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Information on EC 3.4.21.B4 - granzyme K
for references in articles please use BRENDA:EC3.4.21.B4preliminary BRENDA-supplied EC number
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EC Tree
3.4.21.B4 granzyme KSpecify your search results
The enzyme appears in viruses and cellular organisms
Synonyms
granzyme k, fragmentin, granzyme 3, rnk-tryp-2, gzm k, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
granzyme 3
granzyme K
granzyme tryptase K
GRK
GzmK
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
endopeptidase activity. Cleaves after Lys and Arg
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
cleavage of C-N-linkage
hydrolysis of peptide bond
hydrolysis of peptide bond
-
-
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CAS REGISTRY NUMBER
COMMENTARY
196622-94-3
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
benzyloxycarbonyl-Arg p-nitrobenzyl ester + H2O
benzyloxycarbonyl-Arg + p-nitrobenzyl alcohol
-
-
-
?
benzyloxycarbonyl-L-Arg-thiobenzyl ester + H2O
benzyloxycarbonyl-L-Arg + thiobenzyl alcohol
-
-
-
-
?
benzyloxycarbonyl-L-Lys-thiobenzyl ester + H2O
benzyloxycarbonyl-L-Lys + thiobenzyl alcohol
-
-
-
?
benzyloxycarbonyl-Lys-thiobenzyl ester + H2O
benzyloxycarbonyl-Lys + thiobenzyl alcohol
-
-
-
-
?
beta-tubulin + H2O
?
cleaves beta-tubulin after Arg62 (YVPR-/-AV) and Arg282 (QQYR-/-AL)
-
-
?
Bid protein + H2O
tBid protein + ?
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GzmK directly processes Bid to produce its active form tBid
-
-
?
Cbz-L-Arg-4-nitroanilide + H2O
Cbz-L-Arg + 4-nitroaniline
little hydrolyzed by Gr3
-
-
?
Cbz-L-Arg-7-amido-4-methylcoumarin + H2O
Cbz-L-Arg + 7-amino-4-methylcoumarin
little hydrolyzed by Gr3
-
-
?
Cbz-L-Lys-4-nitroanilide + H2O
Cbz-L-Lys + 4-nitroaniline
little hydrolyzed by Gr3
-
-
?
Cys-Gly-Tyr-Gly-Pro-Lys-Lys-Lys-Arg-Lys-Val-Gly-Gly + H2O
Cys-Gly-Tyr-Gly-Pro-Lys + Lys-Lys-Arg + Lys-Val-Gly-Gly
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-
-
-
?
fluorescence resonance energy transfer substrate-25Arg peptide + H2O
?
most effectively hydrolyzes the substrate fluorescence resonance energy transfer substrate-25Arg peptide in the FRETS-25Xaa series tested
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-
?
fluorescence resonance energy transfer substrate-25Lys peptide + H2O
?
far less effectively cleaved than fluorescence resonance energy transfer substrate-25Arg peptide
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-
?
heterogeneous nuclear ribonucleoprotein K + H2O
?
granzyme K and granzyme A cleave with different kinetics at distinct sites
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-
?
redox factor-1/apurinic apyrimidinic endonuclease Ape1 + H2O
?
-
Ape1 cleavage by Granzyme K facilitates intracellular reactive oxygen species accumulation and enhances granzyme K-induced cell death
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-
?
Z-Leu-Arg-Gly-Gly-7-amido-4-methylcoumarin + H2O
Z-Leu-Arg + Gly-Gly-7-amino-4-methylcoumarin
-
-
-
?
additional information
?
-
-
cleaves synthetic thiobenzyl ester substrates after Lys and Arg, no substrates for the mature enzyme: Boc-Ala-Ala-Met-thiobenzyl ester and Boc-Ala-Ala-Asp-thiobenzyl ester
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?
additional information
?
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for single-residue thioester substrates the enzyme shows a 2fold preference for a Lys versus Arg residue at P1. With oligopeptide substrates the enzyme displays peptidolytic activity C-terminal to both Lys and Arg residues with comparable rates of hydrolysis
-
?
additional information
?
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can trigger DNA fragmentation and is involved in apoptosis
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?
additional information
?
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most efficiently hydrolyzes the carboxylic side of Phe-Tyr-Arg (P3-P2-P1) sequence
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-
?
additional information
?
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most efficiently hydrolyzes the carboxylic side of Phe-Tyr-Arg (P3-P2-P1) sequence
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-
?
additional information
?
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granzyme K prefers Arg over Lys at P1 position. Granzyme K and granzyme A display highly restricted substrate specificities that overlapp only partially. Whereas granzyme K and granzyme A cleave SET with similar efficiencies likely at the same sites, both granzymes cleave the pre-mRNA-binding protein heterogeneous ribonuclear protein K with different kinetics at distinct sites. Granzyme K is markedly more efficient in cleaving heterogeneous ribonuclear protein K than granzyme A. Granzyme K, but not granzyme A, cleaves the microtubule network protein beta-tubulin after two distinct Arg residues. Neither GrK cleavage sites in beta-tubulin nor a peptide based proteomic screen reveal a clear granzyme K consensus sequence around the P1 residue, suggesting that GrK specificity depends on electrostatic interactions between exosites of the substrate and the enzyme
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-
?
additional information
?
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substrate identification analysing substrate repertoire and specificity by N-terminal COFRADIC assisted N-terminomics on the homologous enzyme. Comparisons of specificity profiles of human and mouse enzymes revealing only subtle differences and pointed to substrate occupancies in the P1, P1', and P2' position as the main determinants for substrate recognition, overview
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-
?
additional information
?
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substrate identification analysing substrate repertoire and specificity by N-terminal COFRADIC assisted N-terminomics on the homologous enzyme. Comparisons of specificity profiles of human and mouse enzymes revealing only subtle differences and pointed to substrate occupancies in the P1, P1', and P2' position as the main determinants for substrate recognition, overview
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-
?
additional information
?
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no substrates: Boc-Ala-Ala-Met-thiobenzyl ester and Boc-Ala-Ala-Asp-thiobenzyl ester
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?
additional information
?
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granzyme K expressing cytotoxic T lymphocytes protects against influenza virus in granzyme AB-/- mice. GrzK plays an important role in CD8+ T-cell cytotoxicity both in the presence and absence of grzA and B
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-
?
additional information
?
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-
substrate identification analysing substrate repertoire and specificity by N-terminal COFRADIC assisted N-terminomics on the homologous enzyme. Comparisons of specificity profiles of human and mouse enzymes revealing only subtle differences and pointed to substrate occupancies in the P1, P1', and P2' position as the main determinants for substrate recognition, overview
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
redox factor-1/apurinic apyrimidinic endonuclease Ape1 + H2O
?
-
Ape1 cleavage by Granzyme K facilitates intracellular reactive oxygen species accumulation and enhances granzyme K-induced cell death
-
-
?
additional information
?
-
-
can trigger DNA fragmentation and is involved in apoptosis
-
?
additional information
?
-
granzyme K expressing cytotoxic T lymphocytes protects against influenza virus in granzyme AB-/- mice. GrzK plays an important role in CD8+ T-cell cytotoxicity both in the presence and absence of grzA and B
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-
?
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
inter-alpha-inhibitor protein
physiological inhibitor, significantly inhibits catalytic activity in vitro
-
bikunin
-
subunit of inter-alpha-trypsin inhibitor complex, physiologic inhibitor
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Aortic Aneurysm, Abdominal
Granzyme K - A novel marker to identify the presence and rupture of abdominal aortic aneurysm.
Arthritis
Inflammatory Gene Expression Profile and Defective Interferon-? and Granzyme K in Natural Killer Cells From Systemic Juvenile Idiopathic Arthritis Patients.
Arthritis, Juvenile
Inflammatory Gene Expression Profile and Defective Interferon-? and Granzyme K in Natural Killer Cells From Systemic Juvenile Idiopathic Arthritis Patients.
Asthma
Decrease of cytotoxic T cells in allergic asthma correlates with total serum immunglobulin E.
Colorectal Neoplasms
Clonally expanded EOMES+ Tr1-like cells in primary and metastatic tumors are associated with disease progression.
Hepatitis C
Engineering of TEV protease variants by yeast ER sequestration screening (YESS) of combinatorial libraries.
Hepatitis C
Yeast Endoplasmic Reticulum Sequestration Screening for the Engineering of Proteases from Libraries Expressed in Yeast.
Infections
Chlamydia trachomatis serovar L2 infection model using human lymphoid Jurkat cells.
Influenza, Human
Granzyme K expressing cytotoxic T lymphocytes protects against influenza virus in granzyme AB-/- mice.
Influenza, Human
Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin ?1/? dimer of infected host cells.
Leukemia
Purification and cloning of a novel serine protease, RNK-Tryp-2, from the granules of a rat NK cell leukemia.
Lung Neoplasms
Clonally expanded EOMES+ Tr1-like cells in primary and metastatic tumors are associated with disease progression.
Lymphoma
A natural killer cell granule protein that induces DNA fragmentation and apoptosis.
Melanoma
Proteomic analysis and the antimetastatic effect of N-(4-methyl)phenyl-O-(4-methoxy) phenyl-thionocarbamate-induced apoptosis in human melanoma SK-MEL-28 cells.
Multiple Sclerosis
Unexpected role for granzyme K in CD56bright NK cell-mediated immunoregulation of multiple sclerosis.
Neoplasms
Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies.
Neoplasms
CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis.
Neoplasms
Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection.
Neoplasms
Inflammatory Gene Expression Profile and Defective Interferon-? and Granzyme K in Natural Killer Cells From Systemic Juvenile Idiopathic Arthritis Patients.
Neoplasms
Valosin-containing protein cleavage by granzyme K accelerates an endoplasmic reticulum stress leading to caspase-independent cytotoxicity of target tumor cells.
Typhoid Fever
Expression of intra- and extracellular granzymes in patients with typhoid fever.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.0529
cell extract, using benzyloxycarbonyl-Lys-thiobenzyl ester as a substrate, at 25°C
37.1
after 1202.9fold purification, using benzyloxycarbonyl-Arg p-nitrobenzyl ester as a substrate, at 25°C
63.7
after 1202.9fold purification, using benzyloxycarbonyl-Lys-thiobenzyl ester as a substrate, at 25°C
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
10.2
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
from patients with allergic asthma (before and after segmental allergen challenge), and in patients with mild chronic obstructive pulmonary disease (COPD), pneumonia and in healthy controls. Expression of granzyme K is upregulated in acute airway inflammation, both in infectious and non-infectious diseases
brenda
granzyme K is expressed and secreted by cultured classically activated macrophages
brenda
granzyme serum levels are elevated in patients with autoimmune diseases and infections, including sepsis
brenda
additional information
additional information
granzymes are released by cytotoxic lymphocytes
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
physiological function
-
granzyme K induces pro-inflammatory cytokine release (interleukin-6, interleukin-8 and monocyte chemotactic protein-1) through the activation of protease-activated receptor-1, induces activation of both the ERK1/2 and p38 MAP kinase signaling pathways, and significantly increases fibroblast proliferation
physiological function
-
valosin-containing protein cleavage by granzyme K accelerates an endoplasmic reticulum stress leading to caspase-independent cytotoxicity of target tumor cells
physiological function
granzymes are serine proteases released by cytotoxic lymphocytes to induce apoptosis in virus-infected cells and tumor cells. Granzymes also play a role in controlling inflammation. Granzyme K binds to Gram-negative bacteria, e.g. Escherichia coli BL21, Pseudomonas aeruginosa, and Neisseria meningitides, and their cell-wall component lipopolysaccharide. The enzyme synergistically enhances lipopolysaccharide-induced cytokine release in vitro from primary human monocytes and in vivo in a mouse model of lipopolysaccharide challenge. The synergistic effect of the enzyme and lipopolysacchride on monocytes is dependent on cluster of differentiation 14, but the extracellular effects are independent of the enzyme catalytic activity. The enzyme disaggregates lipopolysaccharides from micelles and augments LPS-CD14 complex formation, thereby likely boosting monocyte activation by lipopolysaccharides. The extracellular enzyme is a direct modulator of LPS-TLR4 signaling during the antimicrobial innate immune response, detailed overview
physiological function
-
the enzyme has a role in cytotoxic and inflammatory processes
physiological function
the enzyme has a role in cytotoxic and inflammatory processes
physiological function
extracellular granzyme K proteolytically activates protease-activated receptor-1 leading to increased interleukin 6 and monocyte chemotactic protein 1 production in endothelial cells. Granzyme K also increases tumour necrosis factor alpha-induced inflammatory adhesion molecule expression
physiological function
granzyme K expression in testes is testosterone dependent. Granzyme K is located adjacent to germ cells in seminiferous tubules and may be involved in the degradation of microtubules in ectoplasmic specializations
physiological function
GzmK influences wound healing by augmenting inflammation and impeding epithelialization. GzmK-/- mice exhibit improved wound closure, matrix organization, and tensile strength compared with wild-type mice. Reduced proinflammatory IL-6, ICAM-1, VCAM-1, and MCP-1 expressions are observed at 3 days after injury. GzmK induces IL-6 expression in keratinocytes and skin fibroblasts that is dependent on PAR-1 activation. Keratinocytes, but not skin fibroblasts, exposed to GzmK show impaired wound healing in vitro
physiological function
in burn tissue, granzyme K expression is elevated compared with normal skin, with expression predominantly found in macrophages. Granzyme K is expressed and secreted by cultured human classically activated macrophages
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE