Higher-order substrate recognition of eIF2a by the RNA-dependent protein kinase PKR. Cell 122:887900.
34. Dasgupta, A.,, P. Datta,, M. Kundu, and, J. Basu. 2006. The serine/threonine kinase PknB of Mycobacterium tuberculosis phosphorylates PBPA, a penicillin-binding protein required for cell division. Microbiology 152:493504.
35. Dasgupta, N.,, V. Kapur,, K. K. Singh,, T. K. Das,, S. Sachdeva,, K. Jyothisri, and, J. S. Tyagi. 2000. Characterization of a two-component system, devR-devS, of Mycobacterium tuberculosis. Tuber. Lung Dis. 80:141159.
36. Denu, J. M., and, J. E. Dixon. 1995. A catalytic mechanism for the dual-specific phosphatases. Proc. Natl. Acad. Sci. USA 92:59105914.
37. Deol, P.,, R. Vohra,, A. K. Saini,, A. Singh,, H. Chandra,, P. Chopra,, T. K. Das,, A. K. Tyagi, and, Y. Singh. 2005. Role of Mycobacterium tuberculosis Ser/Thr kinase PknF: implications in glucose transport and cell division. J. Bacteriol. 187:34153420.
38. Dey, M.,, C. Cao,, A. C. Dar,, T. Tamura,, K. Ozato,, F. Sicheri, and, T. E. Dever. 2005. Mechanistic link between PKR dimerization, autophos-phorylation and eIF2a substrate recognition. Cell 122:901913.
39. Domenech, P.,, M. B. Reed, and, C. E. Barry, 3rd. 2005. Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect. Immun. 73:34923501
40. Drews, S. J.,, F. Hung, and, Y. Av-Gay. 2001. A protein kinase inhibitor as an antimycobacterial agent. FEMS Microbiol. Lett. 205:369374.
41. Dubnau, E.,, J. Chan,, C. Raynaud,, V. P. Mohan,, M. A. Yu,, K. Laneelle,, A. Quemard,, I. Smith, and, M. Daffe. 2000. Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol. Microbiol. 36:630637.
42. Durocher, D., and, S. P. Jackson. 2002. The FHA domain. FEBS Lett. 13:5866.
43. Echenique, J.,, A. Kadioglu,, S. Romao,, P. W. Andrew, and, M. C. Trombe. 2004. Protein serine/threonine kinase StkP positively controls virulence and competence in Streptococcus pneumoniae. Infect. Immun. 72:24342437.
44. Eiglmeier, K.,, J. Parkhill,, N. Honore,, T. Garnier,, F. Tekaia,, A. Telenti,, P. Klatser,, K. D. James,, N. R. Thomson,, P. R. Wheeler,, C. Churcher,, D. Harris,, K. Mungall,, B. G. Barrell, and, S. T. Cole. 2001. The decaying genome of Mycobacterium leprae. Lepr. Rev. 72:387398.
45. Ewann, F.,, M. Jackson,, K. Pethe,, A. Cooper,, N. Mielcarek,, D. Ensergueix,, B. Gicquel,, C. Locht, and, P. Supply. 2002. Transient requirement of the PrrA-PrrB two-component system for early intracellular multiplication of Mycobacterium tuberculosis. Infect. Immun. 70:22562263.
46. Fontan P. A.,, S. Walters, and, I. Smith. 2004. Cellular signaling pathways and transcriptional regulation in Mycobacterium tuberculosis: Stress control and virulence. Curr. Sci. 86:122134.
47. Fratti, R. A.,, J. M. Backer,, J. Gruenberg,, S. Corvera, and, V. Deretic. 2001. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J. Cell. Biol. 154:631644.
48. Fulop, V., and, D. T. Jones. 1999. Beta propellers: structural rigidity and functional diversity. Curr. Opin. Struct. Biol. 9:715721.
49. Gaidenko, T. A.,, T. J. Kim, and, C. W. Price. 2002. The PrpC serine-threonine phosphatase and PrkC kinase have opposing physiological roles in stationary-phase Bacillus subtilis cells. J. Bacteriol. 184:61096114.
50. Galperin, M. Y.,, A. N. Nikolskaya, and, E. V. Koonin. 2001. Novel domains of the prokaryotic two-component signal transduction systems. FEMS Microbiol. Lett. 203:1121.
51. Galyov, E. E.,, S. Hakansson,, A. Forsberg, and, H. Wolf-Watz. 1993. A secreted protein kinase of Yersinia pseudotuberculosis is an indispensable virulence determinant. Nature (London) 361:730732.
52. Gao, L.Y.,, F. Laval,, E. H. Lawson,, R. K. Groger,, A. Woodruff,, J. H. Morisaki,, J. S. Cox,, M. Daffe, and, E. J. Brown. 2003. Requirement for kasB in Mycobacterium mycolic acid biosynthesis, cell wall impermeability and intracellular survival: implications for therapy. Mol. Microbiol. 49:15471563.
53. Garnak, M., and, H. C. Reeves. 1979. Phosphorylation of Isocitrate dehydrogenase of Escherichia coli. Science 203:11111112.
54. Gautier, J.,, M. J. Solomon,, R. N. Booher,, J. F. Bazan, and, M. W. Kirschner. 1991. cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2. Cell 67:197211.
55. Glickman, M. S.,, J. S. Cox, and, W. R. Jacobs, Jr. 2000. A novel mycolic acid cyclopropane synthetase is required for cording, persistence and virulence of M. tuberculosis. Mol. Cell 5:717727.
56. Gonzalo Asensio, J.,, C. Maia,, N. L. Ferrer,, N. Barilone,, F. Laval,, C. Y. Soto,, N. Winter,, M. Daffe,, B. Gicquel,, C. Martin, and, M. Jackson. 2006. The virulence-associated two-component PhoP-PhoR system controls the biosynthesis of polyketidederived lipids in Mycobacterium tuberculosis. J. Biol. Chem. 281:13131316.
57. Gopalaswamy, R.,, P. R. Narayanan, and, S. Narayanan. 2004. Cloning, overexpression, and characterization of a serine/threonine protein kinase pknI from Mycobacterium tuberculosis H37Rv. Protein Expr. Purif. 36:8289.
58. Graham, J. E., and, J. E. Clark-Curtiss. 1999. Identification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS). Proc. Natl. Acad. Sci. USA 96:1155411559.
59. Greenstein, A. E.,, C. Grundner,, N. Echols,, L. M. Gay,, T. N. Lombana,, C. A. Miecskowski,, K. E. Pullen,, P. Y. Sung, and, T. Alber. 2005. Structure/function studies of Ser/Thr and Tyr protein phosphorylation in Mycobacterium tuberculosis. J. Mol. Microbiol. Biotechnol. 9:167181.
60. Groisman, E. A. 2001. The pleiotropic two-component regulatory system PhoP–PhoQ. J. Bacteriol. 183:18351842.
61. Grosios, K., and, P. Traxler. 2003. Tyrosine kinase targets in drug discovery. Drug Future 28:679697.
62. Guan, K., and, J. E. Dixon. 1990. Protein tyrosine phosphatase activity of an essential virulence determinant in Yersinia. Science 249:553559.
63. Gupta, S.,, S. Jain, and, A. K. Tyagi. 1999. Analysis, expression and prevalence of the Mycobacterium tuberculosis homolog of bacterial virulence regulating proteins. FEMS Microbiol. Lett. 172:137143.
64. Hakansson, S.,, E. E. Galyov,, R. Rosqvist, and, H. Wolf-Watz. 1996. The Yersinia YpkA Ser/Thr kinase is translocated and subsequently targeted to the inner surface of the HeLa cell plasma membrane. Mol. Microbiol. 20:593603.
65. Hanks, S. K.,, A. M. Quinn, and, T. Hunter. 1988. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:4252.
66. Hanks, S., and, A. M. Quinn. 1991. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 200:3862.
67. Haydel, S. E., and, J. E. Clark-Curtiss. 2004. Global expression analysis of two-component system regulator genes during Mycobacterium tuberculosis growth in human macrophages. FEMS Microbiol. Lett. 236:341347.
68. Haydel, S. E., and, J. E. Clark-Curtiss. 2006. The Mycobacterium tuberculosis TrcR response regulator represses transcription of the intracellularly expressed Rv1057 gene, encoding a seven-bladed beta-propeller. J. Bacteriol. 188:150159.
69. He, H.,, R. Hovey,, J. Kane,, V. Singh, and, T. C. Zahrt. 2006. MprAB is a stress-responsive two-component system that directly regulates expression of sigma factors SigB and SigE in Mycobacterium tuberculosis. J. Bacteriol. 188:21342143.
70. Hilleman, M. R. 2004. Strategies and mechanisms for host and pathogen survival in acute and persistent viral infections. Proc. Natl. Acad. Sci. USA 101(Suppl. 2):1456014566.
71. Hornef, M. W.,, M. J. Wick,, M. Rhen, and, S. Normark. 2002. Bacterial strategies for overcoming host innate and adaptive immune responses. Nat. Immunol. 3:10331040.
72. Houben, E. N.,, L. Nguyen, and, J. Pieters. 2006. Interaction of pathogenic mycobacteria with the host immune system. Curr. Opin. Microbiol. 9:7685.
73. Howell, L. D.,, C. Griffiths,, L. W. Slade,, M. Potts, and, P. J. Kennelly. 1996. Substrate specificity of IphP, a cyanobacterial dual-specificity protein phosphatase with MAP kinase phosphatase activity. Biochemistry 35:75667572.
74. Hunter, T. 1995. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80:225236.
75. Itou, H., and, I. Tanaka. 2001. The OmpR-family of proteins: insight into the tertiary structure and functions of two-component regulator proteins. J. Biochem. (Tokyo) 129:343350.
76. Johnson, P.,, H. L. Ostergaard,, C. Wasden, and, I. S. Trowbridge. 1992. Mutational analysis of CD45. A leukocyte-specific protein tyrosine phosphatase. J. Biol. Chem. 267:80358041.
77. Juris, S. J.,, A. E. Rudolph,, D. Huddler,, K. Orth, and, J. E. Dixon. 2000. A distinctive role for the Yersinia protein kinase: Actin binding, kinase activation and cytoskeletal disruption. Proc. Natl. Acad. Sci. USA 97:94319436.
78. Kaldor, S. W.,, V. J. Kalish,, J. F. Davies II,, B. V. Shetty,, J. E. Fritz,, K. Appelt,, J. A. Burgess,, K. M. Campanale,, N. Y. Chirgadze,, D. K. Clawson,, B. A. Dressman,, S. D. Hatch,, D. A. Khalil,, M. B. Kosa,, P. P. Lubbehusen,, M. A. Muesing,, A. K. Patick,, S. H. Reich,, K. S. Su, and, J. H. Tatlock. 1997. Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. J. Med. Chem. 40:39793985.
79. Kang, C. M.,, D. W. Abbott,, S. T. Park,, C. C. Dascher,, L. C. Cantley, and, R. N. Husson. 2005. The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape. Genes Dev. 19:16921704.
80. Kaniga, K.,, J. Uralil,, J. B. Bliska, and, J. E. Galan. 1996. A secreted protein tyrosine phosphatase with modular effector domains in bacterial pathogen Salmonella typhimurium. Mol. Microbiol. 21:633641.
81. Kennelly, P. J. 2002. Protein kinases and protein phosphatases in prokaryotes: a genomic perspective. FEMS Microbiol. Lett. 206:18.
82. Kim, C. U.,, W. Lew,, M. A. Williams,, H. T. Liu,, L. J. Zhang,, S. Swaminathan,, N. Bischofberger,, M. S. Chen,, D. B. Mendel,, C. Y. Tai,, W. G. Laver, and, R. C. Stevens. 1997. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent antiinfluenza activity. J. Am. Chem. Soc. 119:681690.
83. Kim, E. E.,, C. T. Baker,, M. D. Dwyer,, M. A. Murcko,, B. G. Rao,, R. D. Tung, and, M. A. Navia. 1995. Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally available inhibitor of the enzyme. J. Am. Chem. Soc. 117:11811182.
84. Klein, G.,, C. Dartigalongue, and, S. Raina. 2003. Phosphorylationmediated regulation of heat shock response in Escherichia coli. Mol. Microbiol. 48:269285.
85. Koul, A.,, A. Choidas,, M. Treder,, A. K. Tyagi,, K. Drlica,, Y. Singh, and, A. Ullrich. 2000. Cloning and characterization of secretory tyrosine phosphatase of Mycobacterium tuberculosis. J. Bacteriol. 182:54255432.
86. Koul, A.,, A. Choidas,, A. K. Tyagi,, K. Drlica,, Y. Singh, and, A. Ullrich. 2001. Serine/threonine protein kinases PknF and PknG of Mycobacterium tuberculosis: characterization and localization. Microbiology 147:23072314.
87. Kremer, L.,, A. R. Baulard, and, G. S. Besra. 2000. Genetics of mycolic acid biosynthesis, p. 173–190. In G. F. Hatfull and, W. R. Jacobs, Jr. (ed.), Molecular Genetics of Mycobacteria. ASM Press, Washington, DC.
88. Leonard, C. J.,, L. Aravind, and, E. V. Koonin. 1998. Novel families of putative protein kinases in bacteria and archaea: evolution of the “eukaryotic” protein kinase superfamily. Genome Res. 8:10381047.
89. Liu, K.,, B. Lemon, and, P. Traktman. 1995. The dual-specificity phosphatase encoded by vaccinia virus, VH1, is essential for viral transcription in vivo and in vitro. J. Virol. 69:78237834.
90. Lois, A. F.,, M. Weinstein,, G. S. Ditta, and, D. R. Helinski. 1993. Autophosphorylation and phosphatase activities of the oxygensensing protein FixL of Rhizobium meliloti are coordinately regulated by oxygen. J. Biol. Chem. 268:43704375.
91. Ludwiczak, P.,, M. Gilleron,, Y. Bordat,, C. Martin,, B. Gicquel, and, G. Puzo. 2002. Mycobacterium tuberculosis phoP mutant: lipoarabino-mannan molecular structure. Microbiology 148:30293037.
92. Madec, E.,, A. Laszkiewicz,, A. Iwanicki,, M. Obuchowski, and, S. Seror. 2002. Characterization of a membrane-linked Ser/Thr protein kinase in Bacillus subtilis, implicated in developmental processes, Mol. Microbiol. 2:571586.
93. Malhotra, V.,, D. Sharma,, V. D. Ramanathan,, H. Shakila,, D. K. Saini,, S. Chakravorty,, T. K. Das,, Q. Li,, R. F. Silver,, P. R. Narayanan, and, J. S. Tyagi. 2004. Disruption of response regulator gene, devR, leads to attenuation in virulence of Mycobacterium tuberculosis. FEMS Microbiol. Lett. 231:237245.
94. Manger, M.,, M. Scheck,, H. Prinz,, J. P. von Kries,, T. Langer,, K. Saxena,, H. Schwalbe,, A. Furstner,, J. Rademann, and, H. Waldmann. 2005. Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) inhibitors based on natural products and a fragment-based approach. Chembiochem 6:17491753.
95. Manning, G.,, D. B. Whyte,, R. Martinez,, T. Hunter, and, S. Sudarsanam. 2002. The protein kinase complement of the human genome. Science 298:19121934.
96. Matsuhashi, M.,, M. Wachi, and, F. Ishino. 1990. Machinery for cell growth and division: penicillin-binding proteins and other proteins. Res. Microbiol. 141:89103.
97. Medzhitov, R., and, C. Janeway, Jr. 2000. Innate immune recognition: mechanisms and pathways. Immunol. Rev. 173:8997.
98. Meggio, F., and, L. A. Pinna. 2003. One-thousand-and-one substrates of protein kinase CK2? FASEB J. 17:349368.
99. Molle, V.,, A. K. Brown,, G. S. Besra,, A. J. Cozzone, and, L. Kremer. 2006. The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J. Biol. Chem. 281:3009430103.
100. Molle, V.,, L. Kremer,, C. Girard-Blanc,, G. S. Besra,, A. J. Cozzone, and, J. F. Prost. 2003. An FHA phosphoprotein recognition domain mediates protein EmbR phosphorylation by PknH, a Ser/Thr protein kinase from Mycobacterium tuberculosis. Biochemistry 42:1530015309.
101. Molle, V.,, D. Soulat,, J. M. Jault,, C. Grangeasse,, A. J. Cozzone, and, J. F. Prost. 2004. Two FHA domains on an ABC transporter, Rv1747, mediate its phosphorylation by PknF, a Ser/Thr protein kinase from Mycobacterium tuberculosis. FEMS Microbiol. Lett. 234:215223.
102. Morth, J. P.,, V. Feng,, L. J. Perry,, D. I. Svergun, and, P. A. Tucker. 2004. The crystal and solution structure of a putative transcriptional antiterminator from Mycobacterium tuberculosis. Structure 12:15951605.
103. Mossman, K.,, H. Ostergaard,, C. Upton, and, G. McFadden. 1995. Myxoma virus and Shope fibroma virus encode dual-specificity tyrosine/serine phosphatases which are essential for virus viability. Virology 206:572582.
104. Munoz-Dorado, J.,, S. Inouye, and, M. Inouye. 1991. A gene encoding a protein Serine/threonine kinase is required for the normal development of Myxococcus xanthus, a gram negative bacterium. Cell 67:9951006.
105. Nariya, H., and, S. Inouye. 2002. Activation of 6-phosphofructokinase via phosphorylation by Pkn4, a protein Ser/Thr kinase of Myxococcus xanthus. Mol. Microbiol. 46:13531366.
106. Neu, J. M.,, S. V. MacMillan,, J. R. Nodwell, and, G. D. Wright. 2002. StoPK-1, a serine/threonine protein kinase from the glycopeptide antibiotic producer Streptomyces toyocaensis NRRL 15009, affects oxidative stress response. Mol. Microbiol. 44:417430.
107. Nigou, J.,, M. Gilleron, and, G. Puzo. 2003. Lipoarabinomannans: from structure to biosynthesis. Biochimie 85:153166.
108. Noble, M. E.,, J. A. Endicott, and, L. N. Johnson. 2004. Protein kinase inhibitors: insights into drug design from structure. Science 303:18001805.
109. Novakova, L.,, L. Saskova,, P. Pallova,, J. Janecek,, J. Novotna,, A. Ulrych,, J. Echenique,, M. C. Trombe, and, P. Branny. 2005. Characterization of a eukaryotic type serine/threonine protein kinase and protein phosphatase of Streptococcus pneumoniae and identification of kinase substrates. FEBS J. 272:12431254.
110. Ortiz-Lombardia, M.,, F. Pompeo,, B. Boitel, and, P. M. Alzari. 2003. Crystal structure of the catalytic domain of the PknB serine/threonine kinase from Mycobacterium tuberculosis. J. Biol. Chem. 278:1309413100.
111. Pallen, M.,, R. Chaudhuri, and, A. Khan. 2002. Bacterial FHA domains: neglected players in the phospho-threonine signalling game? Trends Micobiol. 10:556563.
112. Papavinasasundaram, K. G.,, B. Chan,, J. H. Chung,, M. J. Colston,, E. O. Davis, and, Y. Av-Gay. 2005. Deletion of the Mycobacterium tuberculosis pknH gene confers a higher bacillary load during the chronic phase of infection in BALB/c mice. J. Bacteriol. 187:57515760.
113. Parish, T.,, D. A. Smith,, S. Kendall,, N. Casali,, G. J. Bancroft, and, N. G. Stoker. 2003a. Deletion of two-component regulatory systems increases the virulence of Mycobacterium tuberculosis. Infect. Immun. 71:11341140.
114. Parish, T.,, D. A. Smith,, G. Roberts,, J. Betts, and, N. G. Stoker. 2003b. The senX3-regX3 two-component regulatory system of Mycobacterium tuberculosis is required for virulence. Microbiology 149:14231435.
115. Park, H. D.,, K. M. Guinn,, M. I. Harrell,, R. Liao,, M. I. Voskuil,, M. Tompa,, G. K. Schoolnik, and, D. R. Sherman. 2003. Rv3133c/DosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol. Microbiol. 48:833843.
116. Peirs, P.,, L. De Wit,, M. Braibant,, K. Huygen, and, J. Content. 1997. A serine/threonine protein kinase from Mycobacterium tuberculosis. Eur. J. Biochem. 244:604612.
117. Perez, J.,, R. Garcia,, H. Bach,, J. H. de Waard,, W. R. Jacobs, Jr,, Y. Av-Gay,, J. Bubis, and, H. E. Takiff. 2006. Mycobacterium tuberculosis transporter MmpL7 is a potential substrate for kinase PknD. Biochem. Biophys. Res. Commun. 348:612.
118. Perez, E.,, S. Samper,, Y. Bordas,, C. Guilhot,, B. Gicquel, and, C. Martin. 2001. An essential role for phoP in Mycobacterium tuberculosis virulence. Mol. Microbiol. 41:179187.
119. Pieters, J., and, J. Gatfield. 2002. Hijacking the host: survival of pathogenic mycobacteria inside macrophages. Trends Microbiol. 10:142146.
120. Polarek, J. W.,, G. Williams, and, W. Epstein. 1992. The products of the kdpDE operon are required for expression of the Kdp ATPase of Escherichia coli. J. Bacteriol. 174:21452151.
121. Poncet, S.,, I. Mijakovic,, S. Nessler,, V. Gueguen-Chaignon,, V. Chaptal,, A. Galinier,, G. Boel,, A. Maze, and, J. Deutscher. 2004. HPr kinase/phosphorylase, a Walker motif A-containing bifunctional sensor enzyme controlling catabolite repression in Gram-positive bacteria. Biochim. Biophys. Acta 1697:123135.
122. Potts, M.,, H. Sun,, K. Mockaitis,, P. J. Kennelly,, D. Reed, and, N. K. Tonks. 1993. A protein-tyrosine/serine phosphatase encoded by the genome of the cyanobacterium Nostoc commune UTEX 584. J. Biol. Chem. 268:76327635.
123. Prabhakaran, K.,, E. B. Harris, and, B. Randhawa. 2000. Regulation by protein kinase of phagocytosis of Mycobacterium leprae by macrophages. J. Med. Microbiol. 49:339342.
124. Rajagopal, L.,, A. Vo,, A. Silvestroni, and, C. E. Rubens. 2005. Regulation of purine biosynthesis by a eukaryotic-type kinase in Streptococcus agalactiae. Mol. Microbiol. 56:13291346.
125. Ray, M. K.,, G. S. Kumar, and, S. Shivaji. 1994. Phosphorylation of membrane proteins in response to temperature in an Antarctic Pseudomonas syringae. Microbiology 140:32173223.
126. Raynaud, C.,, C. Etienne,, P. Peyron,, M. A. Laneelle, and, M. Daffe. 1998. Extracellular enzyme activities potentially involved in the pathogenicity of Mycobacterium tuberculosis. Microbiology 144:577587.
127. Reed, M. B.,, P. Domenech,, C. Manca,, H. Su,, A. K. Barczak,, B. N. Kreiswirth,, G. Kaplan, and, C. E. Barry III. 2004. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431:8487.
128. Reilly, T. J.,, G. S. Baron,, F. E. Nano, and, M. S. Kuhlenschmidt. 1996. Characterization and sequencing of a respiratory burstinhibiting acid phosphatase from Francisella tularensis. J. Biol. Chem. 271:1097310983.
129. Remaley, A. T.,, S. Das,, P. I. Campbell,, G. M. Larocca,, M. T. Pope, and, R. H. Glew. 1985. Characterization of Leishmania donovani acid phosphatases. J. Biol. Chem. 260:880886.
130. Repik, A.,, A. Rebbapragada,, M. S. Johnson,, J. O. Haznedar,, I. B. Zhulin, and, B. L. Taylor. 2000. PAS domain residues involved in signal transduction by the Aer redox sensor of Escherichia coli. Mol. Microbiol. 36:806816.
131. Rickman, L.,, J. W. Saldanha,, D. M. Hunt,, D. N. Hoar,, M. J. Colston,, J. B. Millar, and, R. S. Buxton. 2004. A two-component signal transduction system with a PAS domain-containing sensor is required for virulence of Mycobacterium tuberculosis in mice. Biochem. Biophys. Res. Commun. 314:259267.
132. Roberts, D. M.,, R. P. Liao,, G. Wisedchaisri,, W. G. Hol, and, D. R. Sherman. 2004. Two sensor kinases contribute to the hypoxic response of Mycobacterium tuberculosis. J. Biol. Chem. 279:2308223087.
133. Römling, U.,, M. Gomelsky, and, M. Y. Galperin. 2005. C-di-GMP: the dawning of a novel bacterial signalling system. Mol. Microbiol. 57:629639.
134. Rosenberger, C. M., and, B. B. Finlay. 2003. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens. Nat. Rev. Mol. Cell. Biol. 4:385396.
135. Rossolini, G. M.,, S. Schippa,, M. L. Riccio,, F. Berlutti,, L. E. Macaskie, and, M. C. Thaller. 1998. Bacterial nonspecific acid phospho-hydrolases: physiology, evolution and use as tools in microbial biotechnology. Cell Mol. Life Sci. 54:833850.
136. Saini, D. K.,, V. Malhotra, and, J. S. Tyagi. 2004. Cross talk between DevS sensor kinase homologue, Rv2027c, and DevR response regulator of Mycobacterium tuberculosis. FEBS Lett. 565:7580.
137. Saleh, M. T., and, J. T. Belisle. 2000. Secretion of an acid phosphatase (SapM) by Mycobacterium tuberculosis that is similar to eukaryotic acid phosphatases. J. Bacteriol. 182:68506853.
138. Sardiwal, S.,, S. L. Kendall,, F. Movahedzadeh,, S. C. Rison,, N. G. Stoker, and, S. Djordjevic. 2005. A GAF domain in the hypoxia/NO-inducible Mycobacterium tuberculosis DosS protein binds haem. J. Mol. Biol. 353:929936.
139. Sassetti, C. M., and, E. J. Rubin. 2003. Genetic requirements for mycobacterial survival during infection. Proc. Natl. Acad. Sci. USA 100:1298912994.
140. Sassetti, C. M.,, D. H. Boyd, and, E. J. Rubin. 2001. Comprehensive identification of conditionally essential genes in mycobacteria. Proc. Natl. Acad. Sci. USA 98:1271212717.
141. Sassetti, C. M.,, D. H. Boyd, and, E. J. Rubin. 2003. Genes required for mycobacterial growth defined by high density mutagenesis. Mol. Microbiol. 48:7784.
142. Schnappinger, D.,, S. Ehrt,, M. I. Voskuil,, Y. Liu,, J. A. Mangan,, I. M. Monahan,, G. Dolganov,, B. Efron,, P. D. Butcher,, C. Nathan, and, G. K. Schoolnik. 2003. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J. Exp. Med. 198:693704.
143. Sham, H. L.,, D. J. Kempf,, A. Molla,, K. C. Marsh,, G. N. Kumar,, C. M. Chen,, W. Kati,, K. Stewart,, R. Lal,, A. Hsu,, D. Betebenner,, M. Korneyeva,, S. Vasavanonda,, E. McDonald,, A. Saldivar,, N. Wideburg,, X. Chen,, P. Niu,, C. Park,, V. Jayanti,, B. Grabowski,, G. R. Granneman,, E. Sun,, A. J. Japour,, J. M. Leonard,, J. J. Plattner, and, D. W. Norbeck. 1998. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob. Agents Chemother. 42:32183224.
144. Sharma, K.,, M. Gupta,, A. Krupa,, N. Srinivasan, and, Y. Singh. 2006b. EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and phosphatase in Mycobacterium tuberculosis. FEBS J. 273:27112721.
145. Sharma, K.,, M. Gupta,, M. Pathak,, N. Gupta,, A. Koul,, S. Sarangi,, R. Baweja, and, Y. Singh. 2006a. Transcriptional control of the mycobacterial embCAB operon by PknH through a regulatory protein, EmbR, in vivo. J. Bacteriol. 188:29362944.
146. Shawver, L. K.,, D. Slamon, and, A. Ullrich. 2002. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1:117123.
147. Singh, A.,, R. Gupta,, R. A. Vishwakarma,, P. R. Narayanan,, C. N. Paramasivan,, V. D. Ramanathan, and, A. K. Tyagi. 2005. Requirement of the mymA operon for appropriate cell wall ultrastructure and persistence of Mycobacterium tuberculosis in the spleens of guinea pigs. J Bacteriol. 187:41734186.
148. Singh, A.,, S. Jain,, S. Gupta,, T. Das, and, A. K. Tyagi. 2003b. mymA operon of Mycobacterium tuberculosis: its regulation and importance in the cell envelope. FEMS Microbiol. Lett. 227:5363.
149. Singh, A.,, Y. Singh,, R. Pine,, L. Shi,, R. Chandra, and, K. Drlica. 2006. Protein kinase I of Mycobacterium tuberculosis: cellular localization and expression during infection of macrophage-like cells. Tuberculosis (Edinburgh) 86:2833.
150. Singh, R.,, V. Rao,, H. Shakila,, R. Gupta,, A. Khera,, N. Dhar,, A. Singh,, A. Koul,, Y. Singh,, M. Naseema,, P. R. Narayanan,, C. N. Paramasivan,, V. D. Ramanathan, and, A. K. Tyagi. 2003a. Disruption of mptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs. Mol. Microbiol. 50:751762.
151. South, S. L.,, R. Nichols, and, T. C. Montie. 1994. Tyrosine kinase activity in Pseudomonas aeruginosa. Mol. Microbiol. 12:903910.
152. Sreevatsan, S.,, K. E. Stockbauer,, X. Pan,, B. N. Kreiswirth,, S. L. Moghazeh,, W. R. Jacobs, Jr.,, A. Telenti, and, J. M. Musser. 1997. Ethambutanol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob. Agents Chemother. 41:16771681
153. Stock, A. M.,, V. L. Robinson, and, P. N. Goudreau. 2000. Two-component signal transduction. Annu. Rev. Biochem. 69:183215.
154. Stock, J. B.,, A. J. Ninfa, and, A. M. Stock. 1989. Protein phosphorylation and regulation of adaptive responses in bacteria. Microbiol. Rev. 53:450490.
155. Stock, J. B.,, M. G. Surette,, M. Levit, and, P. Park. 1995. Two-component signal transduction systems: structure-function relationships and mechanisms of catalysis, p. 25–51. In J. A. Hoch and, T. J. Silhavy (ed.), Two-Component Signal Transduction. ASM Press, Washington, DC.
156. Stone, R. L., and, J. E. Dixon. 1994. Protein tyrosine phosphatases. J. Biol. Chem. 269:3132331326.
157. Streuli, M.,, N. X. Krueger,, T. Thai,, M. Tang, and, H. Saito. 1990. Distinct functional roles of the two intracellular phosphatase like domains of the receptor-linked protein tyrosine phosphatases LCA and LAR. EMBO J. 9:23992407.
158. Treuner-Lange, A.,, M. J. Ward, and, D. R. Zusman. 2001. Pph1 from Myxococcus xanthus is a protein phosphatase involved in vegetative growth and development. Mol. Microbiol. 40:126140.
159. Tyagi, J. S., and, D. Sharma. 2004. Signal transduction systems of mycobacteria with special reference to M. tuberculosis. Curr. Sci. 86:93102.
160. Umeyama, T.,, P. C. Lee, and, S. Horinouchi. 2002. Protein serine/threonine kinases in signal transduction for secondary metabolism and morphogenesis in Streptomyces. Appl. Microbiol. Biotechnol. 59:419425.
161. Vergne, I.,, J. Chua,, H. H. Lee,, M. Lucas,, J. Belisle, and, V. Deretic. 2005. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 102:40334038.
162. Vescovi, E. G.,, Y. M. Ayala,, E. Di Cera, and, E. A. Groisman. 1997. Characterization of the bacterial sensor protein PhoQ. Evidence for distinct binding sites for Mg2+ and Ca2−. J. Biol. Chem. 272:14401443.
163. Via, L. E.,, R. Curcic,, M. H. Mudd,, S. Dhandayuthapani,, R. J. Ulmer, and, V. Deretic. 1996. Elements of signal transduction in Mycobacterium tuberculosis: in vitro phosphorylation and in vivo expression of the response regulator MtrA. J. Bacteriol. 178:33143321.
164. Vieira, O. V.,, R. J. Botelho,, L. Rameh,, S. M. Brachmann,, T. Matsuo,, H. W. Davidson,, A. Schreiber,, J. M. Backer,, L. C. Cantley, and, S. Grinstein. 2001. Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J. Cell Biol. 155:1925.
165. Villarino, A.,, R. Duran,, A. Wehenkel,, P. Fernandez,, P. England,, P. Brodin,, S. T. Cole,, U. Zimny-Arndt,, P. R. Jungblut,, C. Cervenansky, and, P. M. Alzari. 2005. Proteomic identification of M. tuberculosis protein kinase substrates: PknB recruits GarA, a FHA domain-containing protein, through activation loop-mediated interactions. J. Mol. Biol. 350:95363.
166. von Itzstein, M.,, W. Y. Wu,, G. B. Kok,, M. S. Pegg,, J. C. Dyason,, B. Jin,, T. Van Phan,, M. L. Smythe,, H. F. White,, S. W. Oliver,, P. M. Colman,, J. N. Varghese,, D. M. Ryan,, J. M. Woods,, R. C. Bethell,, V. J. Hotham,, J. M. Cameron, and, C. R. Penn. 1993. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363:418423.
167. Walburger, A.,, A. Koul,, G. Ferrari,, L. Nguyen,, C. Prescianotto-Baschong,, K. Huygen,, B. Klebl,, C. Thompson,, G. Bacher, and, J. Pieters. 2004. Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304:18001804.
168. Walters, S. B.,, E. Dubnau,, I. Kolesnikova,, F. Laval,, M. Daffe, and, I. Smith. 2006. The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol. Microbiol. 60:312330.
169. Wehenkel, A.,, P. Fernandez,, M. Bellinzoni,, V. Catherinot,, N. Barilone,, G. Labesse,, M. Jackson, and, P. M. Alzari. 2006. The structure of PknB in complex with mitoxantrone, an ATPcompetitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. FEBS Lett. 580:30183022.
170. Weide, T.,, L. Arve,, H. Prinz,, H. Waldmann, and, H. Kessler. 2006. 3-Substituted indolizine-1-carbonitrile derivatives as phosphatase inhibitors. Bioorg. Med. Chem. Lett. 16:5963.
171. Wu, J.,, N. Ohta,, J. L. Zhao, and, A. Newton. 1999. A novel bacterial tyrosine kinase essential for cell division and differentiation. Proc. Natl. Acad. Sci. USA 96:1306813073.
172. Young, T. A.,, B. Delagoutte,, J. A. Endrizzi,, A. M. Falick, and, T. Alber. 2003. Structure of Mycobacterium tuberculosis PknB supports a universal activation mechanism for Ser/Thr protein kinases. Nat. Struct. Biol. 10:168174.
173. Yuan, M.,, F. Deleuil, and, M. Fallman. 2005. Interaction between the Yersinia tyrosine phosphatase YopH and its macrophage substrate, Fyn-binding protein, Fyb. J. Mol. Microbiol. Biotechnol. 9:214223.
174. Yuvaniyama, J.,, J. M. Denu,, J. E. Dixon, and, M. A. Saper. 1996. Crystal structure of the dual specificity protein phosphatase VHR. Science 272:13281331.
175. Zahrt, T. C., and, V. Deretic. 2000. An essential two-component signal transduction system in Mycobacterium tuberculosis. J. Bacteriol. 182:38323838.
176. Zahrt, T. C., and, V. Deretic. 2001. Mycobacterium tuberculosis signal transduction system required for persistent infections. Proc. Natl. Acad. Sci. USA 98:1270612711.
177. Zhang, W., and, L. Shi. 2005. Distribution and evolution of multiple-step phosphorelay in prokaryotes: lateral domain recruitment involved in the formation of hybrid-type histidine kinases. Microbiology 151:21592173.
178. Zhang, Z. Y.,, B. A. Palfey,, L. Wu, and, Y. Zhao. 1995. Catalytic function of the conserved hydroxyl group in the protein tyrosine phosphatase signature motif. Biochemistry 34:1638916396.
179. Zheng, X.,, K. G. Papavinasasundaram, and, Y. Av-Gay. 2007. Novel substrates of Mycobacterium tuberculosis PknH Ser/Thr kinase. Biochem. Biophys. Res. Commun. 355:162168.
180. Zhou, M. M.,, T. M. Logan,, Y. Theriault,, R. L. Van Etten, and, S. W. Fesik. 1994. Backbone 1H, 13C, and 15N assignments and secondary structure of bovine low molecular weight phosphotyrosyl protein phosphatase. Biochemistry 33:52215229.


Generic image for table
Table 1.

Presence of Ser/Thr/Tyr kinases and phosphatases and two-component systems in mycobacteria

Citation: Tyagi A, Singh R, Gupta V. 2008. 20 The Role of Mycobacterial Kinases and Phosphatases in Growth, Pathogenesis, and Cell Wall Metabolism, p 323-343. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch20

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error