Protective antigen (T3D2593)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (7)XML
Targets (7)
Record Information
Version2.0
Creation Date2009-07-06 18:11:23 UTC
Update Date2014-12-24 20:25:44 UTC
Accession NumberT3D2593
Identification
Common NameProtective antigen
ClassProtein
DescriptionProtective antigen (PA) is a component of the anthrax (Bacillus anthracis) toxins, which allows the translocation of EF and LF into the cytosol. The anthrax toxins consist of three distinct proteins: the protective antigen (PA; 83 kDA), the edema factor (EF; 89 kDA) and the lethal factor (LF; 90 kDa). Individually, none of the three is toxic; PA combined with LF is the lethal toxin (LeTx) and PA combined with EF is the edema toxin (EdTx). (1, 2)
Compound Type
  • Amide
  • Amine
  • Bacterial Toxin
  • Natural Compound
  • Organic Compound
  • Protein
Protein StructureT3d2593
Synonyms
Synonym
Anthrax toxin PA
PA
Chemical FormulaNot Available
Average Molecular Mass85810.325 g/mol
CAS Registry Number643772-15-0
SequenceNot Available
Chemical Taxonomy
DescriptionNot Available
KingdomOrganic Compounds
Super ClassOrganic Acids
ClassCarboxylic Acids and Derivatives
Sub ClassAmino Acids, Peptides, and Analogues
Direct ParentPeptides
Alternative ParentsNot Available
SubstituentsNot Available
Molecular FrameworkNot Available
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular LocationsNot Available
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateLiquid
AppearanceClear solution.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility>10 mg/mL
LogPNot Available
Predicted PropertiesNot Available
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Toxicity Profile
Route of ExposureIngestion (4) ; inhalation (4) ; dermal (4)
Mechanism of ToxicityAfter binding to a host cell surface receptor, PA is cleaved by membrane endoproteases of the furin family. Cleaved PA molecules assemble into heptamers, which then associate with EF and LF. PA heptamers are endocytosed into acidic compartments, where a conformational change of the complex allows translocation of LF and EF into the cytosol. LF and EF act enzymatically on intracellular substrates: LF is a zinc-dependent metallo-protease that cleaves and inactivates most isoforms of MEKs (mitogen-activated protein (MAP) kinase kinases), whereas EF is a calcium- and calmodulin-dependent adenylate cyclase that causes a dramatic increase in cytoplasmic cAMP, leading to an imbalance of water homeostasis. (1, 2)
MetabolismFree toxin may be removed by opsonization via the reticuloendothelial system (primarily the liver and kidneys) or it may be degraded through cellular internalization via the lysosomes. Lysosomes are membrane-enclosed organelles that contain an array of digestive enzymes, including several proteases.
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesProtective antigen (PA) is a component of the anthrax (Bacillus anthracis) toxins. (1, 2)
Minimum Risk LevelNot Available
Health EffectsProtective antigen (PA) is a component of the anthrax (Bacillus anthracis) toxins. Anthrax is an acute diease that may manifest as a pulmonary, gastrointestinal, or cutaneous infection. The toxins are the primary agents of tissue destruction, bleeding, and death of the host. (1, 2, 3)
SymptomsRespiratory infection in humans initially presents with cold or flu-like symptoms. Gastrointestinal infection in causes gastrointestinal difficulty, vomiting of blood, severe diarrhea, acute inflammation of the intestinal tract, and loss of appetite. Some lesions may be found in the intestines and in the mouth and throat. Cutaneous anthrax infection in humans shows up as a boil-like skin lesion that eventually forms an ulcer with a black center (eschar). (3)
TreatmentTreatment for anthrax infection includes large doses of intravenous and oral antibiotics, such as fluoroquinolones, like ciprofloxacin (cipro), doxycycline, erythromycin, vancomycin or penicillin. In possible cases of inhalation anthrax, early antibiotic prophylaxis treatment is crucial to prevent possible death. There is an anthrax vaccination licensed under the trade name BioThrax. (3)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDNot Available
PubChem Compound IDNot Available
ChEMBL IDNot Available
ChemSpider IDNot Available
KEGG IDNot Available
UniProt IDP13423
OMIM ID
ChEBI IDNot Available
BioCyc IDNot Available
CTD IDNot Available
Stitch IDProtective antigen
PDB ID1ACC
ACToR IDNot Available
Wikipedia LinkNot Available
References
Synthesis ReferenceNot Available
MSDSNot Available
General References
  1. Fabbri A, Travaglione S, Falzano L, Fiorentini C: Bacterial protein toxins: current and potential clinical use. Curr Med Chem. 2008;15(11):1116-25. [18473807 ]
  2. Collier RJ, Young JA: Anthrax toxin. Annu Rev Cell Dev Biol. 2003;19:45-70. [14570563 ]
  3. Wikipedia. Anthrax. Last Updated 10 August 2009. [Link]
  4. Wikipedia. Bacterial toxin. Last Updated 27 February 2009. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Dual specificity mitogen-activated protein kinase kinase 1
General Function:
Receptor signaling protein tyrosine phosphatase activity
Specific Function:
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.
Gene Name:
MAP2K1
Uniprot ID:
Q02750
Molecular Weight:
43438.65 Da
References
  1. Fabbri A, Travaglione S, Falzano L, Fiorentini C: Bacterial protein toxins: current and potential clinical use. Curr Med Chem. 2008;15(11):1116-25. [18473807 ]
  2. Collier RJ, Young JA: Anthrax toxin. Annu Rev Cell Dev Biol. 2003;19:45-70. [14570563 ]
Target Details
2. Dual specificity mitogen-activated protein kinase kinase 2
General Function:
Scaffold protein binding
Specific Function:
Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).
Gene Name:
MAP2K2
Uniprot ID:
P36507
Molecular Weight:
44423.735 Da
References
  1. Fabbri A, Travaglione S, Falzano L, Fiorentini C: Bacterial protein toxins: current and potential clinical use. Curr Med Chem. 2008;15(11):1116-25. [18473807 ]
  2. Collier RJ, Young JA: Anthrax toxin. Annu Rev Cell Dev Biol. 2003;19:45-70. [14570563 ]
Target Details
3. Dual specificity mitogen-activated protein kinase kinase 3
General Function:
Protein tyrosine kinase activity
Specific Function:
Dual specificity kinase. Is activated by cytokines and environmental stress in vivo. Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinase p38.
Gene Name:
MAP2K3
Uniprot ID:
P46734
Molecular Weight:
39318.05 Da
References
  1. Fabbri A, Travaglione S, Falzano L, Fiorentini C: Bacterial protein toxins: current and potential clinical use. Curr Med Chem. 2008;15(11):1116-25. [18473807 ]
  2. Collier RJ, Young JA: Anthrax toxin. Annu Rev Cell Dev Biol. 2003;19:45-70. [14570563 ]
Target Details
4. Dual specificity mitogen-activated protein kinase kinase 4
General Function:
Protein tyrosine kinase activity
Specific Function:
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
Gene Name:
MAP2K4
Uniprot ID:
P45985
Molecular Weight:
44287.34 Da
References
  1. Fabbri A, Travaglione S, Falzano L, Fiorentini C: Bacterial protein toxins: current and potential clinical use. Curr Med Chem. 2008;15(11):1116-25. [18473807 ]
  2. Collier RJ, Young JA: Anthrax toxin. Annu Rev Cell Dev Biol. 2003;19:45-70. [14570563 ]
Target Details
5. Dual specificity mitogen-activated protein kinase kinase 5
General Function:
Protein tyrosine kinase activity
Specific Function:
Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex. Activation of this pathway appears to play a critical role in protecting cells from stress-induced apoptosis, neuronal survival and cardiac development and angiogenesis.
Gene Name:
MAP2K5
Uniprot ID:
Q13163
Molecular Weight:
50111.385 Da
References
  1. Fabbri A, Travaglione S, Falzano L, Fiorentini C: Bacterial protein toxins: current and potential clinical use. Curr Med Chem. 2008;15(11):1116-25. [18473807 ]
  2. Collier RJ, Young JA: Anthrax toxin. Annu Rev Cell Dev Biol. 2003;19:45-70. [14570563 ]
Target Details
6. Dual specificity mitogen-activated protein kinase kinase 6
General Function:
Protein tyrosine kinase activity
Specific Function:
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.
Gene Name:
MAP2K6
Uniprot ID:
P52564
Molecular Weight:
37492.055 Da
References
  1. Fabbri A, Travaglione S, Falzano L, Fiorentini C: Bacterial protein toxins: current and potential clinical use. Curr Med Chem. 2008;15(11):1116-25. [18473807 ]
  2. Collier RJ, Young JA: Anthrax toxin. Annu Rev Cell Dev Biol. 2003;19:45-70. [14570563 ]
Target Details
7. Dual specificity mitogen-activated protein kinase kinase 7
General Function:
Protein tyrosine kinase activity
Specific Function:
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K4/MKK4, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4/MKK4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The monophosphorylation of JNKs on the Thr residue is sufficient to increase JNK activity indicating that MAP2K7/MKK7 is important to trigger JNK activity, while the additional phosphorylation of the Tyr residue by MAP2K4/MKK4 ensures optimal JNK activation. Has a specific role in JNK signal transduction pathway activated by proinflammatory cytokines. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.
Gene Name:
MAP2K7
Uniprot ID:
O14733
Molecular Weight:
47484.49 Da
References
  1. Fabbri A, Travaglione S, Falzano L, Fiorentini C: Bacterial protein toxins: current and potential clinical use. Curr Med Chem. 2008;15(11):1116-25. [18473807 ]
  2. Collier RJ, Young JA: Anthrax toxin. Annu Rev Cell Dev Biol. 2003;19:45-70. [14570563 ]