Microbial protein-tyrosine kinases.

Microbial ester kinases identified in the past 3 decades came as a surprise, as protein phosphorylation on Ser, Thr, and Tyr amino acids was thought to be unique to eukaryotes. Current analysis of available microbial genomes reveals that "eukaryote-like" protein kinases are prevalent in prokaryotes and can converge in the same signaling pathway with the classical microbial "two-component" systems. Most microbial tyrosine kinases lack the "eukaryotic" Hanks domain signature and are designated tyrosine kinases based upon their biochemical activity. These include the tyrosine kinases termed bacterial tyrosine kinases (BY-kinases), which are responsible for the majority of known bacterial tyrosine phosphorylation events. Although termed generally as bacterial tyrosine kinases, BY-kinases can be considered as one family belonging to the superfamily of prokaryotic protein-tyrosine kinases in bacteria. Other members of this superfamily include atypical "odd" tyrosine kinases with diverse mechanisms of protein phosphorylation and the "eukaryote-like" Hanks-type tyrosine kinases. Here, we discuss the distribution, phylogeny, and function of the various prokaryotic protein-tyrosine kinases, focusing on the recently discovered Mycobacterium tuberculosis PtkA and its relationship with other members of this diverse family of proteins.

Phosphorylation of Mycobacterium tuberculosis protein tyrosine kinase A PtkA by Ser/Thr protein kinases.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has inflicted about one third of mankind and claims millions of deaths worldwide annually. Signalling plays an important role in Mtb pathogenesis and persistence, and thus represents attractive resource for drug target candidates. Here, we show that protein tyrosine kinase A (PtkA) can be phosphorylated by Mtb endogenous eukaryotic-like Ser/Thr protein kinases (eSTPKs). Kinase assays showed that PknA, PknD, PknF, and PknK can phosphorylate PtkA in dose- and time-dependent manner. Enzyme kinetics suggests that PknA has the highest affinity and enzymatic efficiency towards PtkA. Furthermore, protein-protein interaction assay in surrogate host showed that PtkA interacts with multi-eSTPKs in vivo, including PknA. Lastly, we show that PtkA phosphorylation by eSTPKs occurs on threonine residues and may effect tyrosine phosphorylation levels and thus PtkA activity in vitro. These results demonstrate that PtkA can serve as a substrate to many eSTPKs and suggests that's its activity can be regulated.

Exploring the role of the protein tyrosine kinase a (PtkA) in mycobacterial intracellular survival.

Mycobacterium tuberculosis (Mtb) continues to define new paradigms of host-pathogen interaction. There are several host proteins known which are regulated by Mtb infection. The proteins which regulate host biological processes like apoptosis, cell processes, stress proteins, metabolic enzymes, etc. are targeted by the pathogens. Mtb proteins interact directly or indirectly with host proteins and play an important role in their persistence and intracellular growth. Mtb is an intracellular pathogen. It remains dormant for years within the host without activating its immune system. Mtb Protein tyrosine kinase (PtkA) regulates host anti-apoptotic protein, metabolic enzymes, and several other proteins that are involved in stress regulation, cell proliferation, protein folding, DNA repair, etc. PtkA regulates other mycobacterial proteins and plays an important role in its growth and survival. Here we summarized the current knowledge of PtkA and reviewed its role in mycobacterial intracellular survival as it regulates several other mycobacterial proteins and host proteins. PtkA regulates PtpA secretion which is essential for mycobacterial virulence and could be used as an attractive drug target.