# Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis
## 2 TA Classes and Function  
TA modules are classified into six types based on the mechanism by which the antitoxin inhibits toxin activity [5; 11]. In type I cassettes, heteroduplex formation between the antisense RNA antitoxin and the toxin mRNA blocks the translation of the latter [12; 13]. The toxin and antitoxin proteins in type II TAs form a stable complex in which the active site of the toxin is hidden by the antitoxin [4] (Figure 1). The antidote in type III complexes is a small RNA that interacts directly with the toxin protein to block its activity [14; 15; 16]. In type IV systems, a protein antitoxin acts by binding directly to the target of the toxin thereby protecting this target [17]. In contrast, the antitoxin protein functions as a ribonuclease specific against the toxin mRNA in type V TAs [18]. A type VI module has been proposed recently in which the antitoxin acts as a proteolytic adaptor for the ClpXP protease, which is responsible for degradation of the cognate toxin [19; 20]. Moreover, bacterial restriction-modification systems and the ppGpp-SpoT metabolite-enzyme pair share certain common features with TA modules and may be considered as TA-like systems in some aspects [11; 21]. TAs belonging to types I and II are widely distributed within the prokaryotic world, whereas fewer representatives are known to date for the other classes. However, this situation may change rapidly as extensive bioinformatic analyses  
Figure 1: Action of proteins that belong to a typical type II TA complex. The antitoxin (A; blue) and toxin (T; red) genes are co-expressed from a promoter (p; grey) in a single operon. The TA complex negatively regulates transcription from the promoter by binding specific palindromes within the overlapping operator region. In response to certain environmental conditions, the antitoxin is proteolytically cleaved by Lon or Clp proteases (yellow). The toxin is thereby released to act on its specific intracellular target process (green) to induce cell cycle arrest or death. together with growing availability of results derived from high-throughput screening methods of microbial genomes such as shotgun cloning lead to the identification of many novel TA families [22]. TA operons are abundant within the genomes of most bacterial species, often in multiple copies as in _Escherichia coli_ (Figure 2), and have no established eukaryotic homologues with comparable functions. TA genes were identified first on plasmids and later on chromosomes. TAs also may be located within other mobile genetic elements including prophages, transposons or superintegrons [7; 12; 23; 24; 25; 26]. In these locations, TA modules may ensure stable maintenance of the exogenous DNA during cell division. Daughter cells which fail to inherit these elements are eliminated from the bacterial population by the action of the liberated toxin which remains in the cytoplasm of newly-born cells. The antitoxin cannot be replenished in this situation due to the loss of the genetic element that carries the TA genes. TAs encoded on mobile genetic elements play a pivotal role in the maintenance and dissemination among human pathogens of antibiotic resistance and virulence determinants that also are located on these elements [27; 28]. On the other hand, growing evidence suggests that the bulk of TA modules primarily act as global metabolic stress managers and are especially beneficial for bacteria living in dynamically changing environmental conditions. Accordingly, comprehensive analyses of microbial genomes have revealed that TA loci are more abundant in free-living prokaryotes than in obligatory intracellular parasites, which are practically devoid of TAs [26]. This observation is in agreement with the hypothesis that TAs help bacteria to cope with diverse external stresses by slowing down cell metabolism, initiating cell cycle arrest or even mediating altruistic programmed cell death [29; 30; 31]. The role of individual TAs may be to respond to different groups of stresses, although some TAs may have overlapping functions.