Information on EC 3.4.24.83 - anthrax lethal factor endopeptidase

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The expected taxonomic range for this enzyme is: Bacillus

EC NUMBER
COMMENTARY
3.4.24.83
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RECOMMENDED NAME
GeneOntology No.
anthrax lethal factor endopeptidase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
Preferred amino acids around the cleavage site can be denoted BBBBxHx-/-H, in which B denotes Arg or Lys, H denotes a hydrophobic amino acid, and x is any amino acid. The only known protein substrates are mitogen-activated protein (MAP) kinase kinases
show the reaction diagram
From the bacterium Bacilus anthracis that causes anthrax. One of three proteins that are collectively termed anthrax toxin. Cleaves several MAP kinase kinases near their N-termini, preventing them from phosphorylating the downstream mitogen-activated protein kinases
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Preferred amino acids around the cleavage site can be denoted BBBBxHx-/-H, in which B denotes Arg or Lys, H denotes a hydrophobic amino acid, and x is any amino acid. The only known protein substrates are mitogen-activated protein (MAP) kinase kinases
show the reaction diagram
mechanism
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Preferred amino acids around the cleavage site can be denoted BBBBxHx-/-H, in which B denotes Arg or Lys, H denotes a hydrophobic amino acid, and x is any amino acid. The only known protein substrates are mitogen-activated protein (MAP) kinase kinases
show the reaction diagram
pre-steady-state kinetics of anthrax lethal factor proteolysis follows a four-step mechanism as follows: initial substrate binding, rearrangement of the enzyme-substrate complex, a rate-limiting cleavage step, and product release
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Preferred amino acids around the cleavage site can be denoted BBBBxHx-/-H, in which B denotes Arg or Lys, H denotes a hydrophobic amino acid, and x is any amino acid. The only known protein substrates are mitogen-activated protein (MAP) kinase kinases
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of peptide bond
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SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
anthrax lethal factor
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anthrax lethal factor along with its receptor-binding partner protective antigen forms anthrax lethal toxin
anthrax lethal factor
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anthrax lethal factor is part of the bipartite anthrax lethal toxin
anthrax lethal factor
P15917
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anthrax lethal factor
Bacillus anthracis BH450
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anthrax lethal factor protease
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anthrax lethal toxin
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; LT
anthrax lethal toxin
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the pathological actions of anthrax toxin require the activities of its edema factor and lethal factor enzyme components which gain intracellular access via its receptor-binding component, protective antigen
anthrax LF
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Bacillus anthracis lethal toxin
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lethal factor
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lethal factor combines with protective antigen to form antrax lethal toxin
lethal factor
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lethal toxin is secreted by Bacillus anthracis as a bipartite toxin consisting of protective antigen (PA) and lethal factor (LF)
lethal factor
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part of LeTx
lethal factor
Bacillus anthracis 34F2
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-
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lethal factor of anthrax toxin
Q52NH3
the C-terminal region carries out the metalloprotease activity, while the N-terminal domain (residues 1-288) is responsible for protective antigen binding
lethal toxin
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-
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LeTx
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lethal toxin is composed of lethal factor and the protective antigen
LeTx
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protective antigen from Bacillus anthracis binds to cellular receptors, combines with lethal factor forming lethal toxin LeTx, and facilitates the translocation of lethal factor into the cytosol
LeTx
Bacillus anthracis BH450
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protective antigen from Bacillus anthracis binds to cellular receptors, combines with lethal factor forming lethal toxin LeTx, and facilitates the translocation of lethal factor into the cytosol
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LF
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CAS REGISTRY NUMBER
COMMENTARY
477950-41-7
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9001-92-7
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ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
; single mutant strain RP9 producing active lethal factor and inactive edema factor, and double-mutant strain RPLC2 producing inactive lethal factor and edema factor, action in mouse model and in human epithelial lung cells
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Manually annotated by BRENDA team
Bacillus anthracis 34F2
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Manually annotated by BRENDA team
Bacillus anthracis BH450
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
physiological function
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the cytoplasmic delivery of anthrax lethal factor by anthrax toxin receptor ANTXR2 is mediated by cathepsin B and requires lysosomal fusion with anthrax lethal toxin containing endosomes. Binding of protective antigen to ANXTR1 or -2 triggers autophagy, which facilitates the cytoplasmic delivery of ANTXR2-associated anthrax lethal factor. Whereas cells treated with the membrane-permeable cathepsin B inhibitor CA074-Me- orcathepsin B-deficient cells have no defect in fusion of light chain 3-containing autophagic vacuoles with lysosomes, autophagic flux is significantly delayed
physiological function
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translocation of anthrax lethal factor protective antigen-binding domain LFN through the protective antigen pore is triggered by pH gradient. Residues 14-28 at the N-terminus of LFN are required for LFN to inhibit ion conductance through the pore. The translocation of substrate proteins through the protective antigen pore is dependent on the presence of both acidic and basic residues in the unstructured N-terminal region
physiological function
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secreted type-IIA phospholipase A2sPLA2-IIA expression is induced via a sequential MAPK-NF-kappaB activation and anthrax lethal toxin inhibits this expression likely by interfering with the transactivation of NF-kappaB in the nucleus. Anthrax lethal toxin inhibits IL-1b-induced p38 phosphorylation as well as sPLA2-IIA promoter activity in CHO cells. Inhibition of sPLA2-IIA promoter activity is mimicked by co-transfection with dominant negative construct of p38 and reversed by the active form of p38-MAPK. Both anthrax lethal toxin and the dominant negative construct of p38 decrease IL-1b-induced NF-kappaB luciferase activity. Neither anthrax lethal toxin nor specific p-38 inhibitor interfere with LPS-induced IkappaBalpha degradation or NF-kappaB nuclear translocation in guinea pig alveolar macrophages. Subcutaneous administration of anthrax lethal toxin to guinea pig before LPS challenge reduces sPLA2-IIA levels in broncho-alveolar lavages and ear
physiological function
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the anthrax toxin triggers tyrosine phosphorylation of its own receptors, capillary morphogenesis gene 2 and tumor endothelial marker 8, which is required for efficient toxin uptake. Phosphorylation of the receptors is dependent on src-like kinases, which are activated upon toxin binding. src-Dependent phosphorylation of the receptor is required for its subsequent ubiquitination, which in turn is required for clathrin-mediated endocytosis. Uptake of the anthrax toxin and processing of the lethal factor substrate MEK1 are inhibited by silencing of src and fyn, as well as in src and fyn knockout cells
physiological function
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anthrax lethal factor of Bacillus anthracis is a major factor for lethality of anthrax infection
physiological function
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treatment of rat pulmonary microvascular endothelial cells with anthrax lethal toxin (LeTx) increases endothelial barrier permeability and gap formation between endothelial cells through disrupting p38 signaling. LeTxr educes phosphorylation of p38, MAP kinase 2, and HSP27
physiological function
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anthrax lethal toxin is a virulence factor of Bacilillus anthracis that is a bivalent toxin, containing lethal factor and protective Ag proteins, which causes cytotoxicity and altered macrophage function. Anthrax lethal toxin exposure results in early K+ efflux from macrophages associated with caspase-1 activation and increased interleukin-1beta release
physiological function
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the Lethal Toxin is formed when up to three molecules of lethal factor bind a 63 kDA protective antigen heptamer. Anthrax lethal toxin is a major virulence factor of Bacillus anthracis. Fully assembled lethal toxin binds an anthrax toxin receptor with almost 100fold higher affinity than the protective antigen alone
physiological function
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in lethal systemic anthrax, proliferating bacilli secrete large quantities of the toxins lethal factor (LF) and oedema factor (EF), leading to widespread vascular leakage and shock. Coordinated disruption of the Rab11/Sec15 exocyst by anthrax toxins may contribute to toxin-dependent barrier disruption and vascular dysfunction during Bacillus anthracis infection. LF and EF synergistically inhibit Notch signaling and inhibit Rab11/Sec15-dependent recycling
physiological function
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lethal toxin (LeTx) containing lethal factor is the major virulence factor contributing to anthrax. LeTx-mediated MAPKK inhibition alters endothelial cell function
physiological function
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anthrax lethal toxin disrupts endothelial, intestinal epithelial, alveolar-endothelial and blood brain barriers of the host
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
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activation ability of divalent ions decreases in the follwing order: Zn2+ Ca2+ Mn2+ Mg2+, with Mg2+ completely unable to activate the enzyme
Co2+
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Co2+ is capable of directly replacing lethal factors active site Zn2+ to yield a hyperactive enzyme with 2fold higher kcat value and about 2.5fold increased catalytic efficiency
Zn2+
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contains zinc binding motif HEH
Zn2+
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lethal factor along with its receptor-binding partner protective antigen, forms lethal toxin, a critical virulence factor for bacillus anthracis. Lethal factor is a Zn2+ protease; Zn2+ protease
Zn2+
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activation ability of divalent ions decreases in the follwing order: Zn2+ Ca2+ Mn2+ Mg2+, with Mg2+ completely unable to activate the enzyme
Zn2+
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dependent on Zn2+, contains 0.03 mol Zn2+ per mol of protein
Zn2+
P15917
contains zinc
Zn2+
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dependent on
Zn2+
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a zinc-dependent metalloprotease
Mn2+
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activation ability of divalent ions decreases in the follwing order: Zn2+ Ca2+ Mn2+ Mg2+, with Mg2+ completely unable to activate the enzyme
additional information
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Mg2+ is unable to activate
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(1E,6E)-4-(1,3-dithian-2-ylidene)-1,7-difuran-2-ylhepta-1,6-diene-3,5-dione
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(1Z,6E)-4-(1,3-dithian-2-ylidene)-1,7-difuran-2-ylhepta-1,6-diene-3,5-dione
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(2R)-N4-hydroxy-N1-[(2S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]-2-(2-methylpropyl)butanediamide
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inhibitor identified by in silico high-throughput virtual screening protocol
(3S)-N-hydroxy-4-methyl-3-([[(2R)-1-(methylamino)-1-oxo-4-phenylbutan-2-yl]amino]methyl)pentanamide
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inhibitor identified by in silico high-throughput virtual screening protocol
(4E)-4-[(2,4-dihydroxyphenyl)methylidene]-1,2,5-thiadiazolidin-3-one
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(5E)-5-(1,3-benzothiazol-2-ylimino)-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid
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(5Z)-3-(4-hydroxyphenyl)-5-[[5-(4-nitrophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
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(5Z)-3-(4-methoxyphenyl)-2-thioxo-5-([5-[3-(trifluoromethyl)phenyl]furan-2-yl]methylidene)-1,3-thiazolidin-4-one
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(5Z)-3-(furan-2-ylmethyl)-5-[[5-(3-nitrophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
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(5Z)-3-(furan-2-ylmethyl)-5-[[5-(4-nitrophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
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(5Z)-5-[(2,4-dihydroxyphenyl)methylidene]-2-thioxoimidazolidin-4-one
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(5Z)-5-[[5-(2-nitrophenyl)furan-2-yl]methylidene]-3-(2-phenylethyl)-2-thioxo-1,3-thiazolidin-4-one
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(5Z)-5-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
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(5Z)-5-[[5-(4-bromo-3-chlorophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
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(5Z)-5-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-3-(furan-2-ylmethyl)-2-thioxo-1,3-thiazolidin-4-one
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(5Z)-5-[[5-(4-fluorophenyl)furan-2-yl]methylidene]-3-prop-2-en-1-yl-2-thioxo-1,3-thiazolidin-4-one
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(9E)-N-[2-(2,4,5-trihydroxyphenyl)ethyl]octadec-9-enamide
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(9E)-N-[2-(3,4,5-trihydroxyphenyl)ethyl]octadec-9-enamide
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(9Z)-N-(3,4-dihydroxybenzyl)octadec-9-enamide
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(9Z)-N-[2-(3,4-dihydroxyphenyl)ethyl]octadec-9-enamide
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(D-R)9LPY-CO-NHOH
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-
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(D-R)9VLR-CO-NHOH
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-
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(D-R)9WLM-CO-NHOH
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1-[(1S,2R,3S,4S,6S)-2-amino-6-[(6-amino-2,6-dideoxy-a-D-arabino-hexopyranosyl)oxy]-3,4-dihydroxycyclohexyl]guanidine
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-
2-([benzyl(ethyl)amino]methyl)-6-iodo-4-methylphenol
-
inhibitor identified by in silico high-throughput virtual screening protocol
2-chloro-4-(5-[(Z)-[(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]methyl]furan-2-yl)benzoic acid
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-
2-chloro-4-(5-[(Z)-[4-oxo-3-(pyridin-3-ylmethyl)-2-thioxo-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl)benzoic acid
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2-chloro-4-[5-[(Z)-(4-oxo-3-prop-2-en-1-yl-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]furan-2-yl]benzoic acid
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2-chloro-4-[[(4Z)-4-[[4-(methylsulfanyl)phenyl]methylidene]-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]sulfamoyl]benzoic acid
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2-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)benzoic acid
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2-chloro-5-[(4Z)-3-methyl-4-[[4-(1-methylethyl)phenyl]methylidene]-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
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2-chloro-5-[(4Z)-4-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
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2-chloro-5-[[(4Z)-4-[[4-(methylsulfanyl)phenyl]methylidene]-5-oxo-2-phenylimidazolidin-1-yl]sulfamoyl]benzoic acid
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-
2-hydroxy-5-(5-[(Z)-[2-imino-4-oxo-3-(1,3-thiazol-2-yl)-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl)benzoic acid
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-
2-hydroxy-5-[5-[(Z)-[2-imino-3-[imino(methylsulfanyl)methyl]-4-oxo-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl]benzoic acid
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-
2-thiolacetyl-YPM-amide
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2-[[(2-amino-2-carboxyethyl)sulfanyl]methyl]-5-phenylfuran-3-carboxylic acid
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3,3'-methanediylbis(6-hydroxybenzoic acid)
-
-
3,4-dihydroxy-N'-[(1Z)-(2-hydroxy-5-nitrophenyl)methylidene]benzohydrazide
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3-(5-[(Z)-[1-(3-chlorophenyl)-3,5-dioxopyrazolidin-4-ylidene]methyl]furan-2-yl)benzoic acid
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3-[(5E)-5-[(3-bromo-4-methoxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
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-
3-[(5Z)-5-[(3-bromo-4-methoxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
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3-[(5Z)-5-[[5-(2-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
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3-[(5Z)-5-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
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3-[(5Z)-5-[[5-(4-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
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-
4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid
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4-(5-[(Z)-[3-(4-nitrophenyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl)benzoic acid
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4-[(5Z)-5-[[5-(3-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]butanoic acid
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4-[(5Z)-5-[[5-(4-bromophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]butanoic acid
-
-
4-[5-[(E)-(5-cyano-2-hydroxy-4-methyl-6-oxopyridin-3(6H)-ylidene)methyl]furan-2-yl]benzenesulfonamide
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4-[5-[(Z)-(3-benzyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]furan-2-yl]benzoic acid
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-
4-[5-[(Z)-[4-oxo-2-thioxo-3-[3-(trifluoromethyl)phenyl]-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl]benzoic acid
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4-[[(4-chlorophenyl)carbamoyl]amino]-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide
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-
5-(4-carboxy-3-chlorophenyl)-2-[(Z)-[(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]methyl]furan-3-carboxylic acid
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-
5-bromo-2-(5-[(Z)-[1-(3-carboxyphenyl)-5-oxo-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene]methyl]furan-2-yl)benzoic acid
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-
5-bromo-2-(5-[(Z)-[1-(3-carboxyphenyl)-5-oxo-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene]methyl]uran-2-yl)benzoic acid
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5-chloro-2-[5-[(E)-(1,5-dioxo-6,7,8,9-tetrahydro-5H-[1]benzothieno[3,2-e][1,3]thiazolo[3,2-a]pyrimidin-2(1H)-ylidene)methyl]furan-2-yl]benzoic acid
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-
6-S-(3-aminopropyl)-6-thio-beta-D-cyclodextrin
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6-S-(8-aminooctyl)-6-thio-beta-D-cyclodextin
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6-S-[3-(aminomethyl)benzyl]-6-thio-beta-D-cyclodextrin
-
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6-S-[4-(aminomethyl)benzyl]-6-thio-beta-D-cyclodextrin
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8-[(E)-[[4-(2,3-dihydro-1,3-thiazol-2-ylsulfamoyl)phenyl]imino]methyl]-4H-1,3-benzodioxine-6-carboxylic acid
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-
acetyl-GYbetaARRRRRRRRVLR-hydroxamate
-
-
AcG-Y-betaA-R-R-R-A-R-R-R-R-V-L-R-4-nitroanilide
-
substrate inhibition
-
AcM-L-A-R-R-R-P-V-L-P-4-nitroanilide
-
substrate inhibition
AcR-R-R-R-V-L-R-4-methylcoumarin-7-amide
-
substrate inhibition
AcR-R-R-R-V-L-R-4-nitroanilide
-
substrate inhibition
C-terminal dimer of the protective antigen binding domain of anthrax lethal factor
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-
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C-terminal trimer of the protective antigen binding domain of anthrax lethal factor
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celastrol
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celastrol, a quinine methide triterpene derived from a plant extract used in herbal medicine, inhibits lethal toxin-induced death of RAW264.7 murine macrophages. Celastrol does not prevent cleavage of mitogen activated protein kinase kinase 1. Celastrol confers almost complete protection when it is added up to 1.5 h after intoxication, indicating that it can rescue cells in the late stages of intoxication. Celastrol inhibits the proteasome-dependent degradation of proteins in RAW264.7 cells. Celastrol blocks stimulation of IL-18 processing, indicating that celastrol acts upstream of inflammasome activation
fluvastatin
-
statins attenuate lethal factor action action. statin treatment maintains macrophage cell viability above 60% of untreated control cells even after 9 h of lethal toxin treatment. Statins decrease mitogen-activated protein kinase cleavage
mevastatin
-
statins attenuate lethal factor action action. statin treatment maintains macrophage cell viability above 60% of untreated control cells even after 9 h of lethal toxin treatment. Statins decrease mitogen-activated protein kinase cleavage
N'1,N'4-bis[(1E)-(2-hydroxy-5-methylphenyl)methylidene]benzene-1,4-dicarbohydrazide
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-
N'1-[(1E)-(2-hydroxyphenyl)methylidene]-N'4-[(1Z)-(2-hydroxyphenyl)methylidene]benzene-1,4-dicarbohydrazide
-
-
N'1-[(1E)-(5-fluoro-2-hydroxyphenyl)methylidene]-N'4-[(1Z)-(5-fluoro-2-hydroxyphenyl)methylidene]benzene-1,4-dicarbohydrazide
-
-
N,N''',N'''''',N'''''''''-[[(1R,3S,4S,6R)-4,6-dicarbamimidamidocyclohexane-1,3-diyl]bis(oxybenzene-1,2,4-triyl)]tetraguanidine
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-
N,N'''-[(1R,3S)-4-(2,4-dicarbamimidamidonaphthalen-1-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
N,N'''-[(1R,3S)-4-(2-amino-1H-benzimidazol-7-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
N,N'''-[(1R,3S,4R,5R,6S)-4-[(2,6-dicarbamimidamido-2,6-dideoxy-a-D-glucopyranosyl)oxy]-5,6-dihydroxycyclohexane-1,3-diyl]diguanidine
-
-
N,N'''-[(1R,3S,4R,6R)-4-(2-carbamimidamidophenyl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
N,N'''-[(1R,3S,4R,6R)-4-(4-carbamimidamidonaphthalen-1-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
N,N'''-[(1R,3S,4R,6R)-4-(4-carbamimidamidophenyl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
N,N'''-[(1R,3S,4S,6R)-4-(3-carbamimidamidopyridin-2-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
N,N'''-[(1R,3S,4S,6R)-4-(5-carbamimidamidopyridin-2-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
N,N'''-[(1S,2R,3S,4S,6S)-6-[(6-amino-2-carbamimidamido-2,6-dideoxy-a-D-glucopyranosyl)oxy]-3,4-dihydroxycyclohexane-1,2-diyl]diguanidine
-
-
N,N'''-[4-[(1R,2S,4R,5R)-2,4-dicarbamimidamido-5-hydroxycyclohexyl]benzene-1,3-diyl]diguanidine
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-
N-hydroxy-4-[2-[(9E)-octadec-9-enoylamino]ethyl]benzamide
-
-
N-hydroxy-4-[[(9Z)-octadec-9-enoylamino]methyl]benzamide
-
-
N-oleoyldopamine
-
uncompetitive inhibition
N-terminal dimer of the protective antigen binding domain of anthrax lethal factor
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-
-
N-terminal trimer of the protective antigen binding domain of anthrax lethal factor
-
-
-
neamine
-
mixed-type, noncompetitive inhibition
neomycin B
-
mixed-type, noncompetitive inhibition
NH4Cl
-
blocks mitogen-activated protein kinase kinase 3 proteolysis in anthrax lethal toxin-treated macrophages
simvastatin
-
statins attenuate lethal factor action action. statin treatment maintains macrophage cell viability above 60% of untreated control cells even after 9 h of lethal toxin treatment. Statins decrease mitogen-activated protein kinase cleavage
verapamil
-
blocks mitogen-activated protein kinase kinase 3 proteolysis in anthrax lethal toxin-treated macrophages
[(5Z)-5-([5-[2-chloro-5-(trifluoromethyl)phenyl]furan-2-yl]methylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(2-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(3-chloro-4-methoxyphenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(3-chloro-4-sulfamoylphenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(3-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(4-bromophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(4-chloro-2-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[(5Z)-5-[[5-(4-iodophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]acetic acid
-
-
[4-[(5Z)-5-(furan-2-ylmethylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]phenyl]acetic acid
-
-
[[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]sulfanyl]acetic acid
-
-
MKARRKKVYP-NHOH
-
-
additional information
-
peptides that can block toxin assembly. Minimal peptide sequence TYWWLD can be used to develop potent polyvalent inhibitors of anthrax toxin
-
additional information
-
complete caspase-1 inhibition is required to block antrax lethal toxin-mediated necrosis
-
additional information
-
Ca2+-free medium completely prevents mitogen-activated protein kinase kinase 3 proteolysis in anthrax lethal toxin-treated macrophages
-
additional information
-
statin-mediated effects on lethal toxin action are attributable to disruption of Rho GTPases. The Rho GTPase-inactivating toxin, toxin B, does not significantly affect lethal toxin binding or internalization, suggesting that the Rho GTPases regulate trafficking and/or localization of lethal toxin once internalized
-
additional information
-
fusion protein of N-terminal 27 amino acids deletion of protective antigen-binding domain of anthrax lethal factor Delta27LFn and protective antigen-binding domain of edema factor is a 62-fold more potent toxin inhibitor than protective antigen-binding domain of anthrax lethal factor or protective antigen-binding domain of edema factor in a cell model of intoxication, and this increased activity corresponds to a 39-fold higher protective antigen-binding affinity by Biacore analysis. The fusion protein can protect the highly susceptible Fischer 344 rats from anthrax lethal toxin challenge
-
additional information
-
micromolar-level anthrax lethal factor inhibition can be attained by compounds with non-hydroxamate zinc-binding groups that exhibit monodentate zinc chelation as long as key hydrophobic interactions with at least two anthrax lethal factor subsites are retained
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
matrix metalloproteinase
-
matrix-metalloproteinase-activated lethal toxin has much lower in vivo toxicity than wild type toxin
-
matrix metalloproteinase 2
-
-
-
matrix metalloproteinase 9
-
-
-
additional information
-
monoclonal antibodies PA I 3F3-2-2, PA 2II 2F9-1-1, and PA I 6C3-1-1, directed against protective antigen of Bacillus anthracis, enhance lethal toxin activity in vivo
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0018
-
AcG-Y-betaA-R-R-R-A-R-R-R-R-V-L-R-4-nitroanilide
-
-
-
0.03
-
AcM-L-A-R-R-R-P-V-L-P-4-nitroanilide
-
-
0.082
-
AcR-R-R-R-V-L-R-4-methylcoumarin-7-amide
-
-
0.0095
-
AcR-R-R-R-V-L-R-4-nitroanilide
-
-
0.0023
-
fluorescein-QRRKKVYPYPME
-
wild-type, pH 7.4, 37C
-
0.0174
-
fluorescein-QRRKKVYPYPME
-
mutant E687D, pH 7.4, 37C
-
0.042
-
fluorescein-QRRKKVYPYPME
-
mutant H690A, pH 7.4, 37C
-
0.0086
-
fluorescence resonance energy transfer peptide MAPKKide
-
in 20 mM HEPES, pH 7.4, at 25C
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.01
-
fluorescein-QRRKKVYPYPME
-
mutant H690A, pH 7.4, 37C
-
0.1
-
fluorescein-QRRKKVYPYPME
-
mutant E687D, pH 7.4, 37C
-
0.52
-
fluorescein-QRRKKVYPYPME
-
wild-type, pH 7.4, 37C
-
kcat/KM VALUE [1/mMs-1]
kcat/KM VALUE [1/mMs-1] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.000025
-
Mca-KKPTPIQLN-Dnp
-
in 0.1 M HEPES, pH 7.4 at 37C
0
0.0013
-
Mca-KKVYPYPMEK-Dnp
-
in 0.1 M HEPES, pH 7.4 at 37C
0
0.0023
-
Mca-KKWLMYPLEK-Dnp
-
in 0.1 M HEPES, pH 7.4 at 37C
0
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0027
-
(1E,6E)-4-(1,3-dithian-2-ylidene)-1,7-difuran-2-ylhepta-1,6-diene-3,5-dione
-
-
0.0027
-
(1Z,6E)-4-(1,3-dithian-2-ylidene)-1,7-difuran-2-ylhepta-1,6-diene-3,5-dione
-
-
0.0011
-
(4E)-4-[(2,4-dihydroxyphenyl)methylidene]-1,2,5-thiadiazolidin-3-one
-
-
0.0042
-
(5E)-5-(1,3-benzothiazol-2-ylimino)-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid
-
-
0.0011
-
(5Z)-5-[(2,4-dihydroxyphenyl)methylidene]-2-thioxoimidazolidin-4-one
-
-
0.0017
-
(9E)-N-[2-(3,4,5-trihydroxyphenyl)ethyl]octadec-9-enamide
-
-
0.0022
-
(9Z)-N-(3,4-dihydroxybenzyl)octadec-9-enamide
-
-
0.003
-
(9Z)-N-[2-(3,4-dihydroxyphenyl)ethyl]octadec-9-enamide
-
-
0.00000732
-
(D-R)9LPY-CO-NHOH
-
in 0.1 M HEPES, pH 7.4 at 37C
-
0.00000145
-
(D-R)9VLR-CO-NHOH
-
in 0.1 M HEPES, pH 7.4 at 37C
-
0.00000028
-
(D-R)9WLM-CO-NHOH
-
in 0.1 M HEPES, pH 7.4 at 37C
-
0.0024
-
2-chloro-4-(5-[(Z)-[(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]methyl]furan-2-yl)benzoic acid
-
-
0.0025
-
2-chloro-4-[[(4Z)-4-[[4-(methylsulfanyl)phenyl]methylidene]-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]sulfamoyl]benzoic acid
-
-
0.0056
-
2-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)benzoic acid
-
-
0.0009
-
2-chloro-5-[(4Z)-3-methyl-4-[[4-(1-methylethyl)phenyl]methylidene]-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
-
-
0.0021
-
2-chloro-5-[(4Z)-4-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
-
-
0.0107
-
2-chloro-5-[(4Z)-4-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
-
-
0.0036
-
2-chloro-5-[[(4Z)-4-[[4-(methylsulfanyl)phenyl]methylidene]-5-oxo-2-phenylimidazolidin-1-yl]sulfamoyl]benzoic acid
-
-
0.0031
-
2-hydroxy-5-(5-[(Z)-[2-imino-4-oxo-3-(1,3-thiazol-2-yl)-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0031
-
2-hydroxy-5-[5-[(Z)-[2-imino-3-[imino(methylsulfanyl)methyl]-4-oxo-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl]benzoic acid
-
-
0.011
-
2-thiolacetyl-YPM-amide
-
-
0.0029
-
2-[[(2-amino-2-carboxyethyl)sulfanyl]methyl]-5-phenylfuran-3-carboxylic acid
-
-
0.0024
-
3,3'-methanediylbis(6-hydroxybenzoic acid)
-
-
0.0054
-
3-(5-[(Z)-[1-(3-chlorophenyl)-3,5-dioxopyrazolidin-4-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0072
-
3-(5-[(Z)-[1-(3-chlorophenyl)-3,5-dioxopyrazolidin-4-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0033
-
3-[(5E)-5-[(3-bromo-4-methoxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
-
-
0.0033
-
3-[(5Z)-5-[(3-bromo-4-methoxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
-
-
0.0015
-
4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid
-
-
0.0054
-
4-[5-[(E)-(5-cyano-2-hydroxy-4-methyl-6-oxopyridin-3(6H)-ylidene)methyl]furan-2-yl]benzenesulfonamide
-
-
0.0009
-
4-[[(4-chlorophenyl)carbamoyl]amino]-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide
-
-
0.0024
-
5-(4-carboxy-3-chlorophenyl)-2-[(Z)-[(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]methyl]furan-3-carboxylic acid
-
-
0.0016
-
5-bromo-2-(5-[(Z)-[1-(3-carboxyphenyl)-5-oxo-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0016
-
5-bromo-2-(5-[(Z)-[1-(3-carboxyphenyl)-5-oxo-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene]methyl]uran-2-yl)benzoic acid
-
-
0.0008
-
5-chloro-2-[5-[(E)-(1,5-dioxo-6,7,8,9-tetrahydro-5H-[1]benzothieno[3,2-e][1,3]thiazolo[3,2-a]pyrimidin-2(1H)-ylidene)methyl]furan-2-yl]benzoic acid
-
-
0.0011
-
5-chloro-2-[5-[(E)-(1,5-dioxo-6,7,8,9-tetrahydro-5H-[1]benzothieno[3,2-e][1,3]thiazolo[3,2-a]pyrimidin-2(1H)-ylidene)methyl]furan-2-yl]benzoic acid
-
-
0.0018
-
8-[(E)-[[4-(2,3-dihydro-1,3-thiazol-2-ylsulfamoyl)phenyl]imino]methyl]-4H-1,3-benzodioxine-6-carboxylic acid
-
-
0.000001
-
acetyl-GYbetaARRRRRRRRVLR-hydroxamate
-
-
0.036
-
AcG-Y-betaA-R-R-R-A-R-R-R-R-V-L-R-4-nitroanilide
-
-
-
0.6
-
AcM-L-A-R-R-R-P-V-L-P-4-nitroanilide
-
-
0.17
-
AcR-R-R-R-V-L-R-4-methylcoumarin-7-amide
-
-
0.19
-
AcR-R-R-R-V-L-R-4-nitroanilide
-
-
0.002
-
GM6001
-
-
0.000001
-
MKARRKKVYP-NHOH
-
-
0.06
-
N-hydroxy-4-[2-[(9E)-octadec-9-enoylamino]ethyl]benzamide
-
-
0.0062
-
N-hydroxy-4-[[(9Z)-octadec-9-enoylamino]methyl]benzamide
-
-
0.003
-
N-oleoyldopamine
-
-
0.013
-
neamine
-
in 20 mM HEPES, pH 7.4, at 25C
0.000007
-
neomycin B
-
-
0.00028
-
neomycin B
-
in 20 mM HEPES, pH 7.4, at 25C
0.000032
-
[(5Z)-5-([5-[2-chloro-5-(trifluoromethyl)phenyl]furan-2-yl]methylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.0009
-
[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]acetic acid
-
-
0.0016
-
[[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]sulfanyl]acetic acid
-
-
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.003
-
(1E,6E)-4-(1,3-dithian-2-ylidene)-1,7-difuran-2-ylhepta-1,6-diene-3,5-dione
-
-
0.003
-
(1Z,6E)-4-(1,3-dithian-2-ylidene)-1,7-difuran-2-ylhepta-1,6-diene-3,5-dione
-
-
0.0102
-
(2R)-N4-hydroxy-N1-[(2S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]-2-(2-methylpropyl)butanediamide
-
pH 8.0, 37C
0.0071
-
(3S)-N-hydroxy-4-methyl-3-([[(2R)-1-(methylamino)-1-oxo-4-phenylbutan-2-yl]amino]methyl)pentanamide
-
pH 8.0, 37C
0.0034
-
(4E)-4-[(2,4-dihydroxyphenyl)methylidene]-1,2,5-thiadiazolidin-3-one
-
-
0.0077
-
(5E)-5-(1,3-benzothiazol-2-ylimino)-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid
-
-
0.0377
-
(5Z)-3-(4-hydroxyphenyl)-5-[[5-(4-nitrophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
-
-
0.3
-
(5Z)-3-(4-methoxyphenyl)-2-thioxo-5-([5-[3-(trifluoromethyl)phenyl]furan-2-yl]methylidene)-1,3-thiazolidin-4-one
-
-
0.0383
-
(5Z)-3-(furan-2-ylmethyl)-5-[[5-(3-nitrophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
-
-
0.0126
-
(5Z)-3-(furan-2-ylmethyl)-5-[[5-(4-nitrophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
-
-
0.0034
-
(5Z)-5-[(2,4-dihydroxyphenyl)methylidene]-2-thioxoimidazolidin-4-one
-
-
0.0319
-
(5Z)-5-[[5-(2-nitrophenyl)furan-2-yl]methylidene]-3-(2-phenylethyl)-2-thioxo-1,3-thiazolidin-4-one
-
-
0.0074
-
(5Z)-5-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
-
-
0.007
-
(5Z)-5-[[5-(4-bromo-3-chlorophenyl)furan-2-yl]methylidene]-2-thioxo-1,3-thiazolidin-4-one
-
-
0.15
-
(5Z)-5-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-3-(furan-2-ylmethyl)-2-thioxo-1,3-thiazolidin-4-one
-
-
0.05
-
(5Z)-5-[[5-(4-fluorophenyl)furan-2-yl]methylidene]-3-prop-2-en-1-yl-2-thioxo-1,3-thiazolidin-4-one
-
-
0.07
-
(9E)-N-[2-(2,4,5-trihydroxyphenyl)ethyl]octadec-9-enamide
-
-
0.013
-
(9E)-N-[2-(3,4,5-trihydroxyphenyl)ethyl]octadec-9-enamide
-
-
0.015
-
(9Z)-N-(3,4-dihydroxybenzyl)octadec-9-enamide
-
-
0.015
-
(9Z)-N-[2-(3,4-dihydroxyphenyl)ethyl]octadec-9-enamide
-
-
0.0007
-
1-[(1S,2R,3S,4S,6S)-2-amino-6-[(6-amino-2,6-dideoxy-a-D-arabino-hexopyranosyl)oxy]-3,4-dihydroxycyclohexyl]guanidine
-
-
0.0495
-
2-([benzyl(ethyl)amino]methyl)-6-iodo-4-methylphenol
-
pH 8.0, 37C
0.0042
-
2-chloro-4-(5-[(Z)-[(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]methyl]furan-2-yl)benzoic acid
-
-
0.0099
-
2-chloro-4-(5-[(Z)-[4-oxo-3-(pyridin-3-ylmethyl)-2-thioxo-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0027
-
2-chloro-4-[5-[(Z)-(4-oxo-3-prop-2-en-1-yl-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]furan-2-yl]benzoic acid
-
-
0.0036
-
2-chloro-4-[[(4Z)-4-[[4-(methylsulfanyl)phenyl]methylidene]-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]sulfamoyl]benzoic acid
-
-
0.0068
-
2-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)benzoic acid
-
-
0.0079
-
2-chloro-5-[(4Z)-3-methyl-4-[[4-(1-methylethyl)phenyl]methylidene]-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
-
-
0.0021
-
2-chloro-5-[(4Z)-4-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
-
-
0.0107
-
2-chloro-5-[(4Z)-4-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
-
-
0.0025
-
2-chloro-5-[[(4Z)-4-[[4-(methylsulfanyl)phenyl]methylidene]-5-oxo-2-phenylimidazolidin-1-yl]sulfamoyl]benzoic acid
-
-
0.0048
-
2-hydroxy-5-(5-[(Z)-[2-imino-4-oxo-3-(1,3-thiazol-2-yl)-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0048
-
2-hydroxy-5-[5-[(Z)-[2-imino-3-[imino(methylsulfanyl)methyl]-4-oxo-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl]benzoic acid
-
-
0.0036
-
2-[[(2-amino-2-carboxyethyl)sulfanyl]methyl]-5-phenylfuran-3-carboxylic acid
-
-
0.0031
-
3,3'-methanediylbis(6-hydroxybenzoic acid)
-
-
0.2
-
3,4-dihydroxy-N'-[(1Z)-(2-hydroxy-5-nitrophenyl)methylidene]benzohydrazide
-
DS-998
0.0083
-
3-(5-[(Z)-[1-(3-chlorophenyl)-3,5-dioxopyrazolidin-4-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0105
-
3-(5-[(Z)-[1-(3-chlorophenyl)-3,5-dioxopyrazolidin-4-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0044
-
3-[(5E)-5-[(3-bromo-4-methoxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
-
-
0.0044
-
3-[(5Z)-5-[(3-bromo-4-methoxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
-
-
0.0128
-
3-[(5Z)-5-[[5-(2-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
-
-
0.0008
-
3-[(5Z)-5-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
-
-
0.0027
-
3-[(5Z)-5-[[5-(4-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid
-
-
0.0043
-
4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid
-
-
0.0048
-
4-(5-[(Z)-[3-(4-nitrophenyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.02
-
4-[(5Z)-5-[[5-(3-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]butanoic acid
-
-
0.0023
-
4-[(5Z)-5-[[5-(4-bromophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]butanoic acid
-
-
0.0083
-
4-[5-[(E)-(5-cyano-2-hydroxy-4-methyl-6-oxopyridin-3(6H)-ylidene)methyl]furan-2-yl]benzenesulfonamide
-
-
0.006
-
4-[5-[(Z)-(3-benzyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]furan-2-yl]benzoic acid
-
-
0.0029
-
4-[5-[(Z)-[4-oxo-2-thioxo-3-[3-(trifluoromethyl)phenyl]-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl]benzoic acid
-
-
0.0039
-
4-[[(4-chlorophenyl)carbamoyl]amino]-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide
-
-
0.0042
-
5-(4-carboxy-3-chlorophenyl)-2-[(Z)-[(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]methyl]furan-3-carboxylic acid
-
-
0.0017
-
5-bromo-2-(5-[(Z)-[1-(3-carboxyphenyl)-5-oxo-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene]methyl]furan-2-yl)benzoic acid
-
-
0.0017
-
5-bromo-2-(5-[(Z)-[1-(3-carboxyphenyl)-5-oxo-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene]methyl]uran-2-yl)benzoic acid
-
-
0.0008
-
5-chloro-2-[5-[(E)-(1,5-dioxo-6,7,8,9-tetrahydro-5H-[1]benzothieno[3,2-e][1,3]thiazolo[3,2-a]pyrimidin-2(1H)-ylidene)methyl]furan-2-yl]benzoic acid
-
-
0.0029
-
6-S-(3-aminopropyl)-6-thio-beta-D-cyclodextrin
-
-
0.0003
-
6-S-(8-aminooctyl)-6-thio-beta-D-cyclodextin
-
-
0.0005
-
6-S-[3-(aminomethyl)benzyl]-6-thio-beta-D-cyclodextrin
-
-
0.0007
-
6-S-[4-(aminomethyl)benzyl]-6-thio-beta-D-cyclodextrin
-
-
0.0093
-
8-[(E)-[[4-(2,3-dihydro-1,3-thiazol-2-ylsulfamoyl)phenyl]imino]methyl]-4H-1,3-benzodioxine-6-carboxylic acid
-
-
0.08
-
N'1,N'4-bis[(1E)-(2-hydroxy-5-methylphenyl)methylidene]benzene-1,4-dicarbohydrazide
-
-
0.05
-
N'1-[(1E)-(2-hydroxyphenyl)methylidene]-N'4-[(1Z)-(2-hydroxyphenyl)methylidene]benzene-1,4-dicarbohydrazide
-
-
0.05
-
N'1-[(1E)-(5-fluoro-2-hydroxyphenyl)methylidene]-N'4-[(1Z)-(5-fluoro-2-hydroxyphenyl)methylidene]benzene-1,4-dicarbohydrazide
-
-
0.00065
-
N,N''',N'''''',N'''''''''-[[(1R,3S,4S,6R)-4,6-dicarbamimidamidocyclohexane-1,3-diyl]bis(oxybenzene-1,2,4-triyl)]tetraguanidine
-
-
0.0107
-
N,N'''-[(1R,3S)-4-(2,4-dicarbamimidamidonaphthalen-1-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
0.1537
-
N,N'''-[(1R,3S)-4-(2-amino-1H-benzimidazol-7-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
0.0007
-
N,N'''-[(1R,3S,4R,5R,6S)-4-[(2,6-dicarbamimidamido-2,6-dideoxy-a-D-glucopyranosyl)oxy]-5,6-dihydroxycyclohexane-1,3-diyl]diguanidine
-
-
0.0306
-
N,N'''-[(1R,3S,4R,6R)-4-(2-carbamimidamidophenyl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
0.0314
-
N,N'''-[(1R,3S,4R,6R)-4-(4-carbamimidamidonaphthalen-1-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
0.0149
-
N,N'''-[(1R,3S,4R,6R)-4-(4-carbamimidamidophenyl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
0.0041
-
N,N'''-[(1R,3S,4S,6R)-4-(3-carbamimidamidopyridin-2-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
0.0066
-
N,N'''-[(1R,3S,4S,6R)-4-(5-carbamimidamidopyridin-2-yl)-6-hydroxycyclohexane-1,3-diyl]diguanidine
-
-
0.0005
-
N,N'''-[(1S,2R,3S,4S,6S)-6-[(6-amino-2-carbamimidamido-2,6-dideoxy-a-D-glucopyranosyl)oxy]-3,4-dihydroxycyclohexane-1,2-diyl]diguanidine
-
-
0.0006
-
N,N'''-[4-[(1R,2S,4R,5R)-2,4-dicarbamimidamido-5-hydroxycyclohexyl]benzene-1,3-diyl]diguanidine
-
-
0.032
-
N-hydroxy-4-[2-[(9E)-octadec-9-enoylamino]ethyl]benzamide
-
-
0.042
-
N-hydroxy-4-[[(9Z)-octadec-9-enoylamino]methyl]benzamide
-
-
0.015
-
N-oleoyldopamine
-
-
0.0031
-
[(5Z)-5-[[5-(2-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.000265
-
[(5Z)-5-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.000298
-
[(5Z)-5-[[5-(3-chloro-4-methoxyphenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.0091
-
[(5Z)-5-[[5-(3-chloro-4-sulfamoylphenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.0031
-
[(5Z)-5-[[5-(3-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.00085
-
[(5Z)-5-[[5-(4-bromophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.0005
-
[(5Z)-5-[[5-(4-chloro-2-nitrophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.0009
-
[(5Z)-5-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.0055
-
[(5Z)-5-[[5-(4-iodophenyl)furan-2-yl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
-
-
0.0076
-
[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]acetic acid
-
-
0.14
-
[4-[(5Z)-5-(furan-2-ylmethylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]phenyl]acetic acid
-
-
0.0029
-
[[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]sulfanyl]acetic acid
-
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.4
-
-
assay at
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
additional information
-
anthrax lethal toxin binds and enters murine neutrophils
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Bacillus anthracis BH450
-
-
-
Manually annotated by BRENDA team
-
Bacillus anthracis produces membrane-derived vesicles containing biologically active toxins including lethal factor
Manually annotated by BRENDA team
Bacillus anthracis 34F2
-
Bacillus anthracis produces membrane-derived vesicles containing biologically active toxins including lethal factor
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
89000
-
-
SDS-PAGE
90000
-
Q52NH3
SDS-PAGE
90000
-
-
SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 710000, lethal toxin, SDS-PAGE; x * 91000, lethal factor, SDS-PAGE
?
-
x * 90000, SDS-PAGE
monomer
P15917
1 * 90000, the protein is monomeric in solution, based on gel filtration
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
docking and molecular dynamics calculations to examine the anthrax lethal factor-MEK/MKK interaction along the catalytic channel up to a distance of 20 A from the zinc atom. The Zn-bound water molecule is predicted to form hydrogen bonds with the carbonyl oxygen of Ile, i.e. P1' of substrates MEK1, MKK3b, Leu, ie. P1' of substrate MKK4-1, and Leu, ie. P2 of substrate MKK6b as well as with the hydroxyl group of Thr, i.e. P2' of substrate MKK4-2. This hydrogen bond is an additional contact to the already existing polarization of the carbonyl oxygen between Zn and Glu687 carboxylate
-
in complex with N terminus of MAPKK-2
-
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-20C, purified lethal toxin, at least 3 months, no loss of activity
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
His-Trap HP nickel column chromatography, ammonium sulfate precipitation, and phenyl-Sepharose column chromatography
Q52NH3
Ni-NTA agarose column chromatography
-
Q Sepharose column chromatography and Superdex 200 gel filtration
-
Superose 6 gel filtration
-
the recombinant LFn fusion proteins contain a vector-encoded His6 tag at the amino terminus and are purified by Ni2+-affinity chromatography to greater than 95% purity as determined by Coomassie staining
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expressed in Bacillus megaterium
-
expressed in Escherichia coli BL21 DE3 Star cells
Q52NH3
expressed in Escherichia coli periplasm
-
expression in Escherichia coli
-
fusion protein between lethal factor and the catalytic domain of diphtheria toxin is expressed in Escherichia coli BL21(DE3) cells
-
recombinant anthrax lethal toxin proteins consisting a model CD4 T-cell epitope from chicken ovalbumin (Ova) fused to nontoxic lethal factor (LFn). The antigen tags are generated by annealing single-stranded DNA oligonucleotides to form double-stranded DNA Plasmids are transformed into Escherichia coli BL21
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
E678A
-
mutant fails to induce cell death
E678C
-
catalytically inactive
E687C
-
inactive
E687D
-
mutation in metal-binding site, decrease in catalytic activity
E720C
-
catalytic mutant
H686A
-
inactive
H690A
-
mutation in metal-binding site, decrease in catalytic activity
H690A
-
inactive
K518E/E682G
-
mutation in anthrax lethal factor, mutant is defective at causing pyroptosis in RAW 264.7 cells and at activating the Nlrp1b inflammasome in a heterologous expression system. LF-K518E /E682G does not exhibit an overall impairment of function and LF-K518E /E682G efficiently kills melanoma cells
additional information
-
the responses of various murine dendritic cells to anthrax lethal toxin is investigated: Using a variety of knockout mice, it is shown that depending on the mouse strain, death of bone marrow-derived dendritic cells and macrophages is mediated either by a fast Nalp1b, a member of the NOD-like receptor family, and caspase-1-dependent, or by a slow caspase-1-independent pathway that is triggered by the impairment of MEK1/2 pathways. Caspase-1-independent death is observed in cells of different genetic backgrounds and interestingly occurs only in immature dendritic cells. Maturation, triggered by different types of stimuli, leads to full protection of dendritic cells
additional information
-
in order to examine the role of protective antigen a lethal factor (LFn) fusion protein bearing two epitopes from Ova, one restricted by MHC-II and one restricted by MHC-I is generated. This single LFn fusion protein is capable of stimulating both ovalbumin-specific CD4+ and ovalbumin-specific CD8+ T-cell responses in mice; it is investigated whether lethal factor (LFn) fusion proteins and protective antigen can also be used to deliver antigen to the MHC-II pathway for the stimulation of antigen-specific CD4+ T-cells. A CD4+ T-cell epitope from chicken ovalbumin is fused to nontoxic LFn and demonstrates that this recombinant protein induces an ovalbumin-specific CD4+ T-cell response both in vitro and in mice
additional information
-
effects of anthrax lethal toxin on human primary keratinocytes are investigated. Cells are resistant to LeTx-triggered cytotoxicity, even though all the MEK (MEK1 through 7), except MEK5, are cleaved in these cells. Over the 24 h time course of the study, the levels of two pro-inflammatory molecules, interleukin-6 and granulocyte-macrophage colony stimulating factor (GM-CSF), decline, but the production of RANTES, a known chemoattractant for multiple types of immune cells, increases
additional information
-
non-specific furin cleavage sequence (164RKKR167) of the protective antigen of anthrax toxin is substituted by the cleavage sequence for gelatinase class of matrix metalloproteinase (164GPLGMLSQ171) to prevent non-specific action and enhance target specific action in endothelial cells
additional information
-
intranasal instillationin a mouse model of pulmonary anthrax of a Bacillus anthracis strain RPLC2 bearing inactive lethal toxin (double mutant) lethal toxin stimulates cytokine production (IL-6 and KC, mouse orthologue of IL-8) and polymorphonuclear neutrophils recruitment in lungs. These responses are repressed by a prior instillation of an lethal toxin preparation. In contrast, instillation of a Bacillus anthracis strain expressing active lethal toxin represses lung inflammation. The inhibitory effects of lethal toxin on cytokine production are associated with an alteration of ERK and p38-MAPK phosphorylation, but not JNK phosphorylation. Although NF-kappaB is essential for IL-8 expression, lethal toxin downregulates this expression without interfering with NF-kappaB activation in epithelial cells. Lethal toxin selectively prevents histone H3 phosphorylation at Ser 10 and recruitment of the p65 subunit of NF-kappaB at the IL-8 and KC promoters
additional information
-
preparation of semisynthetic protective antigen-binding domain of anthrax lethal factor, LFN, by native chemical ligation of synthetic LFN residues 14-28 thioester with recombinant N29C-LFN residues 29-263 and comparison with two variants containing alterations in residues 14-28 of the N-terminal region. An analogue with three positively charged residues and an acetylated N-terminus, blocks ion conductance more efficiently than the control analogue, which lacks charged residues in the N-terminal segment. The semisynthesis platform allows for investigation of the interaction of the pore with its substrates
additional information
-
construction of fusion protein of the anthrax toxin lethal factor N-terminal domain LFn, residues 1-254, with beta-lactamase
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
diagnostics
-
the development, performance characteristics and validation using human serum of a robust and rugged format of the LTx neutralization activity (TNA) assay is reported and its application in evaluating immune serum from humans, Rhesus macaques and rabbits. This format uses standardized and characterized reagents in conjunction with customized interpretive software and a novel mathematical algorithm to calculate and extrapolate multiple reportable values, in addition to ED50, with high specificity, analytical sensitivity, accuracy and precision. This LTx neutralization activity (TNA) assay format is proposed as a unifying platform technology
diagnostics
-
the anthrax lethal toxin neutralization assay (TNA) measures the ability of antibodies to neutralize the cytotoxicity of anthrax lethal toxin rather than quantifying total antibody through a conjugated species-specific secondary antibody. TNA may provide a more relevant immunological measure, as it quantitates functional antibodies only rather than total protective antigen-binding antibodies. In this study, TNA data are generated in several different laboratories to measure the immune responses in rabbits, nonhuman primates, and humans. A collaborative study is conducted in which 108 samples from the three species are analyzed in seven independent laboratories. This study demonstrates that the TNA is a panspecies assay that can be performed in several different laboratories with a high degree of quantitative agreement and precision
medicine
-
mice immunized with chloroplast-derived anthrax protective antigen survive anthrax lethal toxin challenge
medicine
-
human medical countermeasures for anthrax
medicine
-
sublethal doses of Bacillus anthracis lethal toxin inhibit inflammation with lipopolysaccharide and Escherichia coli challenge but have opposite effects on survival
medicine
-
inducing strong mucosal and systemic immune responses against both anthrax toxins and bacilli after nasal immunization using a synthetic double-stranded RNA (dsRNA), polyriboinosinic-polyribocytidylic acid as adjuvant. The capsular poly-gamma-D-glutamic acid (PGA) from bacillus is immunogenic when conjugated to a carrier protein and dosed intranasally to mice. The nasal immunization with the poly-gamma-D-glutamic acid-carrier protein conjugate in combination with the anthrax protective antigen (PA) protein induces both anti-PGA and anti-PA immune responses in mouse sera and lung mucosal secretions. The anti-PA antibody response is shown to have anthrax lethal toxin neutralization activity. The anti-PGA Abs induced are able to activate complement and kill PGA-producing bacteria. It is feasible to develop a novel dual-action nasal anthrax vaccine
medicine
-
the antitumor toxin has potential for use in cancer therapy
medicine
-
the use of drugs capable of inhibiting Rho GTPase activity, such as statins, may provide a means to attenuate intoxication during Bacillus anthracis infection
medicine
-
engineered lethal anthrax toxin prevents tumor growth by inhibiting angiogenesis (10 nmol/l engineered protective antigen + 5.5 nmol/l lethal factor)
medicine
-
anthrax toxin entry and activity differs among immune cells. Macrophages, dendritic cells, and B cells display higher activity of a of fusion protein of the anthrax toxin lethal factor N-terminal domain LFn, residues 1-254, with beta-lactamase, i.e. LFnBLA, than CD4+ and CD8+ T cells in both spleen cell suspension and the purified samples of individual cell types. Expression of anthrax toxin receptor CMG2 is higher in CD4+ and CD8+ T cells, which is not correlated to the intracellular LFnBLA activity
medicine
-
neuronal nitric oxide synthase deficiency in mice causes strikingly increased sensitivity to anthrax lethal toxin, while deficiencies in NOS enzymes iNOS and eNOS have no effect on anthrax lethal toxin-mediated mortality. The increased sensitivity of nNOS2/2 mice is independent of macrophage sensitivity to toxin, or cytokine responses, and can be replicated in nNOS-sufficient wild-type mice through pharmacological inhibition of the enzyme with 7-nitroindazole. Anthrax lethal toxin induces architectural changes in heart morphology of nNOS2/2 mice, with rapid appearance of novel inter-fiber spaces but no associated apoptosis of cardiomyocytes. Anthrax lethal toxin-treated wild-type mice have no histopathology observed at the light microscopy level. Electron microscopic analyses reveal striking pathological changes in the hearts of both nNOS2/2 and wild-type mice, varying only in severity and timing. Endothelial andcapillary necrosis and degeneration, inter-myocyte edema, myofilament and mitochondrial degeneration, and altered sarcoplasmic reticulum cisternae are observed in both anthrax lethal toxin-treated wild-type and nNOS2/2 mice. Biomarkers of cardiac injury, myoglobin, cardiac troponin-I, and heart fatty acid binding protein, are elevated in anthrax lethal toxin-treated mice very rapidly and reach concentrations rarely reported in mice. The potent nitric oxide scavenger, 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide, i.e. carboxy-PTIO, shows some protective effect against anthrax lethal toxin
medicine
-
anthrax lethal factor is a specific biomarker of active infection by Bacillus anthracis
medicine
-
blood borne lethal toxin is a novel therapeutic target for combating anthrax
molecular biology
-
microarray analysis is used to investigate the effects of Bacillus anthracis lethal toxin on human neutrophil-like NB-4 cells to identify markers of intoxication. Genes down-regulated after a 2 h lethal toxin exposure include those encoding chemokines and transcription factors. Significant decreases in the mRNA of interleukin-8, CCL20, CCL3 and CCL4 are observed using real-time PCR. The decreases are more pronounced at 4 and 8 h and are lethal toxin-specific. Decreases in chemokine protein levels are evident after 24 h and are sensitive to low concentrations of lethal toxin. Co-incubation with an anti-lethal factor mAb restores levels of interleukin-8 to 100% and 50%, respectively
molecular biology
-
it is shown that treatment of RAW 264.7 murine macrophage cells with anthrax lethaltoxin induces autophagy suggesting a protective role as autophagy inhibition using 3-methyladenine results in an accelerated cell death
molecular biology
-
protein expression profile of murine macrophages RAW264.7 treated with LeTx is analyzed using two-dimensional polyacrylamide gel electrophoresis and MALDI-TOF MS. Among the differentially expressed spots, cleaved mitogen-activated protein kinase kinase 1 acting as a negative element in the signal transduction pathway, and glucose-6-phosphate dehydrogenase playing a role in the protection of cells from hyperproduction of active oxygen are up-regulated LeTx-treated macrophages
molecular biology
-
the cellular damage inflicted by anthrax lethal toxin depends not only on the innate responses but also on the maturation stage of the cell, which modulates the more general caspase-1-independent responses
molecular biology
-
proteasome inhibitors block anthrax lethal toxin-mediated caspase-1 activation and can protect against cell death, indicating that the degradation of at least one cellular protein is required for cell death. Proteins can be degraded by the proteasome via the N-end rule. Using amino acid derivatives that act as inhibitors of this pathway, it is shown that the N-end rule is required for anthrax lethal toxin-mediated caspase-1 activation and cell death. The Streptomyces olivoreti peptide bestatin, which inhibits leucine, alanine and arginine aminopeptidases, protects macrophages against anthrax lethal toxin. c-IAP1, a mammalian member of the inhibitor of apoptosis protein (IAP) family is identified, as a novel N-end rule substrate degraded in macrophages treated with anthrax lethal toxin
molecular biology
-
the in vitro effects of thermal stress on the killing of murine macrophages by anthrax lethal toxin are investigated. Heat shock rapidly halts anthrax lethal toxin-induced cell death without any impact on toxin uptake or mitogen-activated protein kinases cleavage, by a mechanism independent of novel protein synthesis, p38 activation, HSP90 activity or proteasome inhibition. Rather, heat shock prevents the activation of procaspase-1 in anthrax lethal toxin -treated cells, apparently by the sequestration of pro-caspase-1 in a large, inhibitory complex. Heat-shocked cell lysates strongly inhibit the active caspase-1 heterotetramer in vitro, independent of a specific inflammasome platform. Results suggest the presence of a cellular, heat shock-inducible, caspase-1 inhibiting factor
molecular biology
-
toxin effects of lethal toxin and edema toxin of Bacillus anthracis in bone marrow dendritic cells stimulated with either LPS or Legionella pneumophila are analysed. Lethal toxin, not ET, is more toxic for cells from BALB/c mice than from C57BL/6 as measured by 7-AAD uptake. Results support the conclusion that lethal toxin and edema toxin are not uniformly suppressive of dendritic cell function but rather modulate function up or down depending on variables such as the function tested, the microbial stimulus used, and the genetic variation in innate immune response mechanisms in the host cell
molecular biology
-
results suggest that this toxin delivery system is capable of stimulating protective immune responses where effective immunization requires stimulation of both classes of T cells
molecular biology
-
lethal toxin triggers the formation of a membrane-associated inflammasome complex in murine macrophages consisting of caspase-1 and Nalp1b, resulting in cleavage of cytosolic caspase-1 substrates and cell death
molecular biology
-
primary keratinocytes are resistant to LeTx cytotoxicity, and MEK cleavage does not correlate with LeTx cytotoxicity. LeTx is considered as an anti-inflammatory agent, however it upregulates RANTES
molecular biology
-
anthrax lethal toxin treatment of neutrophils disrupts signaling to downstream MAPK targets in response to TLR stimulation. Following anthrax lethal toxin treatment, ERK family and p38 phosphorylation are nearly completely blocked, but signaling to JNK family members persists in vitro and ex vivo. In contrast to previous reports involving human neutrophils, anthrax lethal toxin treatment of murine neutrophils increases their production of superoxide in response to PMA or TLR stimulation in vitro or ex vivo. Although this enhanced superoxide production correlates with effects due to the lethal toxin-induced blockade of ERK signaling, it requires JNK signaling that remains largely intact despite the activity of anthrax lethal toxin
molecular biology
-
the effects of lethal toxin on the transcriptional regulation of the VCAM1 gene, which contains binding sites in its promoter region for NF-kappaB, IFN regulatory factor-1 (IRF-1), Sp1, GATA-2, and AP-1, in primary human endothelial cells is examined. Lethal toxin enhances cytokine-induced activation of NF-kappaB and IRF-1 which are key factors in the lethal toxin-mediated enhancement of TNF-induced VCAM-1 expression. Altering the activity of key transcription factors involved in host response to infection may be a critical mechanism by which lethal toxin contributes to anthrax pathogenesis
molecular biology
-
celastrol is identified as an inhibitor of lethal toxin-mediated macrophage lysis and suggests an inhibitory mechanism involving inhibition of the proteasome pathway
molecular biology
-
Bacillus anthracis represses the immune response, in part by altering chromatin accessibility of IL-8 promoter to NFkappaB in epithelial cells. This epigenetic reprogramming, in addition to previously reported effects of lethal toxin, represents an efficient strategy used by Bacillus anthracis for invading the host
synthesis
-
preparation of semisynthetic protective antigen-binding domain of anthrax lethal factor, LFN, by native chemical ligation of synthetic LFN residues 14-28 thioester with recombinant N29C-LFN residues 29-263 and comparison with two variants containing alterations in residues 14-28 of the N-terminal region. The properties of the variants in blocking ion conductance through the protective antigen pore and translocating across planar phospholipid bilayers in response to a pH gradient are consistent with current concepts of the mechanism of polypeptide translocation through the pore. The semisynthesis platform allows for investigation of the interaction of the pore with its substrates