Information on EC 3.4.21.78 - Granzyme A

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.21.78
-
RECOMMENDED NAME
GeneOntology No.
Granzyme A
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
Hydrolysis of proteins, including fibronectin, type IV collagen and nucleolin. Preferential cleavage: -Arg-/-, -Lys-/- >> -Phe-/- in small molecule substrates
show the reaction diagram
including fibronectin, type IV collagen and nucleolin. Preferential cleavage:-Arg-+-,-Lys-+- >>-Phe-+- in small molecule substrates, he term-+- depicts the point of cleavage
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY hide
143180-73-8
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
sequence contains a putative signal peptide, eight consensus cysteine residues, one conserved IIGG motif and three conserved residues as central elements of the GzmA/K active site
UniProt
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
gene gzmA
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide + H2O
?
show the reaction diagram
Abz-GLFRSLSS(K-dnp)D + H2O
Abz-GLFR + SLSS(K-dnp)D
show the reaction diagram
-
a quenched fluorescence peptide substrate
-
-
?
Abz-VANRSAS(Kdnp)D + H2O
Abz-VANR + SAS(Kdnp)D
show the reaction diagram
-
a quenched fluorescence peptide substrate
-
-
?
Benzyloxycarbonyl-Arg thiobenzyl ester + H2O
?
show the reaction diagram
Benzyloxycarbonyl-Lys-thiobenzyl ester + H2O
?
show the reaction diagram
Boc-Ala-Ala-Arg-SBzl + H2O
?
show the reaction diagram
Boc-Trp-Arg-SBzl + H2O
?
show the reaction diagram
-
thioester substrate, recombinant granzyme A
-
?
CBZ-Lys-SBzl + H2O
?
show the reaction diagram
-
thioester substrate, recombinant granzyme A
-
?
D-(epsilon-Benzyloxycarbonyl)Lys-Pro-Arg 4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
-
-
D-Pro-Phe-Arg 4-nitroanilide + H2O
D-Pro-Phe-Arg + 4-nitroaniline
show the reaction diagram
Gly-Pro-Arg 4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
-
-
H-D-Pro-Phe-Arg p-nitroanilide + H2O
H-D-Pro-Phe-Arg + p-nitroaniline
show the reaction diagram
i.e. S2302, measurement of enzymatic activity of granzyme A activity in lysates of CD8+ TAL
-
-
?
Ku70 double strand break repair protein + H2O
?
show the reaction diagram
-
-
cleavage of Ku70 after R301, disrupting Ku complex binding to DNA and blocking of Ku70 antiapoptotic functions, cleavage of Ku70 after R301, disrupting Ku complex binding to DNA
-
?
N-acetyl-Ile-Glu-Pro-Asp p-nitroanilide + H2O
N-acetyl-Ile-Glu-Pro-Asp + p-nitroaniline
show the reaction diagram
measurement of enzymatic activity of granzyme A activity in lysates of CD8+ TAL
-
-
?
N-alpha-benzyloxycarbonyl-Arg-SBzl + H2O
?
show the reaction diagram
N-alpha-benzyloxycarbonyl-Lys-SBzl + H2O
?
show the reaction diagram
-
-
-
?
PHAPII + H2O
?
show the reaction diagram
Precursor of interleukin-1beta + H2O
Interleucin-1beta
show the reaction diagram
-
i.e. pIL-1beta, cleavage at Arg120
-
-
Pro-Phe-Arg 4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
protein NDUFS3 + H2O
?
show the reaction diagram
PSSCL + H2O
Pro-Ser + Ser-Lys-Lys
show the reaction diagram
-
-
-
?
Suc-AAPR-p-nitroanilide + H2O
?
show the reaction diagram
-
-
-
-
?
Tosyl-Gly-Pro-Arg 4-nitroanilide + H2O
?
show the reaction diagram
-
-
-
-
-
Val-Pro-Arg 4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
Ku70 double strand break repair protein + H2O
?
show the reaction diagram
-
-
cleavage of Ku70 after R301, disrupting Ku complex binding to DNA and blocking of Ku70 antiapoptotic functions
-
?
protein NDUFS3 + H2O
?
show the reaction diagram
-
GzmA cleavage of native Ndufs3 disrupts complex I electron transport
-
-
?
additional information
?
-
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(4-Amidinophenyl)-methanesulfonyl fluoride
-
-
3,4-dichloroisocoumarin
3-aminobenzamidine
-
-
4-aminobenzamidine
-
-
alpha-2-Macroglobulin
-
-
-
Alpha1-proteinase inhibitor
-
-
-
alpha2-Macroglobulin
-
antithrombin III
-
Aprotinin
benzamidine
Bio-x-IGN(AmPhg)P-(Oph)2
-
specific and irreversible inhibition both in vitro and in cells
C1 esterase inhibitor
-
-
-
C6H4CH2SO2-Gly-Pro(4-amidinophenylglycine)P(OPh)2
-
-
D-Pro-Phe-Arg-CH2Cl
-
-
diisopropyl fluorophosphate
guanidinobenzoate
-
-
isocoumarin
-
-
Isocoumarins
-
leupeptin
Natural high MW inhibitors
-
binding to charged surfaces protects the enzyme
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p-guanidino-C6H4-COOC6H4-p-CN
-
-
phenylmethanesulfonyl fluoride
phenylmethylsulfonyl fluoride
-
-
PhNH-CONH-CiTEtOIC
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isocoumarinderivate, best inhibitor
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phosphonate
-
-
Protease nexin-1
-
-
-
rotenone
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the complex I inhibitor hinders GzmA-mediated reactive oxygen species production and cell death
Serpinb6b
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potent inhibitor, Serpinb6b employs an exosite to specifically inhibit dimeric but not monomeric murine enzyme. Kinetic analysis and modeling of the mGzmA-Serpinb6b Michaelis complex, overview
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Soybean trypsin inhibitor
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valinomycin
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pretreatment of K562 cells with 16 nmol valinomycin inhibits GzmA and perforin-induced reactive oxygen species generation
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.12 - 0.315
benzyloxycarbonyl-Arg thiobenzyl ester
0.105 - 0.16
benzyloxycarbonyl-Gly-Arg thiobenzyl ester
0.13 - 0.19
benzyloxycarbonyl-Lys thiobenzyl ester
0.887
Boc-Ala-Ala-Arg-SBzl
-
pH 7.5, 30C
0.17
Boc-Trp-Arg-SBzl
-
pH 7.5, 30C
0.14
tert-butyloxycarbonyl-Ala-Ala-Arg thiobenzyl ester
-
mouse enzyme
0.177
Z-Arg-SBzl
-
pH 7.5, 30C
0.767
Z-Lys-SBzl
-
pH 7.5, 30C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
8.8 - 83
benzyloxycarbonyl-Arg thiobenzyl ester
5.83 - 59
benzyloxycarbonyl-Gly-Arg thiobenzyl ester
21
benzyloxycarbonyl-Lys thiobenzyl ester
Mus musculus
-
mouse enzyme
3.1
Benzyloxycarbonyl-Lys-thiobenzyl ester
Homo sapiens
-
human granzyme A
4980
Boc-Ala-Ala-Arg-SBzl
Homo sapiens
-
pH 7.5, 30C
3960
Boc-Trp-Arg-SBzl
Homo sapiens
-
pH 7.5, 30C
45
tert-butyloxycarbonyl-Ala-Ala-Arg thiobenzyl ester
Mus musculus
-
mouse enzyme
30360 - 30400
Z-Arg-SBzl
22100 - 22140
Z-Lys-SBzl
additional information
additional information
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5 - 8.5
-
D-Pro-Phe-Arg 4-nitroanilide, mouse enzyme
8
-
Gly-Pro-Arg 4-methylcoumarin 7-amide, human enzyme
8 - 8.5
-
D-Pro-Phe-Arg 4-nitroanilide
11
-
tosyl-Gly-Pro-Arg 4-nitroanilide, human enzyme
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
acute lymphoblastic leukemia-derived cell line 697 used as a positive control, granzyme A mediated glucocorticoid-induced apoptosis shown
Manually annotated by BRENDA team
-
primary type II pneumocytes and type II pneumocyte, from patients with chronic obstructive pulmonary disease, enriched by Laser capture microdissection (LCM)
Manually annotated by BRENDA team
-
peripheral lung tissue from patients with chronic obstructive pulmonary disease, enriched by Laser capture microdissection (LCM)
Manually annotated by BRENDA team
medium expression
Manually annotated by BRENDA team
predominant expression
Manually annotated by BRENDA team
predominant expression
Manually annotated by BRENDA team
-
51Cr-release assay applied
Manually annotated by BRENDA team
-
no expression of granzyme A in promyelocytic cell line HL-60 identified
Manually annotated by BRENDA team
medium expression
Manually annotated by BRENDA team
-
standard MTT-assay applied
Manually annotated by BRENDA team
medium expression
Manually annotated by BRENDA team
large intestinal mucosa of rats with experimentally induced ulcerative colitis
Manually annotated by BRENDA team
-
whole-blood leucocyte preparation discriminating between the distinct subpopulations, expression in CD8+ CTLs and in CD56+ NK cells shown
Manually annotated by BRENDA team
less sensitivity to granzyme A-mediated cell death in lymphoblastoid cells carrying the D18N mutation in the 3'-5' DNA repair exonuclease TREX1 identified
Manually annotated by BRENDA team
standard MTT-assay applied
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
-
PBMCs, expression in
Manually annotated by BRENDA team
-
PMNs, polymorphonuclear neutrophils, expression in CD15+ population identified, differentiated cell stage, phagocytic stimuli of PMNs increase expression
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
predominant expression
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
-
the enzyme binds to natural basement membranes in a charge-dependent manner
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
21000 - 30000
-
gel filtration
25820
-
x * 25820, human, unglycosylated protein, calculated from nucleotide sequence
30000
-
x * 60000, mouse, SDS-PAGE under nonreducing condition, x * 30000, SDS-PAGE under reducing condition, mouse
60000
-
x * 60000, mouse, SDS-PAGE under nonreducing condition, x * 30000, SDS-PAGE under reducing condition, mouse
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oligomer
-
-
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
-
proteoglycans containing glycosaminoglycan, various forms of extracellular granzyme A occur in vivo, the regulation of activity may be modified by proteoglycans
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
triclinic space group P1, a = 49.48 A, b = 94.55 A, c = 94.87 A
-
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
extracellular granzyme A circulates in the mature conformation and is bound to proteoglycans that protect it against inactivation by protease inhibitors
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
bone marrow cDNA used to amplify Gzma by PCR
-
cDNA subcloned into the yeast vector pPICzalphaA and heterologously expressed in Pichia pastoris
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commercial preparation
-
expression in Escherichia coli
-
expression in Pichia pastoris
-
expression of human recombinant granzyme A zymogen and its activation by the cysteine proteinase cathepsin
-
granzyme A expressed in Escherichia coli BL21-DE3 as a proenzyme capable of in vitro activation by enterokinase
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HepG2 cells infected with granzyme A recombinant vaccinia virus
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K562 cells treated with perforin and recombinant human GzmA
-
recombinant enzyme expression in Pichia pastoris
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
after spring viraemia of carp virus infection, transcripts accumulate in most immune-related tissues in a time-dependent manner. GzmA/K transcript is up-regulated in thymus tissue of GH transgenic carp
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
N153Q
-
molecular replacement
S176A
-
mutated active site, does not cleave protein NDUFS3
additional information
-
construction of a chimeric protein IGA, consisting of interleukin IL-2 and granzyme A, using IL-2 as a targeting moiety and granzyme A as a killing moiety to overcome multidrug resistance MDR in anticancer therapy. The IGA chimeric protein enters the target sensitive and MDR cancer cells overexpressing IL-2 receptor and induces caspase 3-independent cell death. After its entry, IGA causes a decrease in the mitochondrial potential, and triggers translocation of nm23-H1, a granzyme A-dependent DNase, from the cytoplasm to the nucleus, where it causes single-strand DNA nicks, thus causing cell death. IGA is able to overcome MDR and kill cells resistant to chemotherapeutic drugs
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine