# Structure, Biology, and Therapeutic Application of Toxin-Antitoxin Systems in Pathogenic Bacteria
## 2 Functions of Six Different Types of Bacterial TA Systems
### Type II
Similar to CedB, ParE blocks DNA replication by inhibiting the activity of DNA gyrase [113]. HipA acts as a serine/threonine kinase that phosphorylates glutamyl tRNA synthetase (GltX) and inhibits aminoacylation and translation, which are related to persister formation and multidrug tolerance [63; 64]. Doc is a kinase that phosphorylates a highly conserved threonine (Thr-382) of the translation elongation factor EF-Tu, which hinders its binding to aminoacylated tRNAs and thereby inhibits protein synthesis [61; 62]. _M. tuberculosis_ VapC20 cleaves the well conserved Sarcin-Ricin loop (SRL) of 23S rRNA [59], which is the target of the eukaryotic toxins, \(\alpha\)-Sarcin and Ricin [36; 37]. A protein containing filamentation induced by cAMP (FIC) domain has recently been identified as a toxin of the FiCTA type II TA family [114; 115]. The toxin inhibits DNA replication by catalyzing the AMPylation of DNA gyrase and topoisomerase IV at their ATP binding sites. The molecular process induces cellular growth arrest and filamentation, which is believed to defense against phagocytosis of host immune cells [116].There are toxins that interfere with the association of ribosomal subunits and thus inhibit translation initiation. Ribosome association toxin A (RatA) from _E. coli_ binds to the 50S subunit, blocks its interaction with the 30S subunit, and inhibits the formation of the 70S ribosome [117]. GraT of the GraTA system causes a defect in ribosome subunit assembly by a direct binding to the chaperone DnaK [118], which is known to be involved in late stages of ribosome biogenesis [119]. Many cellular targets and functions of the toxins could be fundamentally explained by even slight differences in their entire or local protein structures. The structures of two toxins, YoeB and Doc, are not homologous and use different mechanisms to inhibit protein synthesis. YoeB, which is structurally similar to RelE, has an RNase fold for interacting with the 50S ribosomal subunit [120]. The structure and function of HigB are similar to those of YoeB [56; 121]. MazF is structurally similar to other family toxins such as Kid/PemK of the R100 plasmid and CcdB of the F plasmid [122]. Consistent with this similarity, the MazF and Kid toxins have similar functions as ribosome-independent, sequence-specific ribonucleases [123]. However, CcdB has a different function as an inhibitor of DNA gyrase, which is one example of structurally similar toxins having dramatically divergent cellular targets and functions. This case is also found in the RelE and CcdB families, which have similar protein folds but show completely different functions. Accumulating structural data on TA systems have revealed complex evolutionary relationships between them. Sequences and folds among toxins or antitoxins are not significantly conserved, and there exist various combinations of toxin and antitoxin folds. The YefM antitoxin of the YefM-YoeB system, which is one of TA modules in _E. coli_, is structurally similar to the Phd antitoxin of the Phd-Doc system of phage P1, although the sequence similarity between the two antitoxins is low [124]. YefM forms a heterotrimeric complex with YoeB in a similar manner to the Phd-Doc complex. Phd is structurally homologous to an antitoxin that binds to the toxin with an endonuclease activity, which is not related to Doc [125]. On the other hand, YoeB is structurally similar to the RelE toxin of the RelBE system. The observations suggest that antitoxin shuffling between different TA systems have evolutionally occurred.