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

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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
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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
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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
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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
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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
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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

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