Tyrosine inhibits the Mycobacterium tuberculosis protein tyrosine phosphatase MptpA

The catalytic action of the low-molecular weight protein tyrosine phosphatase (MptpA), expressed by Mycobacterium tuberculosis, is known to be essential for the pathogenicity of the bacterium. Candidate MptpA inhibitors are, therefore, actively sought and evaluated, and important work has been dedicated to the identi cation of competitive inhibitors. Here, we show that the activity of MptpA at the expense of phosphotyrosine (pTyr) is promptly inhibited by tyrosine, whereas the p-nitrophenol generated from p-nitrophenyl phosphate antagonizes the enzyme to a limited extent. We also report here a Ki of 512 ± 26 μM of MptpA for tyrosine, a value approximately one order of magnitude lower than the corresponding Ki for orthophosphate. Remarkably, the inhibition of MptpA observed when pTyr was used as substrate was e ectively relieved by tyrosinase, the action of which was responsible for maintaining zero-order kinetics up to the generation of 200–400 μM of reaction product. Overall, the di erent sensitivity of MptpA towards tyrosine and p-nitrophenol suggests a signi cant inhibi- tory role of the α-aminocarboxylic acid moiety of the aromatic amino acid. This may, therefore, suggest the design of MptpA competitive inhibitors targeting the portion of the enzyme active site which is distal from the phosphate-binding region.