Mycobacterial Ser/Thr protein kinases and phosphatases: Physiological roles and therapeutic potential

Abstract

Reversible protein phosphorylation is a major regulation mechanism of fundamental biological processes, not only in eukaryotes but also in bacteria. A growing body of evidence suggests that Ser/Thr phosphorylation play important roles in the physiology and virulence of Mycobacterium tuberculosis, the etiological agent of tuberculosis. This pathogen uses 'eukaryotic-like' Ser/Thr protein kinases and phosphatases not only to regulate many intracellular metabolic processes, but also to interfere with signaling pathways of the infected host cell. Disrupting such processes by means of selective inhibitors may thus provide new pharmaceutical weapons to combat the disease. Here we review the current knowledge on Ser/Thr protein kinases and phosphatases in M. tuberculosis, their regulation mechanisms and putative substrates, and we explore their therapeutic potential as possible targets for the development of new anti-mycobacterial compounds.

High-coverage proteome analysis reveals the first insight of protein modification systems in the pathogenic spirochete Leptospira interrogans

“…By contrast, more than a half of the unambiguous phosphosites in L. interrogans matched the target motifs of eukaryotic kinases, and genomic analysis indicates that L. interrogans contains more eukaryotic-like kinases and eukaryotic-like phosphatases than E. coli and B. subtilis. These findings at the proteomic and genomic [19,42]. In L. interrogans, some catalytic enzymes involved in Ser/ Thr phosphorylation only exist in pathogenic Leptospira species (e.g., Ser/Thr kinases, LA1164 and LA3113).…”

“…Posttranslational modifications (PTMs) play crucial roles in regulating protein functions in bacterial physiology and virulence [18][19][20]. In particular, phosphorylation, acetylation and methylation, which are the most extensively studied PTMs, are all acknowledged to be important for regulating protein activities [21][22][23].…”

Biochemical and Spatial Coincidence in the Provisional Ser/Thr Protein Kinase Interaction Network of Mycobacterium tuberculosis*

“…Higher eukaryotes primarily use relatively stable Ser/Thr or Tyr modifications, whereas prokaryotes rely more heavily on histidine kinases (HK) 2 (1). In addition to the chemical differences between these pathways, current data indicate that the network architecture of the cascades may also be fundamentally distinct.…”

Phosphorylation of the Mycobacterium tuberculosis β-Ketoacyl-Acyl Carrier Protein Reductase MabA Regulates Mycolic Acid Biosynthesis

“…It is becoming clear that in M. tuberculosis many of these kinases are involved in the regulation of metabolic processes, transport of metabolites, cell division, or virulence. Therefore, signaling through Ser/Thr phosphorylation has emerged as a key regulatory mechanism in pathogenic mycobacteria (28). In response to its environment, M. tuberculosis activates or represses the expression of a number of genes to rapidly adjust to new conditions.…”