Type VII Toxin/Antitoxin Classification System for Antitoxins that Enzymatically Neutralize Toxins

The new classification type VII is for antitoxins that enzymatically modify toxins through transient interactions, rather than primarily through binding (cf. type II). The improved classification system will simplify toxin/antitoxin (TA) classifications when new types of post-translational modification of toxins by antitoxins are found. The new classification system reserves type V for antitoxins that enzymatically modify substrates other than the toxin. Studying the neutralization mechanisms of antitoxins provides a valuable means to explore the conditions that lead to toxin activation. Prediction of TA systems via bioinformatic searches will be more accurate using the conserved active enzymatic motifs in antitoxin components [e.g., GSX10DXD in minimal NTase (MNT)-domain proteins]. Toxin/antitoxin (TA) systems are present in nearly all bacterial and archaeal strains and consist of a toxin that reduces growth and an antitoxin that masks toxin activity. Currently there are six primary classes for TA systems based on the nature of the antitoxin and the way that the antitoxin inactivates the toxin. Here we show that there now are at least three additional and distinct TA systems in which the antitoxin is an enzyme and the cognate toxin is the direct target of the antitoxin: Hha/TomB (antitoxin oxidizes Cys18 of the toxin), TglT/TakA (antitoxin phosphorylates Ser78 of the toxin), and HepT/MntA (antitoxin adds three AMPs to Tyr104 of the toxin). Thus, we suggest the type VII TA system should be used to designate those TA systems in which the enzyme antitoxin chemically modifies the toxin post-translationally to neutralize it. Defining the type VII TA system using this specific criterion will aid researchers in classifying newly discovered TA systems as well as refine the framework for recognizing the diverse biochemical functions in TA systems. Toxin/antitoxin (TA) systems are present in nearly all bacterial and archaeal strains and consist of a toxin that reduces growth and an antitoxin that masks toxin activity. Currently there are six primary classes for TA systems based on the nature of the antitoxin and the way that the antitoxin inactivates the toxin. Here we show that there now are at least three additional and distinct TA systems in which the antitoxin is an enzyme and the cognate toxin is the direct target of the antitoxin: Hha/TomB (antitoxin oxidizes Cys18 of the toxin), TglT/TakA (antitoxin phosphorylates Ser78 of the toxin), and HepT/MntA (antitoxin adds three AMPs to Tyr104 of the toxin). Thus, we suggest the type VII TA system should be used to designate those TA systems in which the enzyme antitoxin chemically modifies the toxin post-translationally to neutralize it. Defining the type VII TA system using this specific criterion will aid researchers in classifying newly discovered TA systems as well as refine the framework for recognizing the diverse biochemical functions in TA systems. systems that are activated by phage infection and limit viral replication by reducing cell metabolism, thereby providing protection to the bacterial population. an enzyme that catalyzes the transfer of a phosphate group from ATP to a specified molecule (e.g., protein phosphorylation). a salient recurring feature. an enzyme that adds nucleotides to substrates such as nucleic acids, proteins, and antibiotics. post-translational modification by the covalent addition of more than one AMP molecule to a hydroxyl side chain of a protein or RNA. TA loci comprise two genes, one coding for a stable toxin whose overexpression reduces growth or causes growth stasis, and the other coding for an unstable (usually) antitoxin that counteracts the action of the toxin.