Information on EC 3.4.21.78 - Granzyme A and Organism(s) Homo sapiens and UniProt Accession P51124

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Homo sapiens
UNIPROT: P51124
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The taxonomic range for the selected organisms is: Homo sapiens

The enzyme appears in selected viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.21.78
-
RECOMMENDED NAME
GeneOntology No.
Granzyme A
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
-
-
-
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CAS REGISTRY NUMBER
COMMENTARY hide
143180-73-8
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
-
the enzyme belongs to the granzyme serine protease family, key effector molecules expressed by cytotoxic lymphocytes. Peptide substrate specificity profile of mouse and human granzyme A, overview
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
-
MTT, benzyloxy-carbonyl-Lys-thiobenzyl ester, standard MTT-assay measuring loss of mitochondrial respiration, interspecies differences of granzyme A between human and mouse analyzed, different cytotoxic potential identified
-
-
?
Benzyloxycarbonyl-Arg thiobenzyl ester + H2O
?
show the reaction diagram
-
-
-
-
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Benzyloxycarbonyl-Lys-thiobenzyl ester + H2O
?
show the reaction diagram
-
-
-
-
-
Boc-Ala-Ala-Arg-SBzl + H2O
?
show the reaction diagram
-
thioester substrate, recombinant granzyme A
-
?
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
-
-
-
-
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Gly-Pro-Arg 4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
-
-
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-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
Pro-Phe-Arg 4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
-
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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
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3,4-dichloroisocoumarin
alpha-2-Macroglobulin
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-
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Alpha1-proteinase inhibitor
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alpha2-Macroglobulin
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-
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antithrombin III
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-
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Aprotinin
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benzamidine
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Bio-x-IGN(AmPhg)P-(Oph)2
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specific and irreversible inhibition both in vitro and in cells
C6H4CH2SO2-Gly-Pro(4-amidinophenylglycine)P(OPh)2
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diisopropyl fluorophosphate
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guanidinobenzoate
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isocoumarin
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Isocoumarins
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mechanism-based isocoumarin inhibitors substituted with basic guanidino or isothiureidopropoxy groups
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leupeptin
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p-guanidino-C6H4-COOC6H4-p-CN
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phenylmethanesulfonyl fluoride
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phenylmethylsulfonyl fluoride
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PhNH-CONH-CiTEtOIC
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isocoumarinderivate, best inhibitor
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phosphonate
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rotenone
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the complex I inhibitor hinders GzmA-mediated reactive oxygen species production and cell death
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
benzyloxycarbonyl-Arg thiobenzyl ester
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human granzyme A
0.105
benzyloxycarbonyl-Gly-Arg thiobenzyl ester
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human granzyme A
0.19
benzyloxycarbonyl-Lys thiobenzyl ester
-
human granzyme A
0.887
Boc-Ala-Ala-Arg-SBzl
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pH 7.5, 30°C
0.17
Boc-Trp-Arg-SBzl
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pH 7.5, 30°C
0.177
Z-Arg-SBzl
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pH 7.5, 30°C
0.767
Z-Lys-SBzl
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pH 7.5, 30°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
8.8
benzyloxycarbonyl-Arg thiobenzyl ester
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human granzyme A
5.83
benzyloxycarbonyl-Gly-Arg thiobenzyl ester
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human granzyme A
3.1
Benzyloxycarbonyl-Lys-thiobenzyl ester
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human granzyme A
4980
Boc-Ala-Ala-Arg-SBzl
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pH 7.5, 30°C
3960
Boc-Trp-Arg-SBzl
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pH 7.5, 30°C
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
8
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Gly-Pro-Arg 4-methylcoumarin 7-amide, human enzyme
11
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tosyl-Gly-Pro-Arg 4-nitroanilide, human enzyme
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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acute lymphoblastic leukemia-derived cell line 697 used as a positive control, granzyme A mediated glucocorticoid-induced apoptosis shown
Manually annotated by BRENDA team
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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
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peripheral lung tissue from patients with chronic obstructive pulmonary disease, enriched by Laser capture microdissection (LCM)
Manually annotated by BRENDA team
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51Cr-release assay applied
Manually annotated by BRENDA team
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no expression of granzyme A in promyelocytic cell line HL-60 identified
Manually annotated by BRENDA team
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standard MTT-assay applied
Manually annotated by BRENDA team
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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
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CD57+ natural killer cells
Manually annotated by BRENDA team
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PBMCs, expression in
Manually annotated by BRENDA team
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PMNs, polymorphonuclear neutrophils, expression in CD15+ population identified, differentiated cell stage, phagocytic stimuli of PMNs increase expression
Manually annotated by BRENDA team
additional information
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enriched cytoplasmic granules
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
of effector cells
Manually annotated by BRENDA team
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subcellular fractionation, granzyme A in peroxidase-negative granules identified
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
21000 - 30000
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gel filtration
25820
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x * 25820, human, unglycosylated protein, calculated from nucleotide sequence
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 25820, human, unglycosylated protein, calculated from nucleotide sequence
oligomer
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
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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
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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
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
bone marrow cDNA used to amplify Gzma by PCR
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cDNA subcloned into the yeast vector pPICzalphaA and heterologously expressed in Pichia pastoris
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commercial preparation
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expression in Escherichia coli
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expression in Pichia pastoris
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expression of human recombinant granzyme A zymogen and its activation by the cysteine proteinase cathepsin
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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
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recombinant enzyme expression in Pichia pastoris
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
N153Q
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molecular replacement
S176A
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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