Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria
Abstract
:1. Biological Roles of TA Systems
2. Functions of Six Different Types of Bacterial TA Systems
2.1. Type I
2.2. Type II
2.3. Types III–VI
3. TA Modules from Pathogenic Bacteria
3.1. Gram-Positive Bacteria
3.2. Gram-Negative Bacteria
3.3. Mycobacterium Tuberculosis
4. Structural Characteristics of TA Proteins from Pathogenic Bacteria
4.1. MazEF
4.2. CcdAB
4.3. VapBC
4.4. YefM–YoeB
4.5. ε–ζ
4.6. Atypical TA Modules
5. Exploitation of TA Systems for the Development of Novel Antibiotic Drugs
Supplementary Materials
Acknowledgments
Conflicts of Interest
References
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Type | TA Module | Protein Toxin | Antitoxin (Molecular Species) | Toxin Activity | Inhibited Cellular Process | Ref. |
---|---|---|---|---|---|---|
I | istR-tisB | TisB | istR (RNA) | Depolarizes Cell Membrane | ATP Synthesis | [41,42] |
I | sok-hok | Hok | sok (RNA) | Depolarizes Cell Membrane | ATP Synthesis | [43,44] |
I | sibC-ibsC | IbsC | sibC (RNA) | Depolarizes Cell Membrane | ATP Synthesis | [45,46] |
I | ratA-txpA | TxpA | ratA (RNA) | Lyses Cell Membrane | Not Applicable | [47,48] |
I | fst–RNAI–RNAII | Fst | RNAII (RNA) | Damages Cell Membrane | Cell Division | [49,50] |
I | symRE | SymE | symR (RNA) | mRNA Cleavage | Translation | [51] |
II | mazEF | MazF | MazE (protein) | mRNA Cleavage | Translation | [52,53] |
II | kis-kid | Kid | Kis (protein) | mRNA Cleavage | Translation | [54] |
II | higBA | HigA | HigB (protein) | mRNA Cleavage | Translation | [55,56] |
II | relBE | RelE | RelB (protein) | mRNA Cleavage | Translation | [57] |
II | vapBC | VapC | VapB (protein) | RNA Cleavage | Translation | [58,59,60] |
II | phd-doc | Doc | Phd (protein) | Phosphorylation of Translation Elongation Factor EF-Tu | Translation | [61,62] |
II | hipBA | HipA | HipB (protein) | Phosphorylation of Glutamyl tRNA Synthetase | Translation | [63,64] |
II | ccdAB | CcdB | CcdA (protein) | Poison of DNA gyrase | Transcription and Replication | [65,66] |
II | parDE | ParE | ParD (protein) | Poison of DNA gyrase | Transcription and Replication | [65,66] |
II | ω-ε-ζ | ζ | ε (protein) | Phosphorylation of UDP-N-acetylglucosamine | Peptidoglycan Synthesis | [67,68] |
III | toxIN | ToxN | toxI (RNA) | RNA Cleavage | Translation | [69] |
IV | yeeUV | YeeV | YeeU (protein) | Interacts with Cytoskeleton Proteins FtsZ and MreB | Cell Division | [70] |
IV | cptBA | CptA | CptB (protein) | Interacts with Cytoskeleton Proteins FtsZ and MreB | Cell Division | [71] |
V | ghoST | GhoT | GhoS (protein) | Damages Cell Membrane | Not Applicable | [72] |
VI | socAB | SocB | SocA (protein) | Binds to the β sliding clamp DnaN | Replication | [73] |
Pathogenic Bacteria | TA Protein | Oligomeric State (Stoichiometry) | Pfam Annotation/Accession ID | PDB ID/Deposit Date | Ref. |
---|---|---|---|---|---|
Streptococcus pyogenes | ε-ζ Complex | Hetero-tetramer (A2B2) | ε: Bacterial Epsilon Antitoxin Domain/PF08998 | 1GVN/2002-02-19 | [68] |
ζ: Zeta Toxin Family/PF06414 | |||||
Streptococcus pyogenes | ε-ζ Bound to the Substrate | Hetero-tetramer (A2B2) | ε: Bacterial Epsilon Antitoxin Domain/PF08998 | 3Q8X/2011-01-07 | [67] |
ζ: Zeta Toxin Family/PF06414 | |||||
Streptococcus pneumoniae | PezAT Complex | Hetero-tetramer (A2B2) | PezA: 3-layer (αβα) Sandwich Architecture and Rossmann Fold Topology* | 2P5T/2007-03-16 | [140] |
PezT: Zeta Toxin Family/PF06414 | |||||
Enterococcus faecalis | Fst Toxin | Monomer (A) | Toxin Fst Domain/PF13955 | 2KV5/2010-03-08 | [145] |
Staphylococcus aureus | MazF Toxin | Homo-dimer (A2) | PemK-like Protein Family/PF02452 | 4MZM/2013-09-30 | [161] |
Neisseria gonorrhoeae | FitB Toxin | Homo-dimer (A2) | FitB: PIN Domain/PF01850 | 2H1C/2006-05-16 | [162] |
Neisseria gonorrhoeae | FitAB Bound to DNA | Hetero-octamer (A4B4) | FitB: PIN Domain/PF01850 | 2H1O/2006-05-16 | [162] |
FitA: 3-layer (αβα) Sandwich Architecture and Rossmann Fold Topology * | |||||
Rickettsia felis | VapBC2 Bound to DNA | Hetero-octamer (A4B4) | VapB2: Antitoxin MazE Domain/PF04014 | 3ZVK/2011-07-25 | [163] |
VapC2: PIN Domain/PF01850 | |||||
Shigella flexneri | YeeU Antitoxin | Monomer (A) | YagB/YeeU/YfjZ Family/PF06154 | 2INW/2006-10-09 | [125] |
Shigella flexneri | VapBC Complex | Hetero-octamer (A4B4) | VapC: PIN Domain/PF01850 | 3TND/2011-09-01 | [164] |
VapB: Antitoxin MazE Domain/PF04014 | |||||
Escherichia coli O157 | PaaA2 Antitoxin | Monomer (A) | Not Applicable | 3ZBE/2012-11-08 | [165] |
Escherichia coli O157 | PaaA2-ParE2 Complex | Hetero-heptadecamer (A8B8) | PaaA2: Not Applicable | 5CW7/2015-07-27 | [166] |
ParE2: Plasmid Stabilization System Protein/PF05016 | |||||
Escherichia coli K12 | MazEF Complex | Hetero-hexamer (A4B2) | MazE: Antidote-toxin Recognition MazE/PF04014 | 1UB4/2003-03-28 | [122] |
MazF: PemK-like Protein/PF02452 | |||||
Escherichia coli K12 | MazF-Substrate Complex | Homo-dimer (A2) | MazF: PemK-like Protein/PF02452 | 5CR2/2015-07-22 | [167] |
Substrate Sequence: d(AUACAUA) | |||||
Escherichia coli K12 | CcdB Toxin | Homo-dimer | CcdB Protein Domain/PF01845 | 1VUB/1998-04-17 | [168] |
Escherichia coli K12 | CcdB Toxin Bound to Gyrase | Hetero-tetramer (A2B2) | CcdB Protein Domain/PF01845 | 1X75/2004-08-13 | [169] |
Escherichia coli K12 | YefM-YoeB Complex | Hetero-trimer (A2B) | YefM: Antitoxin Phd_YefM Domain/PF02604 | 2A6Q/2005-07-04 | [124] |
YoeB: Plasmid encoded Toxin Txe Family | |||||
Vibrio fischeri | CcdB Toxin | Homo-dimer (A2) | CcdB Protein Domain/PF01845 | 3JSC/2009-09-10 | [170] |
Vibrio fischeri | CcdB Toxin Bound to Gyrase | Hetero-tetramer (A2B2) | CcdB Protein Domain/PF01845 | 4ELZ/2012-04-11 | [171] |
Brucella abortus | BrnT Toxin | Homo-tetramer (A4) | Protein of Unknown Function/PF04365 | 3U97/2011-10-18 | [172] |
Salmonella typhimurium | TacT Toxin | Homo-dimer (A2) | Acetyltransferase (GNAT) Domain/PF13673 | 5FVJ/2016-02-08 | [159] |
Mycobacterium tuberculosis | VapBC5 Complex | Hetero-dimer (AB) | VapB5: Antitoxin Phd_YefM Domain/PF02604 | 3DBO/2008-06-02 | [173] |
VapC5: PIN Domain/PF01850 | |||||
Mycobacterium tuberculosis | VapBC3 Complex | Hetero-octamer (A4B4) | VapB3: Ribbon-helix-helix Protein, copG Family/PF01402 | 3H87/2009-04-28 | [174] |
VapC3: PIN Domain/PF01850 | |||||
Mycobacterium tuberculosis | VapBC15 Complex | Hetero-tetramer (A2B2) | VapB15: Uncharacterized, Conserved Protein/PF09957 | 4CHG/2013-12-02 | [175] |
VapC15: PIN Domain/PF01850 | |||||
Mycobacterium tuberculosis | VapBC30 Complex | Hetero-tetramer (A2B2) | VapB30: Rv0623-like Transcription Factor/PF07704 | 4XGQ/2015-01-02 | [176] |
VapC30: PIN Domain/PF01850 | |||||
Mycobacterium tuberculosis | YefM Antitoxin | Homo-tetramer (A4) | Antitoxin Phd_YefM Domain/PF02604 | 3CTO/2008-04-14 | [177] |
Bacillus subtilis | SpoIISA-SpoIISB Complex | Hetero-tetramer (A2B2) | SpoIISB: Antitoxin SpoIISB Family/PF14185 | 3O6Q/2010-07-29 | [178] |
SpoIISA: Toxin SpoIISA Family/PF14171 | |||||
Bacillus subtilis | MazEF Complex | Hetero-hexamer (A4B2) | MazE: Ribbon-helix-helix Protein, CopG family/PF01402 | 4ME7/2013-08-25 | [179] |
MazF: PemK-like Protein/PF02452 | |||||
Bacillus subtilis | MazF-Substrate Complex | Homo-dimer (A2) | MazF: PemK-like Protein/PF02452 | 4MDX/2013-08-23 | [179] |
Substrate Sequence: UUdUACAUAA |
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Lee, K.-Y.; Lee, B.-J. Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria. Toxins 2016, 8, 305. https://doi.org/10.3390/toxins8100305
Lee K-Y, Lee B-J. Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria. Toxins. 2016; 8(10):305. https://doi.org/10.3390/toxins8100305
Chicago/Turabian StyleLee, Ki-Young, and Bong-Jin Lee. 2016. "Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria" Toxins 8, no. 10: 305. https://doi.org/10.3390/toxins8100305
APA StyleLee, K.-Y., & Lee, B.-J. (2016). Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria. Toxins, 8(10), 305. https://doi.org/10.3390/toxins8100305