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Information on EC 3.4.21.B12 - prostase and Organism(s) Homo sapiens and UniProt Accession Q9Y5K2
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- 3.4.21.B12
- klk4
- kallikreins
- amelogenins
-
amelogenesis
- ameloblastin
- enamelysin
- incisor
- imperfecta
-
maturation-stage
-
amelx
-
amelotin
- medicine
-
secretory-stage
-
hypomineralized
- masp-1
-
hypomaturation
-
crystallite
-
metalloproteinase-20
- analysis
- diagnostics
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
kallikrein 4, serine protease 1, kallikrein-related peptidase 4, emsp1, kallikrein-4, prss17, prostase, kallikrein-related peptidase-4, klk-l1, klk-4 proteinase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
HK4
displays a trypsin-like specificity with strong preference for P1-Arg
kallikrein 4
KLK4
S01.251
-
-
-
-
additional information
PRSS17 is not a member of the kallikrein gene family of serine proteases but has originated prior to the divergence of the kallikrein and trypsin families of proteases
kallikrein 4
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
proteolysis of polypeptides
substrate binding pocket contains an Asp residue
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
226408-87-3
-
9001-01-8
-
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-FR-7-amido-4-methylcoumarin + H2O
benzyloxycarbonyl-FR + 7-amino-4-methylcoumarin
-
-
-
?
benzyloxycarbonyl-LR-7-amido-4-methylcoumarin + H2O
benzyloxycarbonyl-LR + 7-amino-4-methylcoumarin
-
-
-
?
D-Val-Leu-Arg-7-amido-4-trifluoromethyl coumarin + H2O
D-Val-Leu-Arg + 7-amino-4-trifluoromethyl coumarin
-
-
-
?
urokinase-type plasminogen activator receptor + H2O
?
cleaves after Thr-Tyr-Ser-Arg as well as in the sequence Val-Gln-Tyr-Arg-/-Ser-Gly
-
-
?
(Abz)-SKGR-SLIGK(N-[2,4-dintrophenyl]ethylenediamine)-Asp-OH
?
-
fluorescence quenched peptide spanning the PAR-2 activation site, is rapidly cleaved by KLK4
-
-
?
52 kDa prostatic acid phosphatase + H2O
33 kDa prostatic acid phosphatase + 19 kDa fragment
benzoyl-L-Ile-L-Glu-Gly-L-Arg-4-nitroanilide + H2O
benzoyl-L-Ile-L-Glu-Gly-L-Arg + 4-nitroaniline
EKK-7-amido-4-methylcoumarin + H2O
EKK + 7-amino-4-methylcoumarin
-
9% of the activity with VPR-7-amido-4-methylcoumarin
-
-
?
GPR-7-amido-4-methylcoumarin + H2O
GPR + 7-amino-4-methylcoumarin
-
20% of the activity with VPR-7-amido-4-methylcoumarin
-
-
?
human ephrin-B2 + H2O
?
low activity with recombinant human enzyme and human substrate
-
-
?
murine ephrin-B2 + H2O
?
the substrate harbors N-glycosylation sites its extracellular domain sequence, R27-R178, good activity with recombinant human enzyme and murine substrate, the primary enzyme cleavage site in murine ephrin-B2 is verified as located between extracellular domain residues Arg178 and N179
cleavage fragments, overview
-
?
pro-urokinase-type plasminogen activator + H2O
activated urokinase-type plasminogen activator
protease-activated receptor-1 + H2O
?
-
KLK4 cleaves protease-activated receptor-1 at the activation site on intact cell surface
-
-
?
QAR-7-amido-4-methylcoumarin + H2O
QAR + 7-amino-4-methylcoumarin
-
38% of the activity with VPR-7-amido-4-methylcoumarin
-
-
?
tosyl-Gly-Pro-Arg-7-amido-4-methylcoumarin + H2O
tosyl-Gly-Pro-Arg + 7-amino-4-methylcoumarin
-
-
-
-
?
urokinase-type plasminogen activator receptor + H2
?
-
cleavage occurs in D1-D2 linker sequence and, to a lesser extent, in D3 juxtamembrane domain
-
-
?
VLK-7-amido-4-methylcoumarin + H2O
VLK + 7-amino-4-methylcoumarin
-
60% of the activity with VPR-7-amido-4-methylcoumarin
-
-
?
amelogenin + H2O
?
the enzyme plays a pivotal role during dental enamel formation by degrading the major enamel protein, amelogenin, prior to the final steps of enamel hardening. KLK4 self-destructs once amelogenin is degraded. It progressively loses activity, becomes aggregated, and autofragmented when incubated without substrate in both the presence and absence of reducer. However, with non-ionic detergent present as proxy substrate, KLK4 remains active and intact throughout
-
-
?
matrix metalloproteinase-1 + H2O
?
the enzyme activates matrix metalloproteinase-1, a protease that promotes prostate tumor growth and metastasis. Matrix metalloproteinase-1 is produced in the tumor compartment of prostate cancer bone metastases, highlighting its accessibility to KLK4 at this site
-
-
?
polypeptide + H2O
peptides
enzyme is involved in degradation of extracellular matrix and activation of prostate specific antigen PSA and other proteases
-
?
polypeptide + H2O
peptides
enzyme is regulated by steroid hormones
-
?
polypeptide + H2O
peptides
enzyme may be involved in the pathogenesis and/or progression of prostate, breast, and possibly other malgnancies
-
?
thrombospondin-1 + H2O
?
the enzyme liberates an N-terminal product, with purported angiogenic activity, from thrombospondin-1. It cleaves thrombospondin-1 in osteoblast-derived matrix
-
-
?
urokinase-type plasminogen activator + H2O
?
cleaves after Pro-Arg-Phe-Lys
-
-
?
52 kDa prostatic acid phosphatase + H2O
33 kDa prostatic acid phosphatase + 19 kDa fragment
-
recombinant self-activated, chimeric enzyme
products contain 256 and 73 amino acid residues, respectively
?
52 kDa prostatic acid phosphatase + H2O
33 kDa prostatic acid phosphatase + 19 kDa fragment
-
primary cleavage site is the Arg73-Ser74 bond
products contain 256 and 73 amino acid residues, respectively
?
52 kDa prostatic acid phosphatase + H2O
33 kDa prostatic acid phosphatase + 19 kDa fragment
-
inactivation of substrate
products contain 256 and 73 amino acid residues, respectively
?
52 kDa prostatic acid phosphatase + H2O
33 kDa prostatic acid phosphatase + 19 kDa fragment
-
enzyme may be involved in the physiological clearance of prostatic acid phosphatase
-
?
benzoyl-L-Ile-L-Glu-Gly-L-Arg-4-nitroanilide + H2O
benzoyl-L-Ile-L-Glu-Gly-L-Arg + 4-nitroaniline
-
recombinant self-activated, chimeric enzyme
-
-
?
benzoyl-L-Ile-L-Glu-Gly-L-Arg-4-nitroanilide + H2O
benzoyl-L-Ile-L-Glu-Gly-L-Arg + 4-nitroaniline
-
fluorogenic substrate, i.e. S-2222
-
-
?
D-Pro-L-Phe-L-Arg-4-nitroanilide + H2O
D-Pro-L-Phe-L-Arg + 4-nitroaniline
-
recombinant self-activated, chimeric enzyme
-
-
?
D-Pro-L-Phe-L-Arg-4-nitroanilide + H2O
D-Pro-L-Phe-L-Arg + 4-nitroaniline
-
fluorogenic substrate, i.e. S-2302
-
-
?
D-Val-L-Leu-L-Lys-4-nitroanilide + H2O
D-Val-L-Leu-L-Lys + 4-nitroaniline
-
recombinant self-activated, chimeric enzyme
-
-
?
D-Val-L-Leu-L-Lys-4-nitroanilide + H2O
D-Val-L-Leu-L-Lys + 4-nitroaniline
-
fluorogenic substrate, i.e. S-2251
-
-
?
D-Val-Leu-Arg-4-nitroanilide + H2O
D-Val-Leu-Arg + 4-nitroaniline
-
recombinant self-activated, chimeric enzyme
-
-
?
D-Val-Leu-Arg-4-nitroanilide + H2O
D-Val-Leu-Arg + 4-nitroaniline
-
fluorogenic substrate, i.e. S-2266
-
-
?
plasma hepatocyte growth factor activator zymogen + H2O
mature HGF activator + ?
activation, hepatocyte growth factor is mainly secreted from fibroblasts as an inactive single-chain precursor, which lacks biological activity
-
-
?
plasma hepatocyte growth factor activator zymogen + H2O
mature HGF activator + ?
conversion to an active two-chain form
-
-
?
polypeptide + H2O
peptides
-
enzyme plays a role in the physiologic processing of seminal plasma proteins , e.g. pro-PSA, as well as in the pathogenesis of prostate cancer through the activation of pro-PSA
-
?
pro-prostate-specific antigen + H2O
activated prostate-specific antigen
-
activation of substrate
-
?
pro-prostate-specific antigen + H2O
activated prostate-specific antigen
-
recombinant self-activated, chimeric enzyme
-
?
pro-prostate-specific antigen + H2O
activated prostate-specific antigen
-
i.e. PSA
-
?
pro-prostate-specific antigen + H2O
activated prostate-specific antigen
-
activation of PSA
-
?
pro-urokinase-type plasminogen activator + H2O
activated urokinase-type plasminogen activator
-
activation of substrate
-
?
pro-urokinase-type plasminogen activator + H2O
activated urokinase-type plasminogen activator
-
recombinant self-activated, chimeric enzyme
-
?
pro-urokinase-type plasminogen activator + H2O
activated urokinase-type plasminogen activator
-
i.e. pro-uPA
-
?
additional information
?
-
enzyme is regulated by steroid hormones, contains androgen response elements in the proximal promotor region
-
-
?
additional information
?
-
kallikrein-4 is a serine protease expressed during enamel maturation, and proteolytic processing of the enamel matrix by KLK4 is critical for proper enamel formation. In vitro dipeptidyl peptidase I activates pro-KLK4 to cleave a fluorogenic peptide containing a KLK4 cleavage site
-
-
?
additional information
?
-
preference for Arg over Lys at position P1. KLK4 prefers as P2 residue the medium-sized polar Gln over the more hydrophobic Val, Leu, Thr, and Pro, whereas large aromatic and basic side chains are not accepted. Marked specificity for medium-sized to large hydrophobic P4 residues. Activation cleavage site: SCSQ-IING
-
-
?
additional information
?
-
two proteases are secreted into the enamel matrix of developing teeth. The early protease is enamelysin (MMP-20). The late protease is kallikrein 4. KLK4 aggressively degrades the retained organic matrix following the termination of enamel protein secretion. The principle functions of MMP-20 and KLK4 in dental enamel formation are to facilitate the orderly replacement of organic matrix with mineral, generating an enamel layer that is harder, less porous, and unstained by retained enamel proteins
-
-
?
additional information
?
-
-
no activity with serum albumin from human seminal plasma
-
-
?
additional information
?
-
-
enzyme has a trypsin-type substrate specificty
-
-
?
additional information
?
-
-
no activity with pyroglu-Gly-Arg-4-nitroanilide, i.e. S-2444, and with 3-carbomethoxypropionyl-L-Arg-L-Pro-L-Tyr-4-nitroanilide, i.e. S-2586
-
-
?
additional information
?
-
-
enzyme is involved in tissue remodeling and cancer metastasis
-
-
?
additional information
?
-
-
enzyme modulates the tumor-associated urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system activity by either activating the pro-enzyme form of urokinase-type plasminogen activator or cleaving the cell surface-associated urokinase-type plasminogen activator receptor
-
-
?
additional information
?
-
-
enzyme cleaves more efficiently after Arg compared to Lys at the P1 position and exhibits modest specificity for amino acids at P2 and P3 positions
-
-
?
additional information
?
-
-
KLK4 initiates phosphorylation of ERK1/2 via PAR-2
-
-
?
additional information
?
-
the enzyme performs proteolytic autoactivation
-
-
?
additional information
?
-
-
the enzyme performs proteolytic autoactivation
-
-
?
additional information
?
-
position of predicted enzyme cleavage sites within the sequence and the folded protein, structure, overview
-
-
?
additional information
?
-
-
position of predicted enzyme cleavage sites within the sequence and the folded protein, structure, overview
-
-
?
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
amelogenin + H2O
?
the enzyme plays a pivotal role during dental enamel formation by degrading the major enamel protein, amelogenin, prior to the final steps of enamel hardening. KLK4 self-destructs once amelogenin is degraded. It progressively loses activity, becomes aggregated, and autofragmented when incubated without substrate in both the presence and absence of reducer. However, with non-ionic detergent present as proxy substrate, KLK4 remains active and intact throughout
-
-
?
matrix metalloproteinase-1 + H2O
?
the enzyme activates matrix metalloproteinase-1, a protease that promotes prostate tumor growth and metastasis. Matrix metalloproteinase-1 is produced in the tumor compartment of prostate cancer bone metastases, highlighting its accessibility to KLK4 at this site
-
-
?
thrombospondin-1 + H2O
?
the enzyme liberates an N-terminal product, with purported angiogenic activity, from thrombospondin-1. It cleaves thrombospondin-1 in osteoblast-derived matrix
-
-
?
52 kDa prostatic acid phosphatase + H2O
33 kDa prostatic acid phosphatase + 19 kDa fragment
-
enzyme may be involved in the physiological clearance of prostatic acid phosphatase
-
?
plasma hepatocyte growth factor activator zymogen + H2O
mature HGF activator + ?
activation, hepatocyte growth factor is mainly secreted from fibroblasts as an inactive single-chain precursor, which lacks biological activity
-
-
?
polypeptide + H2O
peptides
-
enzyme plays a role in the physiologic processing of seminal plasma proteins , e.g. pro-PSA, as well as in the pathogenesis of prostate cancer through the activation of pro-PSA
-
?
protease-activated receptor-1 + H2O
?
-
KLK4 cleaves protease-activated receptor-1 at the activation site on intact cell surface
-
-
?
polypeptide + H2O
peptides
enzyme is involved in degradation of extracellular matrix and activation of prostate specific antigen PSA and other proteases
-
?
polypeptide + H2O
peptides
enzyme is regulated by steroid hormones
-
?
polypeptide + H2O
peptides
enzyme may be involved in the pathogenesis and/or progression of prostate, breast, and possibly other malgnancies
-
?
pro-prostate-specific antigen + H2O
activated prostate-specific antigen
-
i.e. PSA
-
?
pro-prostate-specific antigen + H2O
activated prostate-specific antigen
-
activation of PSA
-
?
additional information
?
-
enzyme is regulated by steroid hormones, contains androgen response elements in the proximal promotor region
-
-
?
additional information
?
-
kallikrein-4 is a serine protease expressed during enamel maturation, and proteolytic processing of the enamel matrix by KLK4 is critical for proper enamel formation. In vitro dipeptidyl peptidase I activates pro-KLK4 to cleave a fluorogenic peptide containing a KLK4 cleavage site
-
-
?
additional information
?
-
-
enzyme is involved in tissue remodeling and cancer metastasis
-
-
?
additional information
?
-
-
enzyme modulates the tumor-associated urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system activity by either activating the pro-enzyme form of urokinase-type plasminogen activator or cleaving the cell surface-associated urokinase-type plasminogen activator receptor
-
-
?
additional information
?
-
the enzyme performs proteolytic autoactivation
-
-
?
additional information
?
-
-
the enzyme performs proteolytic autoactivation
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
MCoTI-II
a 34-amino acid cyclic peptide found in the seeds of Momordica cochinchinensis. By grafting a preferred KLK4 cleavage sequence into MCoTI-II, a highly potent KLK4 inhibitor is produced that displays 100000fold selectivity over related kallikreins and the ability to penetrate cells. Additionally, by substituting positively charged noncontact residues in this compound, a potent and selective KLK4 inhibitor is produced that does not penetrate cells. The inhibitors are shown to be nontoxic to human cells and stable in human serum. These KLK4 inhibitors provide useful chemical tools to further define the role(s) of both intracellular and extracellular KLK4 in prostate cancer cell lines and disease models
-
siRNA
-
mediates knockdown of endogenous KLK4 in LNCaP prostate cancer cells whereby inhibiting their proliferation
-
Aprotinin
-
complex formation with the self-activated recombinant, chimeric enzyme
Zn2+
-
enzyme activity is high at zinc concentrations below 0.001 mM and decreases to about 30% at 0.1 mM. Zinc affects the K4 active site via the salt-bridge formed between the N terminus and Asp194 required for a functional active site
additional information
inhibition of KLK4 expression results in diminished invasive potential in OSCC cell lines
-
additional information
-
inhibition of KLK4 expression results in diminished invasive potential in OSCC cell lines
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.065
acetyl-FVQR-4-nitroanilide
pH 7.4, temperature not specified in the publication
0.0207
Z-FVR-p-nitroanilide
-
in 50 mM HEPES (pH 7.0), 150 mM NaCl, 10 mM CaCl2 buffer, at 25°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3.64
Z-FVR-p-nitroanilide
-
in 50 mM HEPES (pH 7.0), 150 mM NaCl, 10 mM CaCl2 buffer, at 25°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.31
-
purified recombinant enzyme, substrate H-D-Val-L-Leu-L-Lys-4-nitroanilide
0.67
-
purified recombinant enzyme, substrate N-benzoyl-L-Ile-L-Glu-Gly-L-Arg-4-nitroanilide
1.12
-
purified recombinant enzyme, substrate H-D-Pro-L-Phe-L-Arg-4-nitroanilide
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
prostate carcinoma cell line, enzyme is upregulated by androgens
KLK4 is differentially expressed in oral carcinomas. OSCC cell lines with high invasive and metastatic potential have the highest levels of KLK4 expression
-
downregulated expression in efussions compared to solid tumors, higher expression as compared to malignant mesothelioma
-
mesothelioma cell of both peritoneal and pleural origin express K4, with downregulated expression in efussions compared to solid tumors
-
co-expression of agonist and PAR-2 in primary prostate cancer (benign glands of benign prostatic hyperplasia, prostatic intraepithelial neoplasia and cancer) and prostate cancer bone metastasis
-
KLK4 protein is significantly overexpressed in malignant prostate compared with normal prostate. No significant differences in expression levels among well or poorly differentiated tumors
-
KLK4 mRNA and protein is not significantly changed in SaOs2 cells treated with conditioned media from either PC-3 cells or LNCaP cells. KLK4 mRNA is clearly increased following direct co-culture of SaOs2 cells with either PC-3 orLNCaP cells
additional information
breast carcinoma cell line, enzyme is upregulated by progetsins and androgens
restricted expression in hormonally responsive normal and neoplastic epithelial tissue, but not in prostate stromal constituents
two proteases are secreted into the enamel matrix of developing teeth. The early protease is enamelysin (MMP-20). The late protease is kallikrein 4. Kallikrein 4 is secreted by transition and maturation stage ameloblasts
-
KLK4 mRNA and protein is increased following treatment with conditioned media from SaOs-2 cells
-
abundance of K4 comparable to that in breast carcinoma, higher expression as compared to malignant mesothelioma
-
KLK4 induces loss of PAR-2 from the cell surface and receptor internalisation
-
KLK4 mRNA and protein is increased following treatment with conditioned media from SaOs-2 cells
-
enzyme expression is regulated by estrogen and progesterone in prostate cancer cells and overexpressed in prostate cancer
-
KLK4 is produced exclusively by the epithelial cancer cells
expression of human kallikrein 1-related peptidase 4 in prostate cancer patients with bone metastasis or advanced stage, immunohistochemic analysis of 62 prostate cancer samples
additional information
no expression in stomach, heart, spleen, placenta, liver, pancrease, kidney, skeletal muscle, small intestine
additional information
-
no expression in stomach, heart, spleen, placenta, liver, pancrease, kidney, skeletal muscle, small intestine
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
additional information
enzyme contains an amino-terminal pre-propeptide sequence, indicating a potential secretory function
-
additional information
-
enzyme contains an amino-terminal pre-propeptide sequence, indicating a potential secretory function
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
KLK4 dysfunction causes some types of developmental defect in enamel
metabolism
KLK4 activates matrix metalloproteinase-1, a protease that promotes prostate tumor growth and metastasis. It is a potential multifunctional regulator of prostate cancer progression
physiological function
physiological function
physiological function
the enzyme plays a pivotal role during dental enamel formation by degrading the major enamel protein, amelogenin, prior to the final steps of enamel hardening. KLK4 binds hydroxyapatite directly
physiological function
the enzyme serves vital functions in dental enamel formation. KLK4 is involved in degradation of extracellular matrix proteins and it is thought that this proteolytic activity can also promote tumor invasion and metastasis. KLK4 expression is stronger in primary tumors that later either recurred or developed metastases, suggesting that its preferential expression in OSCC might contribute to individual tumor biology
physiological function
-
kallikrein-related peptidase-4 (KLK4) initiates tumor-stroma interactions in prostate cancer through protease-activated receptor-1 (PAR-1). KLK4 triggers transmembrane signaling and upregulates interleukin-6 in WPMY-1 cells through PAR-1. Cancer epithelium produces KLK4 to activate PAR-1 in the surrounding stroma, which in-turn releases cytokines (interleukin-6) that stimulate cancer cells to proliferate and increase production of kallikreins
physiological function
the enzyme activates the hepatocyte growth factor, a multifunctional growth factor that plays an important role in cancer progression via its specific receptor tyrosine kinase MET, a c-met proto-oncogene product. Correlation between phospho-MET, MET, KLK4 expression and clinicopathological parameters, overview
physiological function
the enzyme substrate murine ephrin-B2 is glycosylated and this post-translational modification may regulate the enzyme cleavage activity
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
enzyme forms complexes with alpha1-antitrypsin, alpha2-antiplasmin and alpha2-macroglobulin
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
KLK4 is secreted as an inactive zymogen, pro-KLK4
proteolytic modification
proteolytic modification
-
recombinant chimeric enzyme with exchange of the pro-piece of the zymogen for that of prostate-specific antigen PSA to create an activation site suceptible for trypsin-type proteases proteolytically activates itself
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
by vapor diffusion in hanging drops. K4 crystallised in the presence of 10 mM Ni2+ reveals tetragonal space group P4. In the presence of Zn2+ it reveals tetragonal space group P41212. In the presence of 10 mM Co2+ it reveals monoclinic space group P21. The three different K4 crystal forms with bound Ni2+, Zn2, and Co2+ contain two, four and 16 crystallographically independent K4 molecules per asymmetric unit, respectively. K4 possesses an unusual 99-loop that creates a groove-like acidic S2 subsite
-
hanging drop vapour diffusion method using 20% PEG-MME 2000, 100 mM Tris (pH 8.5) and 10 mM NiCl2, or 100 mM HEPES (pH 6.5) and 100 mM NaCl with 1.6 M ammonium sulfate, or with 10 mM CoCl2, 100 mM Mes buffer (pH 6.0) and 1.6 M ammonium sulfate
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E77A
H25A
additional information
additional information
-
naturally occuring gene mutation G214A results in a truncated enzyme that lacks residue S207 of the catalytic triad. Mutation affects tooth enamel formation causing the enamel crystallites to grow incompletely in thickness or width but to normal length, i.e. autosomal recessive hypomaturation amelogenesis imperfecta
additional information
-
KLK-4 mutant (g.2142G>A), enamel is of normal thickness but opaque throughout its width compared with normal enamel. Enamel has a normal prismatic structure and generally a well-organized and discernable crystallite composition. In some areas, globular structures are present where crystallites are not discernable or appear to have an altered morphology. The KLK-4 mutant enamel has an increased protein content compared with normal enamel
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
nickel-nitrilotriacetic acid-Sepharose column chromatography and benzamidine-Sepharose column chromatography
recombinant chimeric enzyme after isolation from inclusion bodies and refolding
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA sequence determination and analysis, chromosome mapping and genomic organization
DNA sequence determination and analysis, chromosome mapping and genomic organization, promotor analysis
expressed in Escherichia coli M15(pREP4) cells and in insect cells (nur hk5)
construction of a chimeric enzyme with exchange of the pro-piece of the zymogen for that of prostate-specific antigen PSA to create an activation site suceptible for trypsin-type proteases, expression in Escherichia coli strain BL21(DE3)
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gene KLK4, coupling of the coding sequence of mature enzyme to the pro-domain of prostate specific antigen at the 5' end, and V5 and poly-histidine encoding sequences at the 3' end in plasmid pIBm recombinant expression as inactive zymogen in Spodoptera frugiperda insect cell line Sf9
into the BamH/HindIII restriction sites of the pQE30 vector and expressed in Escherichia coli M15[pREP4] cells
-
KLK4, 5, 6, and 7 full-length cDNA cloned into vector pRc/RSV. OV-MZ-6 ovarian cancer cells stably co-transfected with plasmids expressing K4-7. These OVKLK4+5+6+7 cells inoculated into the peritoneal cavity of nude mice
-
KLK4-pIB/V5-His construct expressed in Sf9 cells. PC-3 cell stimulated with KLK4
-
DNA sequence determination and analysis, chromosome mapping and genomic organization
DNA sequence determination and analysis, chromosome mapping and genomic organization
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
isolation from inclusion bodies after recombinant expression in Escherichia coli, refolding with self-activation during the process
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
medicine
analysis
-
enzyme-specific sandwich-type immunoassay using a monoclonal antibody, detection limit is 0.02 microgram per liter, and less than 0.1% cross-reactivity with other human kallikreins
medicine
diagnostics
four-kallikrein panel is a prostate screening test. An important proportion number of men presenting for biopsy falls outside the diagnostic grey zone, having a positive digital rectal exam or prostate-specific antigen 10-25 ng/ml. The four kallikrein panel has good discrimination in these men, and use of the panel reduces biopsy rates in this group of men by over 20%. The use of the panel in men with positive digital rectal exam or prostate-specific antigen 10-25 is justified
medicine
KLK4 can serve as a potential therapeutic target in patients with oral cancer. Inhibition of KLK4 expression results in diminished invasive potential in OSCC cell lines
medicine
-
naturally occuring gene mutation G214A results in a truncated enzyme that lacks residue S207 of the catalytic triad. Mutation affects tooth enamel formation causing the enamel crystallites to grow incompletely in thickness or width but to normal length, i.e. autosomal recessive hypomaturation amelogenesis imperfecta
medicine
-
no significant differences in enzyme protein content between healthy prostate tissue and malignant or benign prostate
medicine
-
patients with epithelial ovarian carcinoma, carcinoma cells expressed enzyme in 80% of effusions and 82% of solid tumors, levels are highest in effusions. Enzyme expression does not predict survival
medicine
-
K4 is not only expressed in prostate cancer cells, but also osteoblasts, in bone metastases. Thus, K4 may have proteolytic roles as a potential mediator of cellular interactions between prostate cancer and bone cells. Complex interactions may occur between prostate cancer and bone cells in the metastatic environment. Co-culture models are a crucial tool in evaluating cellular interactions
medicine
-
KLK-4 proteinase is essential for the final crystallite growth of enamel but is not critical for crystallite orientation, prism formation or enamel thickness
medicine
-
KLK4 initiates Ca2+ mobilization via PAR-1 and PAR-2 but not via PAR-4. KLK4 has greater efficacy for initiating Ca2+ signalling via PAR-2 than PAR-1. Signals induced by KLK4 via PARs may be important in prostate cancer
medicine
-
KLK4 is a proliferative factor with effects on cell cycle-related gene expression. It may have an important role in prostate cancer development and progression
medicine
-
tumor-associated overexpression of tissue kallikreins contributes to ovarian cancer progression. OV-MZ-6 ovarian cancer cells simultaneously expressing K4-7 display similar proliferative capacity as the vector-transfected control cells, but show significantly increased invasive behavior. Simultaneous expression of K4-7 in OV-MZ-6 cells and inoculated into the peritoneum of nude mice, results in a remarkable 92% mean increase in tumor burden compared to control cell line
medicine
-
kallikrein 4 quantification serves as an independent biomarker for the discrimination between the malignant and the benign nature of prostate tumors
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M.C.; Estreicher, A.; Gasteiger, E.; Martin M.J.; Michoud, K.; O'Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M.
The SWISS-PROT protein knowledgebase and its supplement TrEMBL
Nucleic Acids Res.
31
365-370
2003
Homo sapiens (Q9Y5K2)
Yousef, G.M.; Diamandis, E.P.
The new human tissue kallikrein gene family: structure, function, and association to disease
Endocr. Rev.
22
184-204
2001
Homo sapiens (Q9Y5K2)
Yousef, G.M.; Obiezu, C.V.; Luo, L.Y.; Black, M.H.; Diamandis, E.P.
Prostase/KLK-L1 is a new member of the human kallikrein gene family, is expressed in prostate and breast tissues, and is hormonally regulated
Cancer Res.
59
4252-4256
1999
Homo sapiens (Q9Y5K2), Homo sapiens
Stephenson, S.A.; Verity, K.; Ashworth, L.K.; Clements, J.A.
Localization of a new prostate-specific antigen-related serine protease gene, KLK4, is evidence for an expanded human kallikrein gene family cluster on chromosome 19q13.3-13.4
J. Biol. Chem.
274
23210-23214
1999
Homo sapiens (Q9Y5K2)
Nelson, P.S.; Gan, L.; Ferguson, C.; Moss, P.; Gelinas, R.; Hood, L.; Wang, K.
Molecular cloning and characterization of prostase, an androgen-regulated serine protease with prostate-restricted expression
Proc. Natl. Acad. Sci. USA
96
3114-3119
1999
Homo sapiens (Q9Y5K2), Homo sapiens
Hu, J.C.C.; Zhang, C.; Sun, X.; Yang, Y.; Cao, X.; Ryu, O.; Simmer, J.P.
Characterization of the mouse and human PRSS17 genes, their relationship to other serine proteases, and the expression of PRSS17 in developing mouse incisors
Gene
251
1-8
2000
Homo sapiens (Q9Y5K2), Homo sapiens, Mus musculus (Q9JIS2), Mus musculus
Takayama, T.K.; McMullen, B.A.; Nelson, P.S.; Matsumura, M.; Fujikawa, K.
Characterization of hK4 (prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase
Biochemistry
40
15341-15348
2001
Homo sapiens
Beaufort, N.; Debela, M.; Creutzburg, S.; Kellermann, J.; Bode, W.; Schmitt, M.; Pidard, D.; Magdolen, V.
Interplay of human tissue kallikrein 4 (hK4) with the plasminogen activation system: hK4 regulates the structure and functions of the urokinase-type plasminogen activator receptor (uPAR)
Biol. Chem.
387
217-222
2006
Homo sapiens
Prezas, P.; Arlt, M.J.; Viktorov, P.; Soosaipillai, A.; Holzscheiter, L.; Schmitt, M.; Talieri, M.; Diamandis, E.P.; Krueger, A.; Magdolen, V.
Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells
Biol. Chem.
387
807-811
2006
Homo sapiens
Davidson, B.; Xi, Z.; Klokk, T.I.; Trope, C.G.; D?rum, A.; Scheistr?en, M.; Saatcioglu, F.
Kallikrein 4 expression is up-regulated in epithelial ovarian carcinoma cells in effusions
Am. J. Clin. Pathol.
123
360-368
2005
Homo sapiens
Obiezu, C.V.; Michael, I.P.; Levesque, M.A.; Diamandis, E.P.
Human kallikrein 4: enzymatic activity, inhibition, and degradation of extracellular matrix proteins
Biol. Chem.
387
749-759
2006
Homo sapiens
Xi, Z.; Klokk, T.I.; Korkmaz, K.; Kurys, P.; Elbi, C.; Risberg, B.; Danielsen, H.; Loda, M.; Saatcioglu, F.
Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer
Cancer Res.
64
2365-2370
2004
Homo sapiens
Obiezu, C.V.; Shan, S.J.; Soosaipillai, A.; Luo, L.Y.; Grass, L.; Sotiropoulou, G.; Petraki, C.D.; Papanastasiou, P.A.; Levesque, M.A.; Diamandis, E.P.
Human kallikrein 4: quantitative study in tissues and evidence for its secretion into biological fluids
Clin. Chem.
51
1432-1442
2005
Homo sapiens
Hart, P.S.; Hart, T.C.; Michalec, M.D.; Ryu, O.H.; Simmons, D.; Hong, S.; Wright, J.T.
Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta
J. Med. Genet.
41
545-549
2004
Homo sapiens
Westermann, D.; Schultheiss, H.P.; Tschoepe, C.
New perspective on the tissue kallikrein-kinin system in myocardial infarction: role of angiogenesis and cardiac regeneration
Int. Immunopharmacol.
8
148-154
2008
Homo sapiens
Debela, M.; Magdolen, V.; Schechter, N.; Valachova, M.; Lottspeich, F.; Craik, C.S.; Choe, Y.; Bode, W.; Goettig, P.
Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences
J. Biol. Chem.
281
25678-25688
2006
Homo sapiens (Q9Y5K2)
Debela, M.; Magdolen, V.; Grimminger, V.; Sommerhoff, C.; Messerschmidt, A.; Huber, R.; Friedrich, R.; Bode, W.; Goettig, P.
Crystal structures of human tissue kallikrein 4: activity modulation by a specific zinc binding site
J. Mol. Biol.
362
1094-1107
2006
Homo sapiens
Klokk, T.I.; Kilander, A.; Xi, Z.; Waehre, H.; Risberg, B.; Danielsen, H.E.; Saatcioglu, F.
Kallikrein 4 is a proliferative factor that is overexpressed in prostate cancer
Cancer Res.
67
5221-5230
2007
Homo sapiens
Davidson, B.; Xi, Z.; Saatcioglu, F.
Kallikrein 4 is expressed in malignant mesothelioma--further evidence for the histogenetic link between mesothelial and epithelial cells
Diagn. Cytopathol.
35
80-84
2007
Homo sapiens
Wright, J.T.; Daly, B.; Simmons, D.; Hong, S.; Hart, S.P.; Hart, T.C.; Atsawasuwan, P.; Yamauchi, M.
Human enamel phenotype associated with amelogenesis imperfecta and a kallikrein-4 (g.2142G>A) proteinase mutation
Eur. J. Oral Sci.
114 Suppl 1; 13-7
discussion 39-41, 379
2006
Homo sapiens
Ramsay, A.J.; Dong, Y.; Hunt, M.L.; Linn, M.; Samaratunga, H.; Clements, J.A.; Hooper, J.D.
Kallikrein-related peptidase (KLK) 4 initiates intracellular signalling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression
J. Biol. Chem.
283
12293-12304
2008
Homo sapiens
Gao, J.; Collard, R.L.; Bui, L.; Herington, A.C.; Nicol, D.L.; Clements, J.A.
Kallikrein 4 is a potential mediator of cellular interactions between cancer cells and osteoblasts in metastatic prostate cancer
Prostate
67
348-360
2007
Homo sapiens
Debela, M.; Beaufort, N.; Magdolen, V.; Schechter, N.M.; Craik, C.S.; Schmitt, M.; Bode, W.; Goettig, P.
Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7
Biol. Chem.
389
623-632
2008
Homo sapiens (Q9Y5K2)
Lu, Y.; Papagerakis, P.; Yamakoshi, Y.; Hu, J.C.; Bartlett, J.D.; Simmer, J.P.
Functions of KLK4 and MMP-20 in dental enamel formation
Biol. Chem.
389
695-700
2008
Homo sapiens (Q9Y5K2)
Tye, C.E.; Pham, C.T.; Simmer, J.P.; Bartlett, J.D.
DPPI may activate KLK4 during enamel formation
J. Dent. Res.
88
323-327
2009
Homo sapiens (Q9Y5K2)
Wang, W.; Mize, G.J.; Zhang, X.; Takayama, T.K.
Kallikrein-related peptidase-4 initiates tumor-stroma interactions in prostate cancer through protease-activated receptor-1
Int. J. Cancer
126
599-610
2010
Homo sapiens
Avgeris, M.; Stravodimos, K.; Scorilas, A.
Kallikrein-related peptidase 4 gene (KLK4) in prostate tumors: quantitative expression analysis and evaluation of its clinical significance
Prostate
71
1780-1789
2011
Homo sapiens
Lisle, J.E.; Mertens-Walker, I.; Stephens, C.R.; Stansfield, S.H.; Clements, J.A.; Herington, A.C.; Stephenson, S.A.
Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: implications for xenograft models of human prostate cancer
Exp. Cell Res.
333
136-146
2015
Homo sapiens (Q9YSK2), Homo sapiens
Mukai, S.; Yorita, K.; Yamasaki, K.; Nagai, T.; Kamibeppu, T.; Sugie, S.; Kida, K.; Onizuka, C.; Tsukino, H.; Kamimura, T.; Kamoto, T.; Kataoka, H.
Expression of human kallikrein 1-related peptidase 4 (KLK4) and MET phosphorylation in prostate cancer tissue: immunohistochemical analysis
Hum. Cell
28
133-142
2015
Homo sapiens (Q9YSK2), Homo sapiens
Swedberg, J.E.; Ghani, H.A.; Harris, J.M.; de Veer, S.J.; Craik, D.J.
Potent, selective, and cell-penetrating inhibitors of kallikrein-related peptidase 4 based on the cyclic peptide MCoTI-II
ACS Med. Chem. Lett.
9
1258-1262
2018
Homo sapiens (Q9Y5K2), Homo sapiens
Papagerakis, P.; Pannone, G.; Zheng, L.I.; Athanassiou-Papaefthymiou, M.; Yamakoshi, Y.; McGuff, H.S.; Shkeir, O.; Ghirtis, K.; Papagerakis, S.
Clinical significance of kallikrein-related peptidase-4 in oral cancer
Anticancer Res.
35
1861-1866
2015
Homo sapiens (Q9Y5K2), Homo sapiens
Perez, V.; Mangum, J.; Hubbard, M.
Direct evidence that KLK4 is a hydroxyapatite-binding protein
Biochem. Biophys. Res. Commun.
495
1896-1900
2017
Homo sapiens (Q9Y5K2)
Yang, F.; Aubele, M.; Walch, A.; Gross, E.; Napieralski, R.; Zhao, S.; Ahmed, N.; Kiechle, M.; Reuning, U.; Dorn, J.; Sweep, F.; Magdolen, V.; Schmitt, M.
Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer
Biol. Chem.
398
1151-1164
2017
Homo sapiens (Q9Y5K2), Homo sapiens
Fuhrman-Luck, R.A.; Stansfield, S.H.; Stephens, C.R.; Loessner, D.; Clements, J.A.
Prostate cancer-associated kallikrein-related peptidase 4 activates matrix metalloproteinase-1 and thrombospondin-1
J. Proteome Res.
15
2466-2478
2016
Homo sapiens (Q9Y5K2)
Vickers, A.; Vertosick, E.A.; Sjoberg, D.D.; Roobol, M.J.; Hamdy, F.; Neal, D.; Bjartell, A.; Hugosson, J.; Donovan, J.L.; Villers, A.; Zappala, S.; Lilja, H.
Properties of the 4-kallikrein panel outside the diagnostic gray zone meta-analysis of patients with positive digital rectal examination or prostate specific antigen 10 ng/ml and above
J. Urol.
197
607-613
2017
Homo sapiens (Q9Y5K2)
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