Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Dec 23;9(1):14.
doi: 10.3390/microorganisms9010014.

Therapeutic Targeting of Protein Tyrosine Phosphatases from Mycobacterium tuberculosis

Kasi Viswanatharaju Ruddraraju  1 , Devesh Aggarwal  1 , Zhong-Yin Zhang  1   2   3
Affiliations
Review

Therapeutic Targeting of Protein Tyrosine Phosphatases from Mycobacterium tuberculosis

Kasi Viswanatharaju Ruddraraju et al. Microorganisms. .

Abstract

Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization, an estimated 10 million people developed TB in 2018. The occurrence of drug-resistant TB demands therapeutic agents with novel mechanisms of action. Antivirulence is an alternative strategy that targets bacterial virulence factors instead of central growth pathways to treat disease. Mycobacterium protein tyrosine phosphatases, mPTPA and mPTPB, are secreted by Mtb into the cytoplasm of macrophages and are required for survival and growth of infection within the host. Here we present recent advances in understanding the roles of mPTPA and mPTPB in the pathogenesis of TB. We also focus on potent, selective, and well-characterized small molecule inhibitors reported in the last decade for mPTPA and mPTPB.

Keywords: Mycobacterium tuberculosis (Mtb); PTP inhibitors; oxamic acids; pathogenic microorganisms; protein tyrosine phosphatases (PTPs); salicylic acid derivatives; signal transduction; tuberculosis (TB); virulence factors.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The dephosphorylation mechanism of protein tyrosine phosphatases with mPTPA and mPTPB as examples. The residues are labeled in blue for mPTPA and in green for mPTPB. The dianionic phosphotyrosine (pTyr) binds to the positively charged active site of PTPs. The active site cysteine thiol (Cys11 in mPTPA, Cys160 in mPTPB) possesses a pKa of ~5 and is predominantly in the thiolate form at neutral pH. When binding to pTyr substrates, aspartic acid, acting as a general acid (Asp126 in mPTPA, Asp82 in mPTPB), moves closer to the active site to neutralize the leaving group and facilitates nucleophilic attack by cysteine at the phosphorus atom of the substrate. The dephosphorylated substrate leaves the active site, giving a water molecule an opportunity to attack at the phosphocysteine intermediate to regenerate the cysteine thiolate.
Figure 2
Figure 2
Roles of mPTPA and mPTPB in mediating pathogen−host interactions. mPTPA and mPTPB are secreted by Mtb during macrophage infection (shown by green arrows). mPTPA has been demonstrated to translocate to the macrophage cytosol. mPTPA binds to subunit H of V-ATPase (Step 1) to selectively localize to its catalytic substrate VPS33B at the phagosome–lysosome fusion interface. Dephosphorylation of VPS33B (Step 2) results in the exclusion of V-ATPase from the mycobacterial phagosome. mPTPB activity leads to increased Akt phosphorylation (green arrow) and decreased ERK1/2 and p38 phosphorylation (red arrows), resulting in decreased apoptotic activity and reduced production of IL-6 (red arrow), respectively.
Figure 3
Figure 3
Comparison of the structures of mPTPA and the human LMW-PTPA. Ribbon diagram showing the superposition of mPTPA (red, PDB code: 1U2Q) and the human LMW-PTPA (green, PDB code: 5PNT). Chloride ion and glycerol molecule (shown in yellow) are shown in the active site of mPTPA, and the 2-(N-morpholino)-ethanesulfonic acid molecule (shown in orange) in the human LMW-PTPA.
Figure 4
Figure 4
X-ray crystal structures of mPTPB. (A) X-ray structure of phosphate bound mPTPB in the flexible lid closed form (PDB code: 1YWF). Product phosphate shown in red. The flexible lid (α7-α8) is in closed form. (B) X-ray structure of OMTS ((oxalylamino-methylene)-thiophene sulphonamide) bound mPTPB in open form (PDB code: 2OZ5). Proximal OMTS shown in magenta and distal OMTS shown in green. The flexible lid (α7-α8) is in the open form to accommodate OMTS molecules. The p-loop and β-sheets (β1, β2, β3 and β4) are shown in green and orange, respectively.
Figure 5
Figure 5
(A) The complex of mPTPB and OMTS (pdb code: 2OZ5) is shown in orange. The proximal and distal molecules of OMTS are shown in magenta and green, respectively. P-loop residues 159HCFAGKDR166 are shown in red. (B) A comparison of P-loop residues of mPTPB and other members of the PTP family. The residues in the P-loop that make contacts to OMTS are shown in red and are unique in mPTPB compared to other PTPs (shown in blue color). (C) Molecular interactions between proximal OMTS (in magenta) and P-loop residues (in green) in mPTPB (pdb code: 2OZ5). Hydrogen bonding interactions shown as yellow dotted lines.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Munro S.A., Lewin S.A., Smith H.J., Engel M.E., Fretheim A., Volmink J. Patient adherence to tuberculosis treatment: A systematic review of qualitative research. PLoS Med. 2007;4:e238. doi: 10.1371/journal.pmed.0040238. - DOI - PMC - PubMed
    1. 2019 Antibacterial Agents in Clinical Development: An Analysis of the Antibacterial Clinical Development Pipeline. World Health Organization; Geneva, Switzerland: 2019.
    1. Zhang Y. The magic bullets and tuberculosis drug targets. Annu. Rev. Pharmacol. Toxicol. 2005;45:529–564. doi: 10.1146/annurev.pharmtox.45.120403.100120. - DOI - PubMed
    1. Yu Z.-H., Zhang Z.-Y. Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases. Chem. Rev. 2017;118:1069–1091. doi: 10.1021/acs.chemrev.7b00105. - DOI - PMC - PubMed
    1. Ruddraraju K.V., Zhang Z.-Y. Covalent inhibition of protein tyrosine phosphatases. Mol. Biosyst. 2017;13:1257–1279. doi: 10.1039/C7MB00151G. - DOI - PMC - PubMed

LinkOut - more resources

-