Biochemical and functional characterizations of tyrosine phosphatases from pathogenic and nonpathogenic mycobacteria: indication of phenyl cyclopropyl methyl-/phenyl butenyl azoles as tyrosine phosphatase inhibitors

Abstract

Tyrosine phosphorylation is one of the most common means of posttranslational modifications which can generate novel recognition motifs for protein interactions and thereafter affecting cellular localization, protein stability, and enzyme activity. Mycobacterium tuberculosis (Mtb) possesses a wide range of signal transduction systems, including two protein tyrosine phosphatases (PtpA and PtpB). Since functional diversities between protein tyrosine phosphatases (PTPases) are illustrated by regulatory domains and subunits, we have characterized the nature of tyrosine phosphatases from slow-grower pathogenic species Mtb and from fast-grower nonpathogenic species Mycobacterium smegmatis (MS). The findings delineate that the enzymes present in MS have significantly lesser phosphatase activity than PTPases of Mtb as evidenced by low K cat/K m of recombinantly expressed proteins. The K cat/K m for Mtb PtpA was 500-1000-fold higher than MS PTPases. We have designed and synthesized phenyl cyclopropyl methyl-/phenyl butenyl azoles which inhibit growth of mycobacteria, in culture and in macrophages. The mechanism of efficacy of these compounds against mycobacteria was identified and suggested that the inhibition may possibly be mediated via the targeting of Mtb tyrosine phosphatase. The results further added that these compounds exclusively inhibit PtpA of Mtb.

Proteomic analysis of the rice (Oryza officinalis) provides clues on molecular tagging of proteins for brown planthopper resistance

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iTRAQ‐based proteomics of sunflower cultivars differing in resistance to parasitic weed Orobanche cumana

“…In plants, pathogen‐associated proteins directly related to the defense system are induced on pathogen/parasite attack. But, how these proteins accumulate or activate plant defense system during compatible and incompatible interaction actually decides the sustainability of resistance .…”

Natural products and their analogues acting against Mycobacterium tuberculosis: A recent update

“…M.tb possesses a wide range of signal transduction systems, including two PTPs (PtpA and PtpB) which will directly alter host signaling to avoid the antibacterial functions of the host. Among all the compounds, 114 and 116 inhibit M.tb PTP A (PtpA) with IC 50 values of 14 and 24 µg/mL, respectively (Chatterjee et al, 2015; Liu et al, 2013). Also, 116 displayed modest growth inhibitory activity against S. aureus with a MIC value of 12.5 µg/mL (Liu et al, 2013).…”