Information on EC 3.4.24.85 - S2P endopeptidase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea

EC NUMBER
COMMENTARY hide
3.4.24.85
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RECOMMENDED NAME
GeneOntology No.
S2P endopeptidase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
Cleaves several transcription factors that are type-2 transmembrane proteins within membrane-spanning domains. Known substrates include sterol regulatory element-binding protein (SREBP) -1, SREBP-2 and forms of the transcriptional activator ATF6. SREBP-2 is cleaved at the site DRSR_ILL_483-/-CVLTFLCLSFNPLTSLLQWGGA, in which the membrane-spanning segment is underlined. The residues NP (bold), 11 residues distal to the site of cleavage in the membrane-spanning domain, are important for cleavage by S2P endopeptidase. Replacement of either of these residues does not prevent cleavage, but there is no cleavage if both of these residues are replaced.
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
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CAS REGISTRY NUMBER
COMMENTARY hide
167140-48-9
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752251-31-3
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
strain RB50
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
Methanothermobacter thermautotrophicum
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
ATF-6 + H2O
?
show the reaction diagram
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endoplasmic reticulum membrane-anchored transcription factor, sequential processing by enzyme and S1P endopeptidase. Bulky ATF6 luminal domain blocks cleavage by enzyme, cleavage by S1P endopeptidase reduces the size of the luminal domain and prepares for hydrolysis by enzyme
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?
ATF6 + H2O
?
show the reaction diagram
ATF6 protein + H2O
?
show the reaction diagram
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?
beta-casein + H2O
?
show the reaction diagram
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?
beta-lactamase signal peptide + H2O
?
show the reaction diagram
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cleaves within the hydrophobic core at Pro12-Phe13. Cleavage of signal peptide requires a preceding processing of preproteins by Lep
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?
cAD1 pheromone + H2O
?
show the reaction diagram
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?
cAD1 protein + H2O
?
show the reaction diagram
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?
cCF10 protein + H2O
?
show the reaction diagram
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?
CED-9 + H2O
?
show the reaction diagram
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artificial protein substrate, Caenorhabditis elegans protein 9, homolog to human Bcl-2
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?
cPD1 protein + H2O
?
show the reaction diagram
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?
CREBH protein + H2O
?
show the reaction diagram
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?
FtsL protein + H2O
?
show the reaction diagram
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?
HurR protein + H2O
?
show the reaction diagram
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?
iAD1 protein + H2O
?
show the reaction diagram
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?
iCF10 protein + H2O
?
show the reaction diagram
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?
LivK signal peptide + H2O
?
show the reaction diagram
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?
MSIQHFRVALIPFFAAFCLPVFA + H2O
MSIQHFRVALIP + FFAAFCLPVFA
show the reaction diagram
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?
MtuA protein + H2O
?
show the reaction diagram
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?
MucA protein + H2O
?
show the reaction diagram
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?
OASIS protein + H2O
?
show the reaction diagram
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?
PBP3 protein + H2O
?
show the reaction diagram
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?
PodJ protein + H2O
?
show the reaction diagram
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?
PodJS + H2O
?
show the reaction diagram
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truncated form of transmembrane protein PodJ which provides the spatial cues for biogenesis of several polar organelles. Enzyme cleaves within or near the transmembrane segment of PodJS releasing it into cytoplasm for complete proteolysis
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?
pro-deltaK protein + H2O
deltaK protein + N-terminal fragment of 20 amino acids of pro-deltaK protein
show the reaction diagram
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?
pro-sigma K + H2O
?
show the reaction diagram
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?
RseA protein + H2O
?
show the reaction diagram
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?
RsiW protein + H2O
?
show the reaction diagram
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?
Sre1 protein + H2O
?
show the reaction diagram
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?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
sterol regulatory element binding protein + H2O
?
show the reaction diagram
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?
TcpP protein + H2O
?
show the reaction diagram
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?
additional information
?
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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
ATF6 + H2O
?
show the reaction diagram
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?
ATF6 protein + H2O
?
show the reaction diagram
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?
beta-lactamase signal peptide + H2O
?
show the reaction diagram
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cleaves within the hydrophobic core at Pro12-Phe13. Cleavage of signal peptide requires a preceding processing of preproteins by Lep
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?
cAD1 protein + H2O
?
show the reaction diagram
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?
cCF10 protein + H2O
?
show the reaction diagram
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?
cPD1 protein + H2O
?
show the reaction diagram
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?
CREBH protein + H2O
?
show the reaction diagram
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?
FtsL protein + H2O
?
show the reaction diagram
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?
HurR protein + H2O
?
show the reaction diagram
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?
iAD1 protein + H2O
?
show the reaction diagram
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?
iCF10 protein + H2O
?
show the reaction diagram
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?
LivK signal peptide + H2O
?
show the reaction diagram
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?
MSIQHFRVALIPFFAAFCLPVFA + H2O
MSIQHFRVALIP + FFAAFCLPVFA
show the reaction diagram
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?
MtuA protein + H2O
?
show the reaction diagram
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?
MucA protein + H2O
?
show the reaction diagram
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?
OASIS protein + H2O
?
show the reaction diagram
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?
PBP3 protein + H2O
?
show the reaction diagram
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?
PodJ protein + H2O
?
show the reaction diagram
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?
PodJS + H2O
?
show the reaction diagram
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truncated form of transmembrane protein PodJ which provides the spatial cues for biogenesis of several polar organelles. Enzyme cleaves within or near the transmembrane segment of PodJS releasing it into cytoplasm for complete proteolysis
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?
pro-deltaK protein + H2O
deltaK protein + N-terminal fragment of 20 amino acids of pro-deltaK protein
show the reaction diagram
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?
RseA protein + H2O
?
show the reaction diagram
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?
RsiW protein + H2O
?
show the reaction diagram
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?
Sre1 protein + H2O
?
show the reaction diagram
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?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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?
sterol regulatory element binding protein + H2O
?
show the reaction diagram
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Zn
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zinc metalloprotease
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
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1,10-phenanthroline specifically inhibits substrate cleavage in a concentration-dependent manner
7,8-dimethoxy-1,2,3,11a-tetrahydro-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine-5,11-dione
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analog of nelfinavir, inhibits cleavage of artificial protein substrate CED-9 in an in vitro proteolysis assay. Inhibits castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of site-2 protease cleavage activity
BofA protein
cholesterol
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inhibits the first cleavage of SREBP and indirectly S2P cleavage
nelfinavir
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nelfinavir and its analogs inhibit cleavage of artificial protein substrate CED-9 in an in vitro proteolysis assay. Nelfinavir and its analogs inhibit castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of site-2 protease cleavage activity
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
A23187
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homocysteine
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thapsigargin
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cells treated with thapsigargin exhibit proteolytic cleavage of SREBP-2
tunicamycin
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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validation of cellular assay for enzyme and S1P endopeptidase activity based on release of N-terminus of sterol regulatory element binding protein driving the expression of a luciferase reporter gene
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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transmembrane protein
Manually annotated by BRENDA team
additional information
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enzyme is unifirmly distributed around the cell and present throughout the cell cycle
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Manually annotated by BRENDA team
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 45000, SDS-PAGE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in CHO cell line
expressed in Escherichia coli
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expressed in M19 cell line
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expressed in pKK10 and pKK11 plasmid
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expressed in pKK6
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
induction of sll0528 gene expression is observed under salt, cold and hyperosmotic stress. The gene is induced to a much smaller extent by high light and mixotrophic growth with glucose
oxidative stress significantly up-regulates site-2 protease expression in CHO cells
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wild-type displays transient induction after transfer from pH 7.5 to 6.5
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
H22F
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active site mutant
D402N
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abolished activity
E23Q
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abolished activity
H26F
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abolished activity
D467N
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mutation of aspartate abolish activity suggesting that is the third residue that coordinates the zinc active site of S2P
N337Q
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mutation at glycosylation site N337 does not abolish activity
N508Q
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mutation does not abolish activity
D148A
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mutant exhibits markedly compromised protease activity
E55A
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mutant exhibits markedly compromised protease activity
H54A
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mutant exhibits markedly compromised protease activity
H54A/D148A
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mutant exhibits markedly compromised protease activity
H58A
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mutant exhibits markedly compromised protease activity
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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nelfinavir and its analogs inhibit castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of site-2 protease cleavage activity. This leads to accumulation of precursors of sterol regulatory element-binding protein SREBP-1 and activating transcription factor ATF6, and development of insufficient reserves of their transcriptionally-active forms
synthesis
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in absence of cholesterol, SREBP double cleavage leads to activation of transcription of genes encoding multiple enzymes of the cholesterol biosynthetic pathway