Protein tyrosine kinase, PtkA, is required for Mycobacterium tuberculosis growth in macrophages

Wong, Dennis; Li, Wu; Chao, Joseph D.; Zhou, Peifu; Narula, Gagandeep; Tsui, Clement K. M.; Ko, Mary; Xie, Jingwei; Martinez-Frailes, Carlos

doi:10.1038/s41598-017-18547-9

Cited by 38 publications

(29 citation statements)

References 48 publications

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“…However, the related analogue 415 is a human tyrosine kinase TrkB inhibitor . Protein tyrosine kinase is required for M. tuberculosis growth in macrophages, and holds promise for kinase inhibitor repurposing. The related pyrimidinone‐pyrazole 416 (MMV393995) has been identified as both a noncompetitive inhibitor of divalent metal transporter DMt1/SLC11A2 and as a binding ligand to the G‐protein‐coupled adenosine A 2A receptor .…”

Section: Tuberculosismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Tuberculosismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…The interaction of Mtb protein-tyrosine phosphatase MptpA with the host defense machinery plays an important role in the mycobacterial virulence (17). Moreover, PtkA was recently shown to play a central role in promoting the growth of Mtb in macrophages (21), further underlining the significance of the interaction studies between MptpA and its cognate kinase PtkA and its role in Mtb regulation. Both enzymes represent potential candidates for rational drug design, where inactivation of either one of the partners or their interaction may inhibit the pathogen survival.…”

Section: Discussionmentioning

confidence: 99%

“…MptpA and PtkA, even if they do not represent typical on/off switches of signal transduction (19), are part of the Mtb regulatory system and therefore important target candidates for anti-TB therapy. Moreover, recent studies show the essential role of PtkA for Mtb growth in macrophages, establishing a central role for the PtkA-MptpA operon in Mtb pathogenesis (21). In this context, the lack of structural information of PtkA hampers a general understanding of the interactions between MptpA and PtkA, impairing the development of strategies for rational design of TB inhibitors.…”

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confidence: 99%

The domain architecture of PtkA, the first tyrosine kinase from Mycobacterium tuberculosis, differs from the conventional kinase architecture

Niesteruk

Jonker

Richter

et al. 2018

Journal of Biological Chemistry

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The discovery that MptpA (low-molecular-weight protein tyrosine phosphatase A) from () has an essential role for virulence has motivated research of tyrosine-specific phosphorylation in and other pathogenic bacteria. The phosphatase activity of MptpA is regulated via phosphorylation on Tyr and Tyr Thus far, only a single tyrosine-specific kinase, protein-tyrosine kinase A (PtkA), encoded by the gene has been identified within the genome. MptpA undergoes phosphorylation by PtkA. PtkA is an atypical bacterial tyrosine kinase, as its sequence differs from the sequence consensus within this family. The lack of structural information on PtkA hampers the detailed characterization of the MptpA-PtkA interaction. Here, using NMR spectroscopy, we provide a detailed structural characterization of the PtkA architecture and describe its intra- and intermolecular interactions with MptpA. We found that PtkA's domain architecture differs from the conventional kinase architecture and is composed of two domains, the N-terminal highly flexible intrinsically disordered domain (IDD) and the C-terminal rigid kinase core domain (KCD). The interaction between the two domains, together with the structural model of the complex proposed in this study, reveal that the IDD is unstructured and highly dynamic, allowing for a "fly-casting-like" mechanism of transient interactions with the rigid KCD This interaction modulates the accessibility of the KCD active site. In general, the structural and functional knowledge of PtkA gained in this study is crucial for understanding the MptpA-PtkA interactions, the catalytic mechanism, and the role of the kinase-phosphatase regulatory system in virulence.

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“…1C). In M. tuberculosis, the secreted Tyr-specific PtkA kinase and PtpA phosphatase, which are encoded in the same operon, are both required for macrophage intracellular growth [83,88,89]. Inside macrophages, PtpA dephosphorylates and inactivates the host vacuolar protein sorting-associated protein 33B (VPS33B).…”

Section: Host Establishmentmentioning

confidence: 99%

Importance of protein Ser/Thr/Tyr phosphorylation for bacterial pathogenesis

et al. 2020

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Protein phosphorylation regulates a large variety of biological processes in all living cells. In pathogenic bacteria, the study of serine, threonine, and tyrosine (Ser/Thr/Tyr) phosphorylation has shed light on the course of infectious diseases, from adherence to host cells to pathogen virulence, replication, and persistence. Mass spectrometry (MS)-based phosphoproteomics has provided global maps of Ser/Thr/Tyr phosphosites in bacterial pathogens. Despite recent developments, a quantitative and dynamic view of phosphorylation events that occur during bacterial pathogenesis is currently lacking. Temporal, spatial, and subpopulation resolution of phosphorylation data is required to identify key regulatory nodes underlying bacterial pathogenesis. Herein, we discuss how technological improvements in sample handling, MS instrumentation, data processing, and machine learning should improve bacterial phosphoproteomic datasets and the information extracted from them. Such information is expected to significantly extend the current knowledge of Ser/ Thr/Tyr phosphorylation in pathogenic bacteria and should ultimately contribute to the design of novel strategies to combat bacterial infections.

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Protein tyrosine kinase, PtkA, is required for Mycobacterium tuberculosis growth in macrophages

Cited by 38 publications

References 48 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

The domain architecture of PtkA, the first tyrosine kinase from Mycobacterium tuberculosis, differs from the conventional kinase architecture

Importance of protein Ser/Thr/Tyr phosphorylation for bacterial pathogenesis

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