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

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     3 Hydrolases
         3.4 Acting on peptide bonds (peptidases)
             3.4.21 Serine endopeptidases
                3.4.21.78 Granzyme A
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Select one or more organisms in this record:
This record set is specific for:
Homo sapiens
UNIPROT: P51124 not found.
Word Map
  • 3.4.21.78
  • thrombospondin-1
  • angiogenesis
  • perforin
  • angiogenic
  • granule
  • killer
  • antiangiogenic
  • cytolytic
  • t-cells
  • metastasis
  • matricellular
  • microvessels
  • collagen
  • integrins
  • microvascular
  • lytic
  • exocytosis
  • tgf-beta1
  • neovascularization
  • integrin-associated
  • granulysin
  • ifn-gamma
  • angiostatic
  • granule-associated
  • metronomic
  • clpap
  • tregs
  • endostatin
  • factor-beta
  • proangiogenic
  • lymphocyte-mediated
  • vegf-a
  • angiogenesis-related
  • medicine
  • ctl-mediated
  • alphavbeta3
  • corneal
  • caspase-independent
  • lymphokine-activated
  • properdin
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
Autocrine thymic lymphoma granzyme-like serine protease, CTL tryptase, CTLA3, Cytotoxic T lymphocyte serine protease, GrA, Gzm A, Gzma, GzmA/K, H factor, Hanukkah factor, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Autocrine thymic lymphoma granzyme-like serine protease
-
-
-
-
CTL tryptase
-
-
-
-
CTLA3
-
-
-
-
Cytotoxic T lymphocyte serine protease
-
-
-
-
Gzm A
283345
-
H factor
-
-
-
-
Hanukkah factor
-
-
-
-
HuTPS
-
-
-
-
T-cell associated protease 1
-
-
-
-
T-cell derived serine proteinase 1
-
-
-
-
TSP-1
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY hide
143180-73-8
-
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
-
-
-
-
-
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
-
-
-
-
-
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
-
-
-
-
-
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 SUBSTRATE
NATURAL PRODUCT
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
?
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(4-Amidinophenyl)-methanesulfonyl fluoride
-
-
3,4-dichloroisocoumarin
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
C6H4CH2SO2-Gly-Pro(4-amidinophenylglycine)P(OPh)2
-
-
diisopropyl fluorophosphate
-
-
guanidinobenzoate
-
-
isocoumarin
-
-
Isocoumarins
-
mechanism-based isocoumarin inhibitors substituted with basic guanidino or isothiureidopropoxy groups
-
leupeptin
-
-
p-guanidino-C6H4-COOC6H4-p-CN
-
-
phenylmethanesulfonyl fluoride
-
-
phenylmethylsulfonyl fluoride
-
-
PhNH-CONH-CiTEtOIC
-
isocoumarinderivate, best inhibitor
-
phosphonate
-
-
rotenone
-
the complex I inhibitor hinders GzmA-mediated reactive oxygen species production and cell death
Soybean trypsin inhibitor
-
-
-
valinomycin
-
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
-
human granzyme A
0.105
benzyloxycarbonyl-Gly-Arg thiobenzyl ester
-
human granzyme A
0.19
benzyloxycarbonyl-Lys thiobenzyl ester
-
human granzyme A
0.887
Boc-Ala-Ala-Arg-SBzl
-
pH 7.5, 30C
0.17
Boc-Trp-Arg-SBzl
-
pH 7.5, 30C
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
benzyloxycarbonyl-Arg thiobenzyl ester
-
human granzyme A
5.83
benzyloxycarbonyl-Gly-Arg thiobenzyl ester
-
human granzyme A
3.1
Benzyloxycarbonyl-Lys-thiobenzyl ester
-
human granzyme A
4980
Boc-Ala-Ala-Arg-SBzl
-
pH 7.5, 30C
3960
Boc-Trp-Arg-SBzl
-
pH 7.5, 30C
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
-
Gly-Pro-Arg 4-methylcoumarin 7-amide, human enzyme
11
-
tosyl-Gly-Pro-Arg 4-nitroanilide, human enzyme
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
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
-
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
-
standard MTT-assay applied
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
-
CD57+ natural killer cells
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
additional information
-
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
-
subcellular fractionation, granzyme A in peroxidase-negative granules identified
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
Sequence
GRAM_HUMAN
257
0
27545
Swiss-Prot
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
21000 - 30000
-
gel filtration
25820
-
x * 25820, human, unglycosylated protein, calculated from nucleotide sequence
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
-
x * 25820, human, unglycosylated protein, calculated from nucleotide sequence
dimer
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
-
PROTEIN VARIANTS
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
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
-
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
-
HepG2 cells infected with granzyme A recombinant vaccinia virus
-
K562 cells treated with perforin and recombinant human GzmA
-
recombinant enzyme expression in Pichia pastoris
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Odake, S.; Kam, C.M.; Narasimhan, L.; Poe, M.; Blake, J.T.; Krahenbuhl, O.; Tschopp, J.; Powers, J.C.
Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins
Biochemistry
30
2217-2227
1991
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Gershenfeld, H.K.; Hershberger, R.J.; Shows, T.B.; Weissman, I.L.
Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease
Proc. Natl. Acad. Sci. USA
85
1184-1188
1988
Homo sapiens
Manually annotated by BRENDA team
Simon, M.M.; Kramer, M.D.
Granzyme A
Methods Enzymol.
244
68-79
1994
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Kummer, J.A.; Kamp, A.M.; Citarella, F.; Horrevoets, A.J.G.; Hack, C.E.
Expression of human recombinant granzyme A zymogen and its activation by the cysteine proteinase cathepsin C
J. Biol. Chem.
271
9281-9286
1996
Homo sapiens
Manually annotated by BRENDA team
Spaeny-Dekking, E.H.A.; Kamp, A.M.; Froelich, C.J.; Hack, C.E.
Extracellular granzyme A, complexed to proteoglycans, is protected against inactivation by protease inhibitors
Blood
95
1465-1472
2000
Homo sapiens
Manually annotated by BRENDA team
Bell, J.K.; Goetz, D.H.; Mahrus, S.; Harris, J.L.; Fletterick, R.J.; Craik, C.S.
The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity
Nat. Struct. Biol.
10
527-534
2003
Homo sapiens
Manually annotated by BRENDA team
Hink-Schauer, C.; Estebanez-Perpina, E.; Kurschus, F.C.; Bode, W.; Jenne, D.E.
Crystal structure of the apoptosis-inducing human granzyme A dimer
Nat. Struct. Biol.
10
535-540
2003
Homo sapiens
Manually annotated by BRENDA team
Beresford, P.J.; Kam, C.M.; Powers, J.C.; Lieberman, J.
Recombinant human granzyme A binds to putative HLA-associated proteins and cleaves one of them
Proc. Natl. Acad. Sci. USA
94
9285-9290
1997
Homo sapiens
Manually annotated by BRENDA team
Grossman, W.J.; Verbsky, J.W.; Tollefsen, B.L.; Kemper, C.; Atkinson, J.P.; Ley, T.J.
Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells
Blood
104
2840-2848
2004
Homo sapiens
Manually annotated by BRENDA team
Mahrus, S.; Craik, C.S.
Selective chemical functional probes of granzymes A and B reveal granzyme B Is a major effector of natural killer cell-mediated lysis of target cells
Chem. Biol.
12
567-577
2005
Homo sapiens
Manually annotated by BRENDA team
Zhu, P.; Zhang, D.; Chowdhury, D.; Martinvalet, D.; Keefe, D.; Shi, L.; Lieberman, J.
Granzyme A, which causes single-stranded DNA damage, targets the double-strand break repair protein Ku70
EMBO Rep.
7
431-437
2006
Homo sapiens
Manually annotated by BRENDA team
Martinvalet, D.; Zhu, P.; Lieberman, J.
Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis
Immunity
22
355-370
2005
Homo sapiens
Manually annotated by BRENDA team
Bade, B.; Boettcher, H.E.; Lohrmann, J.; Hink-Schauer, C.; Bratke, K.; Jenne, D.E.; Virchow, J.C., Jr.; Luttmann, W.
Differential expression of the granzymes A, K and M and perforin in human peripheral blood lymphocytes
Int. Immunol.
17
1419-1428
2005
Homo sapiens (P51124)
Manually annotated by BRENDA team
Shacklett, B.L.; Cox, C.A.; Quigley, M.F.; Kreis, C.; Stollman, N.H.; Jacobson, M.A.; Andersson, J.; Sandberg, J.K.; Nixon, D.F.
Abundant expression of granzyme A, but not perforin, in granules of CD8+ T cells in GALT: implications for immune control of HIV-1 infection
J. Immunol.
173
641-648
2004
Homo sapiens
Manually annotated by BRENDA team
Vernooy, J.H.; Moeller, G.M.; van Suylen, R.J.; van Spijk, M.P.; Cloots, R.H.; Hoet, P.H.; Pennings, H.J.; Wouters, E.F.
Increased granzyme A expression in type II pneumocytes of patients with severe chronic obstructive pulmonary disease
Am. J. Respir. Crit. Care Med.
175
464-472
2007
Homo sapiens, Homo sapiens (P12544)
Manually annotated by BRENDA team
Buzza, M.S.; Bird, P.I.
Extracellular granzymes: current perspectives
Biol. Chem.
387
827-837
2006
Homo sapiens (P12544)
Manually annotated by BRENDA team
Hochegger, K.; Eller, P.; Huber, J.M.; Bernhard, D.; Mayer, G.; Zlabinger, G.J.; Rosenkranz, A.R.
Expression of granzyme A in human polymorphonuclear neutrophils
Immunology
121
166-173
2007
Homo sapiens, Homo sapiens (P12544)
Manually annotated by BRENDA team
Kaiserman, D.; Bird, C.H.; Sun, J.; Matthews, A.; Ung, K.; Whisstock, J.C.; Thompson, P.E.; Trapani, J.A.; Bird, P.I.
The major human and mouse granzymes are structurally and functionally divergent
J. Cell Biol.
175
619-630
2006
Homo sapiens, Homo sapiens (P12544), Mus musculus, Mus musculus (P11032)
Manually annotated by BRENDA team
Myoumoto, A.; Nakatani, K.; Koshimizu, T.; Matsubara, H.; Adachi, S.; Tsujimoto, G.
Glucocorticoid-induced granzyme A expression can be used as a marker of glucocorticoid sensitivity for acute lymphoblastic leukemia therapy
J. Hum. Genet.
52
328-333
2007
Homo sapiens, Homo sapiens (P12544)
Manually annotated by BRENDA team
Lee-Kirsch, M.A.; Chowdhury, D.; Harvey, S.; Gong, M.; Senenko, L.; Engel, K.; Pfeiffer, C.; Hollis, T.; Gahr, M.; Perrino, F.W.; Lieberman, J.; Hubner, N.
A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus
J. Mol. Med.
85
531-537
2007
Homo sapiens (P12544)
Manually annotated by BRENDA team
Martinvalet, D.; Dykxhoorn, D.M.; Ferrini, R.; Lieberman, J.
Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death
Cell
133
681-692
2008
Homo sapiens
Manually annotated by BRENDA team
Yoshikawa, Y.; Hirayasu, H.; Tsuzuki, S.; Fushiki, T.
Granzyme A and thrombin differentially promote the release of interleukin-8 from alveolar epithelial A549 cells
Cytotechnology
62
325-332
2010
Homo sapiens
Manually annotated by BRENDA team
Van Damme, P.; Maurer-Stroh, S.; Hao, H.; Colaert, N.; Timmerman, E.; Eisenhaber, F.; Vandekerckhove, J.; Gevaert, K.
The substrate specificity profile of human granzyme A
Biol. Chem.
391
983-997
2010
Homo sapiens
Manually annotated by BRENDA team
Ilzecka, J.
Granzymes A and B levels in serum of patients with amyotrophic lateral sclerosis
Clin. Biochem.
44
650-653
2011
Homo sapiens
Manually annotated by BRENDA team
Grodzovski, I.; Lichtenstein, M.; Galski, H.; Lorberboum-Galski, H.
IL-2-granzyme A chimeric protein overcomes multidrug resistance (MDR) through a caspase 3-independent apoptotic pathway
Int. J. Cancer
128
1966-1980
2011
Homo sapiens
Manually annotated by BRENDA team
Kaiserman, D.; Stewart, S.E.; Plasman, K.; Gevaert, K.; Van Damme, P.; Bird, P.I.
Identification of Serpinb6b as a species-specific mouse granzyme A inhibitor suggests functional divergence between human and mouse granzyme A
J. Biol. Chem.
289
9408-9417
2014
Homo sapiens, Homo sapiens (P12544), Mus musculus
Manually annotated by BRENDA team
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