Biochemical and functional characterizations of tyrosine phosphatases from pathogenic and nonpathogenic mycobacteria: indication of phenyl cyclopropyl methyl-/phenyl butenyl azoles as tyrosine phosphatase inhibitors.
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.
Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226 031, India.
Aditi
A
Chatterjee
Sapna
S
Pandey
Pramod K
PK
Singh
Navendu Prakash
NP
Pathak
Niyati
N
Rai
Ravishankar
R
Ramachandran
Rama Pati
RP
Tripathi
Kishore K
KK
Srivastava
D000995:Antitubercular Agents / Q000378:metabolism*; D001393:Azoles / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D007700:Kinetics; D020102:Mycobacterium smegmatis / Q000201:enzymology*; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000995:Antitubercular Agents; D001393:Azoles; D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases