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Information on EC 3.4.21.112 - site-1 protease and Organism(s) Homo sapiens and UniProt Accession Q14703
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3.4.21.112 site-1 proteaseSpecify your search results
Word Map
- 3.4.21.112
-
srebps
- proprotein
- furin
-
site-2
- atf6
-
subtilase
-
lassa
- arenaviruses
- medicine
-
cleavage-activating
-
mbtps1
-
nonbasic
-
crimean-congo
-
mucolipidosis
- glcnac-1-phosphotransferase
-
n-acetylglucosamine-1-phosphotransferase
- degradation
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Reaction Schemes
processes precursors containing basic and hydrophobic/aliphatic residues at P4 and P2, respectively, with a relatively relaxed acceptance of amino acids at P1 and P3
Synonyms
ski-1, ski-1/s1p, site-1 protease, site 1 protease, pcsk8, hski-1, convertase site 1 protease, srebp site 1 protease, subtilisin kexin isozyme 1/site 1 protease, subtilisin-kexin isoenzyme-1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CAS REGISTRY NUMBER
COMMENTARY
167140-48-9
-
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
Ac-AISRRLL-7-amido-4-methylcoumarin + H2O
Ac-AISRRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-FISRRLL-7-amido-4-methylcoumarin + H2O
Ac-FISRRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-IAVGRTLK-7-amido-4-methylcoumarin + H2O
Ac-IAVGRTLK + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-IYISRRLL-7-amido-4-methylcoumarin + H2O
Ac-IYISRRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-QKSIAVGRTLK-7-amido-4-methylcoumarin + H2O
Ac-QKSIAVGRTLK + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-RKLL-7-amido-4-methylcoumarin + H2O
Ac-RKLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-RRLL-7-amido-4-methylcoumarin + H2O
Ac-RRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-RRLQ-7-amido-4-methylcoumarin + H2O
Ac-RRLQ + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-RTLK-7-amido-4-methylcoumarin + H2O
Ac-RTLK + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-SFITRRLQ-7-amido-4-methylcoumarin + H2O
Ac-SFITRRLQ + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-YISRRLL-7-amido-4-methylcoumarin + H2O
Ac-YISRRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-YSSVSRKLL-7-amido-4-methylcoumarin + H2O
Ac-YSSVSRKLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Dabcyl-Arg-His-Ser-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Leu-Glu-Gly-Gly-Lys(tetramethylrhodamine)-OH + H2O
?
-
-
-
?
Dabcyl-Ser-Gly-Ser-Gly-Arg-Ser-Val-Leu-Ser-Phe-Glu-Ser-Gly-Ser-Lys(tetramethylrhodamine)-Arg-OH + H2O
?
-
-
-
?
Lassa virus envelope glycoprotein precursor + H2O
?
the enzyme recognition motif RRLL is critical for the processing of the Lassa virus envelope glycoprotein in the endoplasmic reticulum/cis-Golgi compartment
-
-
?
2-aminobenzoic acid-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala + H2O
2-aminobenzoic acid-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu + Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala
-
cleaves between Leu and Gly
-
?
2-aminobenzoic acid-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-3-nitrotyrosyl-Ala-CONH2 + H2O
2-aminobenzoic acid-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu + Gly-Thr-Phe-Thr-3-nitrotyrosyl-Ala-CONH2
-
-
-
-
?
2-aminobenzoyl-ALVLRKPLFLDSY(NO2)-Ala + H2O
?
-
cleaves between Leu and Phe
-
?
2-aminobenzoyl-Arg-Asn-Thr-Pro-Arg-Arg-Glu-Arg-Arg-Arg-Lys-Lys-Arg-Gly-Leu-(3-nitro)Tyr-Ala + H2O
2-aminobenzoyl-Arg-Asn-Thr-Pro-Arg-Arg-Glu-Arg-Arg-Arg-Lys-Lys-Arg-Gly-Leu + (3-nitro)Tyr-Ala
-
cleaves between Leu and 3-nitrotyrosine
-
?
2-aminobenzoyl-Arg-His-Ser-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Ile-(3-nitro)Tyr-Ala + H2O
2-aminobenzoyl-Arg-His-Ser-Ser-Arg-Arg-Leu-Leu + Arg-Ala-Ile-(3-nitro)Tyr-Ala
-
cleaves between Leu and Arg
-
?
2-aminobenzoyl-Arg-Ser-Leu-Lys-Tyr-Ala-Glu-Ser-Asp-(3-nitro)-Tyr-Ala + H2O
2-aminobenzoyl-Arg-Ser-Leu-Lys + Tyr-Ala-Glu-Ser-Asp-(3-nitro)-Tyr-Ala
-
cleaves between Lys and Tyr
-
?
2-aminobenzoyl-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Leu-Glu-(3-nitro)Tyr-Ala + H2O
2-aminobenzoyl-Ser-Arg-Arg-Leu-Leu + Arg-Ala-Leu-Glu-(3-nitro)Tyr-Ala
-
cleaves between Leu and Arg
-
?
2-aminobenzoyl-SSGSRRLLSEESY(NO2)-Ala + H2O
?
-
cleaves between Leu and Ser
-
?
2-aminobenzoyl-Val-Phe-Arg-Ser-Leu-Lys-Tyr-Ala-Glu-Ser-Asp-(3-nitro)Tyr-Ala + H2O
2-aminobenzoyl-Val-Phe-Arg-Ser-Leu-Lys + Tyr-Ala-Glu-Ser-Asp-(3-nitro)Tyr-Ala
-
cleaves between Lys and Tyr
-
?
Abz-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala-CONH2 + H2O
Abz-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu + Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala-CONH2
-
i.e. QPC251-263
-
-
?
Abz-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala-NH2 + H2O
?
-
favored quenched fluorogenic substrate
-
-
?
Abz-DIYISRRLLGTFTY(NO2)A + H2O
?
-
S1P displays pronounced positive cooperativity with this substrate derived from the viral coat glycoprotein of the lassa virus
-
-
?
ATF6 precursor + H2O
nuclear ATF6
-
rSt-1 and rSt-2 seem to affect the processing of ATF6 by SKI-1
-
-
?
brain-derived neurotrophic factor precursor + H2O
?
-
cleaves at an RGLTLS site between Thr and Ser
-
?
CREB4 + H2O
?
-
i.e. androgen-induced leucine zipper protein, C-terminal domain of CREB4 somehow confers resistance to cleavage by S1P, which can be released either by removal of the region or physiologically by some regulatory signal
-
-
?
Crimean Congo hemorrhagic fever virus glycoprotein + H2O
glycoprotein precursor Gn + glycoprotein precursor Gc
-
-
-
-
?
glycoprotein + H2O
?
-
S1P is involved in the processing of the glycoproteins of the genetically more-distant South American hemorrhagic fever viruses Guanarito, Machupo, and Junin
-
-
?
Lassa virus glycoprotein precursor GP-C + H2O
Lassa virus glycoprotein GP-2 + ?
-
cleavage at the C-terminal end of the recognition motif R-R-L-L
-
-
?
Lassa virus glycoprotein precursor protein + H2O
peripheral virion attachment protein GP1 + fusion-active transmembrane protein GP2
-
-
Arg-Arg-Leu-Leu + Gly-Thr-Phe
-
?
lymphocytic choriomeningitis virus glycoprotein precursor protein + H2O
peripheral virion attachment protein GP1 + fusion-active transmembrane protein GP2
-
-
Arg-Arg-Leu-Ala + Gly-Thr-Phe
-
?
succinyl-YISRRLL-7-amido-4-methylcoumarin + H2O
succinyl-YISRRLL + 7-amino-4-methylcoumarin
-
-
-
-
?
arenavirus envelope glycoprotein precursor + H2O
?
activation, F259A replacement at P7 of the viral protein substrate impaires the reaction, while replacement of with F does not affect enzyme processing. The catalytic pocket of the enzyme may interact with additional substrate residues distal from the actual cleavage site. Residue Y285 of the enzyme, located distal from the catalytic triad, is implicated in the molecular recognition of the aromatic signature residue at P7 and is crucial for efficient processing of OW and clade C NW arenavirus glycoprotein precursor
-
-
?
arenavirus envelope glycoprotein precursor + H2O
?
activation/maturation
-
-
?
Crimean Congo hemorrhagic fever virus glycoprotein + H2O
?
-
cleavage at RRLL-sites
-
-
?
Crimean Congo hemorrhagic fever virus glycoprotein + H2O
?
-
posttranslational cleavage by furin/PC-mediated processing at its N-terminus at RSKR247 and by SKI-1 at its C-terminus at RRLL519
-
-
?
additional information
?
-
the enzyme performs autocatalytic cleavage and activation. The cleavage of arenavirus glycoproteins, but not cellular substrates, critically depends on the autoprocessing of the enzyme, suggesting differences in the processing of cellular and viral substrates. The exogenous soluble enzyme is unable to process arenavirus lymphocytic choriomeningitis virus and pathogenic Lassa virus envelope glycoproteins displayed at the surface of enzyme-deficient cells, indicating that glycoprotein processing occurs in an intracellular compartment
-
-
?
additional information
?
-
zymogen activation of the enzyme involving sequential autocatalytic processing of its N-terminal prodomain at sites B'/B followed by the C'/C sites. Enzyme autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. All incompletely matured intermediates of SKI-1/S1P show full catalytic activity toward cellular substrates, whereas optimal cleavage of viral glycoproteins depends on B'/B processing. Incompletely matured forms of SKI-1/S1P further process cellular and viral substrates in distinct subcellular compartments
-
-
?
additional information
?
-
substrate specificity and activity of wild-type enzyme and pro-domain mutants towards cellular and viral substrates, construction and evaluation of a cell-based chimeric protein molecular sensor, containing the LASVGPC cleavage site IYISRRLL-/-G, to monitor endogenous enzyme activity, overview
-
-
?
additional information
?
-
the SKI-1/S1P recognition site RRLL is present in the enzyme SKI-1/S1P prodomain and Lassa virus envelope glycoprotein precursor , but not in the lymphocytic choriomeningitis virus envelope glycoprotein precursor, it is crucial for the processing of the Lassa virus glycoprotein in the endoplasmic reticulum/cis-Golgi compartment
-
-
?
additional information
?
-
-
peptides containing RSLK and RRLL are cleaved best
-
?
additional information
?
-
-
RRLL peptide representing the Gn processing site is efficiently cleaves but an RKPL peptide representing the GC processing site is cleaved at negligible levels
-
?
additional information
?
-
-
SKI-1 cleaves inactive proproteins at the motif R-X-(hydrophobic)-Z with Z being mostly Leu
-
-
?
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
Ac-AISRRLL-7-amido-4-methylcoumarin + H2O
Ac-AISRRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-FISRRLL-7-amido-4-methylcoumarin + H2O
Ac-FISRRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-IAVGRTLK-7-amido-4-methylcoumarin + H2O
Ac-IAVGRTLK + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-IYISRRLL-7-amido-4-methylcoumarin + H2O
Ac-IYISRRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-QKSIAVGRTLK-7-amido-4-methylcoumarin + H2O
Ac-QKSIAVGRTLK + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-RKLL-7-amido-4-methylcoumarin + H2O
Ac-RKLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-RRLL-7-amido-4-methylcoumarin + H2O
Ac-RRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-RRLQ-7-amido-4-methylcoumarin + H2O
Ac-RRLQ + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-RTLK-7-amido-4-methylcoumarin + H2O
Ac-RTLK + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-SFITRRLQ-7-amido-4-methylcoumarin + H2O
Ac-SFITRRLQ + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-YISRRLL-7-amido-4-methylcoumarin + H2O
Ac-YISRRLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Ac-YSSVSRKLL-7-amido-4-methylcoumarin + H2O
Ac-YSSVSRKLL + 7-amino-4-methylcoumarin
an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
-
-
?
Lassa virus glycoprotein precursor protein + H2O
peripheral virion attachment protein GP1 + fusion-active transmembrane protein GP2
-
-
Arg-Arg-Leu-Leu + Gly-Thr-Phe
-
?
lymphocytic choriomeningitis virus glycoprotein precursor protein + H2O
peripheral virion attachment protein GP1 + fusion-active transmembrane protein GP2
-
-
Arg-Arg-Leu-Ala + Gly-Thr-Phe
-
?
succinyl-YISRRLL-7-amido-4-methylcoumarin + H2O
succinyl-YISRRLL + 7-amino-4-methylcoumarin
-
-
-
-
?
arenavirus envelope glycoprotein precursor + H2O
?
activation, F259A replacement at P7 of the viral protein substrate impaires the reaction, while replacement of with F does not affect enzyme processing. The catalytic pocket of the enzyme may interact with additional substrate residues distal from the actual cleavage site. Residue Y285 of the enzyme, located distal from the catalytic triad, is implicated in the molecular recognition of the aromatic signature residue at P7 and is crucial for efficient processing of OW and clade C NW arenavirus glycoprotein precursor
-
-
?
arenavirus envelope glycoprotein precursor + H2O
?
activation/maturation
-
-
?
additional information
?
-
the enzyme performs autocatalytic cleavage and activation. The cleavage of arenavirus glycoproteins, but not cellular substrates, critically depends on the autoprocessing of the enzyme, suggesting differences in the processing of cellular and viral substrates. The exogenous soluble enzyme is unable to process arenavirus lymphocytic choriomeningitis virus and pathogenic Lassa virus envelope glycoproteins displayed at the surface of enzyme-deficient cells, indicating that glycoprotein processing occurs in an intracellular compartment
-
-
?
additional information
?
-
zymogen activation of the enzyme involving sequential autocatalytic processing of its N-terminal prodomain at sites B'/B followed by the C'/C sites. Enzyme autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. All incompletely matured intermediates of SKI-1/S1P show full catalytic activity toward cellular substrates, whereas optimal cleavage of viral glycoproteins depends on B'/B processing. Incompletely matured forms of SKI-1/S1P further process cellular and viral substrates in distinct subcellular compartments
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CaCl2
-
recombinant S1P-1 activity can be stimulated by Ca2+, but is not dependent on Ca2+. Increases activity of recombinant S1P-1 60% at 4 mM, higher concentrations of CaCl2 lowers the activity
KCl
-
increases activity of recombinant S1P-1 25% dependent on the substrate used
NaCl
-
increases activity of recombinant S1P-1 25% at 50 mM dependent on the substrate used
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(R)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
inhibits endogenous SREBP processing in Chinese hamster ovary cells. Compound down-regulates the signal from an SRE-luciferase reporter gene in human embryonic kidney 293 cells and the expression of endogenous SREBP target genes in cultured HepG2 cells. In mice treated with the compound for 24 h, the expression of hepatic SREBP target genes is suppressed, and the hepatic rates of cholesterol and fatty acid synthesis are reduced
decanoyl-RRLL-chloromethylketone
the selective and cell-permeable small-peptide inhibitor inhibits the enzyme and leads to suppression of proliferation and metabolic activity of melanoma cells in vitro. The inhibitor induces classical apoptosis of melanoma cells in vitro and affects expression of several SKI-1 target genes including activating transcription factor 6. The compound induces cell death in an ATF6-independent manner
(2R,2'R)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino[(2S)-1-oxo-4-phenylbutane-2,1-diyl]imino]]bis(3-phenylpropanoic acid)
-
-
(2S,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-methylbutanoic acid)
-
-
(2S,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(4-phenylbutanoic acid)
-
-
(3S,4S,5S,6R)-2-([(2R,3S,4S,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-4-yl]amino)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol
-
i.e. BJ-12-26-1, greatly reduces SKI-1 zymogen processing, and abolishes the processing of substrate SREBP-2
(3S,4S,5S,6R)-2-([(2S,3S,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3-yl]amino)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol
-
i.e. BJ-12-21-2, greatly reduces SKI-1 zymogen processing, and abolishes the processing of substrate SREBP-2
1-(4-[[2-(2-methoxyphenyl)ethyl](pyrrolidin-3-yl)carbamoyl]benzyl)piperidine-3-carboxamide
-
-
2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]diacetic acid
-
-
3,4-dichloroisocoumarin
-
potent slow binding inhibitor, 100% inhibition by 0.05 mM
4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride
-
inhibits SKI-1 and the autocatalytic generation of St-1
4-(2-azabicyclo[2.2.1]hept-2-ylmethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-(6-azabicyclo[3.2.1]oct-6-ylmethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-([[(1S,2S)-2-hydroxycyclohexyl]amino]methyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-[(diethylamino)methyl]-N-[2-(2-ethoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-[(3R)-pyrrolidin-3-yl]benzamide
-
-
4-[(diethylamino)methyl]-N-[2-(2-methylphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-[[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
benzyl N-[(2-[(E)-[2-(2-oxo-2-[[(1S)-2-oxo-2-phenoxy-1-phenylethyl]amino]ethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-phenylalaninate
-
competitive. E-isomer is thermally stable
benzyl N-[(2-[(E)-[2-(2-[[(2S)-3-methyl-1-oxo-1-phenoxybutan-2-yl]amino]-2-oxoethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-leucinate
-
competitive. E-isomer is thermally stable
dibenzyl (2R,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-methylbutanoate)
-
-
dibenzyl (2R,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-phenylpropanoate)
-
-
N-[(2-[(E)-[2-(2-[[(1S)-1-carboxy-2-methylpropyl]amino]-2-oxoethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-leucine
-
competitive. E-isomer is thermally stable
N-[2-(2,6-dichlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(2-chlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(2-methoxyphenyl)ethyl]-4-(piperidin-1-ylmethyl)-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(2-methoxyphenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(4-chlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
-
-
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
-
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
purified S-enantiomer
PF-429242
-
potent S1P inhibitor both in vitro and in cell-based assays, PF-429242 inhibits S1P-mediated processing of arenavirus arenavirus glycoprotein precursor protein
additional information
-
decanoyl-RVKR-chloromethylketone does not affect SKI-1-mediated processing
-
additional information
-
(Z-LL)2-chloromethylketone and PN1 have no effect on St-2 production. Overexpressed rSt-1 or rSt-2 impede ATF6 processing by SKI-1
-
additional information
-
decanoyl-RVKR-chloromethylketone inhibition is selective to furin/PCs and does not affect SKI-1-mediated processing
-
additional information
-
not inhibited by Mn2+, 7B2 C-terminal peptide, ProSAAS235-244 peptide, ProSAAS235-246 peptide, trypsin inhibitor from bovine pancreas, trypsin inhibitor from soybean, Pefabloc SC (4-(2-aminoethyl) benzene sulphonyl fluoride), benzamidine, p-aminobenzamidine and chymostatin
-
additional information
-
SKI-1/S1P inhibition by overexpression of proSKI variants, results in reduced cholesterol synthesis and mRNA levels of the rate-limiting enzymes HMG-CoA reductase and squalene epoxidase in the cholesterol synthetic pathway. Inhibitory effect is maintained in the presence of homocysteine-induced endoplasmic reticulum stress. SKI-1/S1P inhibition also affects glycolysis and citric acid cycle
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
cellular stress induced by tunicamycin does not regulate the production of St-2
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.028
2-aminobenzoyl-Arg-Asn-Thr-Pro-Arg-Arg-Glu-Arg-Arg-Arg-Lys-Lys-Arg-Gly-Leu-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.02
2-aminobenzoyl-Arg-His-Ser-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Ile-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.00096
2-aminobenzoyl-Arg-Ser-Leu-Lys-Tyr-Ala-Glu-Ser-Asp-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.0044
2-aminobenzoyl-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.023
2-aminobenzoyl-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Leu-Glu-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.00428
2-aminobenzoyl-Val-Phe-Arg-Ser-Leu-Lys-Tyr-Ala-Glu-Ser-Asp-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.0504
Ac-AISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.067
Ac-AISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0123
Ac-FISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.015
Ac-FISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0226
Ac-IAVGRTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0846
Ac-IAVGRTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0047
Ac-IYISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0074
Ac-IYISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0025
Ac-QKSIAVGRTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0156
Ac-QKSIAVGRTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0274
Ac-RKLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0564
Ac-RKLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0153
Ac-RRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0228
Ac-RRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0971
Ac-RRLQ-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.2263
Ac-RRLQ-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0967
Ac-RTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.2167
Ac-RTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0443
Ac-SFITRRLQ-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0784
Ac-SFITRRLQ-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0028
Ac-YISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.005
Ac-YISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0056
Ac-YISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0057
Ac-YISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0212
Ac-YSSVSRKLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0281
Ac-YSSVSRKLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.14
(2R,2'R)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino[(2S)-1-oxo-4-phenylbutane-2,1-diyl]imino]]bis(3-phenylpropanoic acid)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.075
(2S,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-methylbutanoic acid)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.225
(2S,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(4-phenylbutanoic acid)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.265
2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]diacetic acid
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
231
4-(2-aminoethyl benzene)sulfonyl fluoride
-
substrate Abz-DIYISRRLL-GTFT-Tyx-A, 37°C, pH 7.4
57.7
Ac-VFRSLK-4-(2-aminoethyl benzene)sulfonyl fluoride
-
substrate Abz-DIYISRRLL-GTFT-Tyx-A, 37°C, pH 7.4
0.0118
benzyl N-[(2-[(E)-[2-(2-oxo-2-[[(1S)-2-oxo-2-phenoxy-1-phenylethyl]amino]ethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-phenylalaninate
-
pH 7.4, 37°C
0.125
benzyl N-[(2-[(E)-[2-(2-[[(2S)-3-methyl-1-oxo-1-phenoxybutan-2-yl]amino]-2-oxoethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-leucinate
-
pH 7.4, 37°C
0.125
dibenzyl (2R,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-methylbutanoate)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.0118
dibenzyl (2R,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-phenylpropanoate)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.0758
N-[(2-[(E)-[2-(2-[[(1S)-1-carboxy-2-methylpropyl]amino]-2-oxoethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-leucine
-
pH 7.4, 37°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000175 - 0.0005
(R)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
0.000393 - 0.000971
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
0.00016
1-(4-[[2-(2-methoxyphenyl)ethyl](pyrrolidin-3-yl)carbamoyl]benzyl)piperidine-3-carboxamide
Homo sapiens
-
-
0.000095
4-(2-azabicyclo[2.2.1]hept-2-ylmethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.000029
4-(6-azabicyclo[3.2.1]oct-6-ylmethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00059
4-(benzyloxy)-N-[2-(2-chlorophenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00031
4-(benzyloxy)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00051
4-(benzyloxy)-N-[2-(3-chlorophenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.0001
4-([[(1S 2S)-2-hydroxycyclohexyl]amino]methyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.016
4-[(diethylamino)methyl]-N-[2-(2-ethoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00054
4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00017
4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-[(3R)-pyrrolidin-3-yl]benzamide
Homo sapiens
-
-
0.0016
4-[(diethylamino)methyl]-N-[2-(2-methylphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00014
4-[[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00043
N-[2-(2 6-dichlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.0014
N-[2-(2-chlorophenyl)ethyl]-4-(1-methylethoxy)-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00084
N-[2-(2-chlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.000008
N-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
most potent inhibitor
0.009
N-[2-(2-fluorophenyl)ethyl]-4-(1-methylethoxy)-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00025
N-[2-(2-methoxyphenyl)ethyl]-4-(piperidin-1-ylmethyl)-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.000037
N-[2-(2-methoxyphenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.0096
N-[2-(3-chlorophenyl)ethyl]-4-(1-methylethoxy)-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.0037
N-[2-(4-chlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.000175
(R)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
Homo sapiens
inhibitory profile is determined by measuring the luciferase activity of a transfected sterol regulatory element (SRE)-TATA-luciferase construct into HEK-293 cells
0.0005
(R)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
Homo sapiens
in HepG2 cells, compound inhibits cholesterol synthesis, with an IC50 of 0.0005 mM
0.000393
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
Homo sapiens
inhibitory profile is determined by measuring the luciferase activity of a transfected sterol regulatory element (SRE)-TATA-luciferase construct into HEK-293 cells
0.000971
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
Homo sapiens
purified S-enantiomer, inhibitory profile is determined by measuring the luciferase activity of a transfected sterol regulatory element (SRE)-TATA-luciferase construct into HEK-293 cells
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.007
-
first 997 amino acids of human S1P lacking the C-terminal transmembrane region prepared from Trichoplusia ni egg, High Five cells
0.022
-
first 997 amino acids of human S1P lacking the C-terminal transmembrane region prepared from Sf21 cells, 103fold purified
0.2
-
first 997 amino acids of human S1P lacking the C-terminal transmembrane region prepared from Sf21 cells
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
the enzyme SKI-1 is constitutively expressed in human pigment cells with higher SKI activity in seven out of eight melanoma cell lines compared with normal melanocytes, also detectable in tumor cells of melanoma metastases
additional information
additional information
subtilisin-kexin isoenzyme-1 (SKI-1) expression and activity in human pigment cells in vitro, as well as in normal human skin and metastatic melanoma, overview
additional information
-
subtilisin-kexin isoenzyme-1 (SKI-1) expression and activity in human pigment cells in vitro, as well as in normal human skin and metastatic melanoma, overview
additional information
-
SW-13 cell, infected with crimean-Congo hemorrhagic fever virus
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
the truncated mutant DELTA AC SKI-1/S1P BTMD, truncated before the transmembrane domain, stays in the endoplasmic reticulum
-
-
relocalization of SP1 and SP2 with brefeldin A, reconstitution of the sequential cleavage of ATF6
-
SP1 localizes to the same compartment as SP2, the cis/medial Golgi
-
most of membrane-bound SKI-1 and its stumps St-1 and St-2 localize to the Golgi and can enter the endosomal/lysosomal compartments but do not sort to the cell surface
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
physiological function
additional information
malfunction
enzyme SKI-1 inhibition induces apoptosis of melanoma cells by a non-ATF6-dependent mechanism, overview
malfunction
soluble enzyme is unable to process arenavirus glycoproteinss at the cell surface
physiological function
a crucial step in the life cycle of arenaviruses is the biosynthesis of the mature fusion-active viral envelope glycoprotein that is essential for virus-host cell attachment and entry. The maturation of the arenavirus envelope glycoprotein precursor critically depends on proteolytic processing by the cellular proprotein convertase subtilisin kexin isozyme-1/site-1 protease
physiological function
the arenaviruses are an important family of emerging viruses that includes several causative agents of severe hemorrhagic fevers in humans that represent serious public health problems. A crucial step of the arenavirus life cycle is maturation of the envelope glycoprotein precursor by the cellular subtilisin kexin isozyme 1/site 1 protease
physiological function
the enzyme plays crucial roles in cellular homeostatic functions and is hijacked by pathogenic viruses for the processing of their envelope glycoproteins. Zymogen activation of the enzyme involves sequential autocatalytic processing of its N-terminal prodomain at sites B'/B followed by the C'/C sites. All incompletely matured intermediates of SKI-1/S1P showed full catalytic activity toward cellular substrates, whereas optimal cleavage of viral glycoproteins depended on B'/B processing. Incompletely matured forms of SKI-1/S1P further process cellular and viral substrates in distinct subcellular compartments
physiological function
the enzyme regulates cartilage development, bone mineralization, and processing of viral glycoproteins, its overexpression is linked to carcinogenesis in some solid tumors, biological role of enzyme SKI-1 in melanoma development, overview
physiological function
-
inhibition of S1P enzymatic activity in human hepatoma Huh-7.5.1 cells results in a robust reduction of the numbers of lipid droplets and lipid droplet-positive areas and effectively inhibits infection by dengue virsu DENV. Pre-treatment of Huh-7.5.1 cells with PF-429242 results in a dose-dependent inhibition of DENV and an about 3-log decrease in DENV-2 titer with 20 microM of PF-429242. Post-treatment of DENV-2 infected Huh-7.5.1 cells with PF-429242 does not affect viral RNA abundance, but it does compromise the assembly and/or release of infectious virus particles. PF-429242 antiviral activity is reversed by exogenous oleic acid
physiological function
-
inhibition of site-1 protease leads to a profound reduction in plasmablast number linked to induction of autophagy. Plasmablasts generated in the presence of site-1 protease inhibitor segregate into CD38high and CD38low populations, the latter characterized by a marked reduction in the capacity to secrete IgG. Site-1 protease inhibition is accompanied by a distinctive change in gene expression associated with amino acid, steroid and fatty acid synthesis pathways
additional information
9 amino acid residues at the cleavage site (P1-P8) and P1' are necessary and sufficient to define the subcellular location of processing and to determine to what extent processing of a substrate depends on SKI-1/S1P maturation
additional information
modeling of the SKI-1/S1P catalytic pocket identifies Y285 as a residue that potentially interacts with arenavirus envelope glycoprotein precursor residue Y253. The the catalytic triad is formed by residues D218, H249, and S414
additional information
-
modeling of the SKI-1/S1P catalytic pocket identifies Y285 as a residue that potentially interacts with arenavirus envelope glycoprotein precursor residue Y253. The the catalytic triad is formed by residues D218, H249, and S414
additional information
the transmembrane anchorage and the cytoplasmic domain of SKI-1/S1P are dispensable for arenavirus glycoprotein processing
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). MBTP1_HUMAN
1052
1
117749
Swiss-Prot
Secretory Pathway (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
98000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
glycoprotein
proteolytic modification
proteolytic modification
the enzyme performs autocatalytic cleavage and activation depending on the recognition site RRLL, present in the enzyme prodomain
proteolytic modification
zymogen activation of the enzyme involves sequential autocatalytic processing of its N-terminal prodomain at sites B'/B followed by the C'/C sites. Autocatalytic maturation by sequential cleavages of the N-terminal pro-domain first at sites B'/B (RKVF2RSLK1372), followed by site C (RRLL1862), with crucial roles for R and V/L residues at P4 and P2 (fourth and second residue upstream the scissile bond, respectively). Enzyme autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. 9 Amino acid residues at the cleavage site (P1-P8) and P1' are necessary and sufficient to define the subcellular location of processing and to determine to what extent processing of a substrate depends on SKI-1/S1P maturation. Mature enzyme retains prodomain fragments of different lengths, overview. The post-translational modifications are crucial for the subcellular localization of autoprocessing intermediates of the enzyme
proteolytic modification
-
proSKI-1 is processed into two membrane-bound forms of SKI-1: 120000 Da and 106000 Da
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H249A
R130E/R134E
site-directed mutagenesis, the double mutations at the B'/B site prevents autoprocessing
R134E
site-directed mutagenesis, the single prodomain mutant, at the B autoprocessing site, allows maturation comparably with the wild-type enzyme
H249A
-
active site mutant, autocatalytic generation of St-1 is abrogated, St-2 fragment is generated at a level of ca. 15%
P1003S
-
natural mutation identified in a female patient. The mutant protein is able to complement lipid and cholesterol biosynthetic capacities in cells that lack S1P and is abundant in both the ER and the Golgi
R130A/K131A
-
proSKI variant that exhibits no basic residue at the P4 position, has no effect on HMG-CoA reductase mRNA levels
R134E
-
proSKI variant that lacks autocatalytic primary cleavage site RSLK, most efficient inhibitor of HMG-CoA reductase expression
additional information
H249A
site-directed mutagenesis, catalytically inactive mutant showing no autoprocessing
additional information
the soluble form of the enzyme is truncated before the transmembrane domain and comprised the ectodomain, followed by a C-terminal V5 tag, i.e. DELTA AC SKI-1/S1P BTMD. Extended mutagenesis performed on a region proximal to the C site results in normal SKI-1/S1P maturation at the B'/B intermediate state, suggesting that processing at B'/B either precedes or occurs independently of C site cleavage. The combined mutation at the C and C' sites results in marked reduction of the mature C form indicating that, similar to B'/B, mutation of both C and C' processing sites is required to prevent maturation
additional information
-
Crimean Congo hemorrhagic fever virus-infected cells deficient in SKI-1/S1P produce no infectious virus, although precursor Gn and precursor Gc accumulate normally in the Golgi apparatus, the site of virus assembly. Complementation of SKI-1/S1P-deficient cells with a SKI-1/S1P expression vector restores release of infectious virus
additional information
-
in the triple shedding site mutant KLL/A autocatalytic generation of St-1 is abrogated, St-2 fragment is generated at a level of ca. 15%
additional information
-
using SRD12B mutant cells lacking the S1P gene, it is shown that lack of glycoprotein processing of Junin virus dramatically reduces production of infectious virus and prevents cell-to-cell propagation. Infection of S1P-deficient cells results in viral persistence over several weeks without the emergence of escape variants able to use other cellular proteases for GP processing
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant C-terminally His6-tagged wild-type mutant enzyme from HEK-293T cell medium by immobilized metal affinity chromatography
first 997 amino acids of human S1P lacking the C-terminal transmembrane region 103fold purified by immobilised metal affinity chromatography on Co2+ column
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cDNA encoding amino acids 17 to 997, encompassing the prodomain, catalytic domain, and cysteine-rich domain of soluble site 1 protease (sS1P) is expressed in CHO cells
functional expression of full-length wild-type enzyme, which undergoes complete autoprocessing, in SRD12B cells. Recombinant expression HEK-293T and CHO cells, real-time quantitative PCR expression analysis
transient expression of C-terminally His6-tagged full-length wild-type enzyme and a soluble enzyme variant truncated before the transmembrane domain, the catalytically inactive mutant H249A, B'/B, B' mutants of enzyme in HEK-293T cells, secretion of proteins. Wild-type and the DELTA AC SKI-1/S1P FL mutant are expressed in the SKI-I/S1P-deficient CHO cell line SRD12B, which lacks active endogenous enzyme
transient expression of wild-type and mutant enzymes in enzyme-deficient SRD12B cells
first 997 amino acids of human S1P lacking the C-terminal transmembrane region. Full-length sequence of human S1P. Both tagged with a C-terminal 8 x His-tag, subcloned into the entry vector pDONR201 and expressed by baculovirus expression vector system in Sf9 cells. Additionally, first 997 amino acids of human S1P lacking the C-terminal transmembrane region expressed in Sf21 cells and Trichoplusia ni egg, High Five cells
-
full length SKI-1 and its H249A mutant expressed in HEK-293 cells, M19 cells, HuH7 cells and Hep-G2 cells. Wild-type SKI-1 and mutants H249A, L925A and K948A expressed in SRD-12B and CHO-K1 cells. Wild-type SKI-1 or a secretable form of St-1 containing a signal peptide followed by a FLAG tag at the N terminus and a V5 tag at the C terminus overexpressed in CHO-K1 cells. rSt-1 coexpressed with protease inhibitors in CHO-K1 and Neuro-2a cells. Mutants I985A, I989L, M990L, M990A, M990I, Y994A, N995A, and double mutant Y994A/N995A expressed in CHO-K1 cells
-
SKI-1/S1P deficient SRD12B cells transiently transfected with SKI-1/S1P-containing vector
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
degradation
-
S1P reduces the size of the luminal domain to prepare ATF6 to be an optimal S2P substrate
medicine
additional information
-
cleaves glycoprotein, the only cleaved glycoprotein is incorporated into virions and this is necessary for the formation of infectious virus
medicine
small-molecule S1P inhibitors are capable of reducing cholesterol and fatty acid synthesis in vivo and, therefore, represent a potential new class of therapeutic agents for dyslipidemia and for a variety of cardiometabolic risk factors associated with diabetes, obesity, and the metabolic syndrome
medicine
-
SKI-1/S1P processing is strictly required for incorporation of viral glycoproteins. SKI-1/S1P may represent a promising antiviral target
medicine
-
useful role of SKI-1/S1P in controlling cholesterol synthesis, particularly in the presence of endoplasmic reticulum stress. SKI-1/S1P inhibition may be a potential tool for the treatment of alcohol-induced liver steatosis
medicine
-
a female patient with a heterozygous missense mutation in the transmembrane domain of S1P (Pro1003Ser) displays episodic, activity-induced, focal myoedema and myalgias with hyperCKemia. The clinical phenotype includes gastrointestinal hypomotility, ocular migraines, and polycystic ovary syndrome. The mutation leads to increased activation of protein response and lipid and cholesterol regulatory pathways and localization of S1P Pro1003Ser in the Golgi
medicine
-
in fibroblasts of mucolipidosis type II mice and Niemann-Pick type C patients characterized by aberrant cholesterol accumulation, the proteolytic cleavage of the alpha/beta-subunit precursor of N -acetylglucosamine-1-phosphotransferase is not impaired
medicine
-
S1P is a potential target for indirect-acting pan-serotypic anti-dengue virus agents
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Basak, A.; Chretien, M.; Seidah, N.G.
A rapid fluorometric assay for the proteolytic activity of SKI-1/S1P based on the surface glycoprotein of the hemorrhagic fever Lassa virus
FEBS Lett.
514
333-339
2002
Homo sapiens
Toure, B.B.; Munzer, J.S.; Basak, A.; Benjannet, S.; Rochemont, J.; Lazure, C.; Chretien, M.; Seidah, N.G.
Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment
J. Biol. Chem.
275
2349-2358
2000
Homo sapiens
Vincent, M.J.; Sanchez, A.J.; Erickson, B.R.; Basak, A.; Chretien, M.; Seidah, N.G.; Nichol, S.T.
Crimean-Congo hemorrhagic fever virus glycoprotein proteolytic processing by subtilase SKI-1
J. Virol.
77
8640-8649
2003
Homo sapiens
Seidah, N.G.; Mowla, S.J.; Hamelin, J.; Mamarbachi, A.M.; Benjannet, S.; Toure, B.B.; Basak, A.; Munzer, J.S.; Marcinkiewicz, J.; Zhong, M.; Barale, J.C.; Lazure, C.; Murphy, R.A.; Chretien, M.; Marcinkiewicz, M.
Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization
Proc. Natl. Acad. Sci. USA
96
1321-1326
1999
Homo sapiens, Rattus norvegicus (Q9WTZ3)
Basak, S.; Stewart, N.A.; Chretien, M.; Basak, A.
Aminoethyl benzenesulfonyl fluoride and its hexapeptide (Ac-VFRSLK) conjugate are both in vitro inhibitors of subtilisin kexin isozyme-1
FEBS Lett.
573
186-194
2004
Homo sapiens
Shen, J.; Prywes, R.
Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6
J. Biol. Chem.
279
43046-43051
2004
Homo sapiens
Seidah, N.G.; Chretien, M.
Proprotein convertase SKI-1/SIP
Handbook of Proteolytic Enzymes (Barrett, A. J. , Rawlings, N. D. , Woessner, J. F. , Eds. ) Academic Press
2
1845-1847
2004
Arabidopsis thaliana, Cricetulus griseus, Homo sapiens, Mus musculus, Oryza sativa, Rattus norvegicus
-
Sanchez, A.J.; Vincent, M.J.; Erickson, B.R.; Nichol, S.T.
Crimean-congo hemorrhagic fever virus glycoprotein precursor is cleaved by Furin-like and SKI-1 proteases to generate a novel 38-kilodalton glycoprotein
J. Virol.
80
514-525
2006
Homo sapiens
Stirling, J.; OHare, P.
CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P
Mol. Biol. Cell
17
413-426
2005
Homo sapiens
Lenz, O.; Ter Meulen, J.; Klenk, H.D.; Seidah, N.G.; Garten, W.
The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P
Proc. Natl. Acad. Sci. USA
98
12701-12702
2001
Homo sapiens
Hay, B.A.; Abrams, B.; Zumbrunn, A.Y.; Valentine, J.J.; Warren, L.C.; Petras, S.F.; Shelly, L.D.; Xia, A.; Varghese, A.H.; Hawkins, J.L.; Van Camp, J.A.; Robbins, M.D.; Landschulz, K.; Harwood, H.J.
Aminopyrrolidineamide inhibitors of site-1 protease
Bioorg. Med. Chem. Lett.
17
4411-4414
2007
Homo sapiens
De Windt, A.; Rai, M.; Bernier, L.; Thelen, K.; Soini, J.; Lefebvre, C.; Chintawar, S.; Lavigne, J.; Saarinen, L.; Kytoemaeki, L.; Munzer, J.S.; Luetjohann, D.; Pandolfo, M.; Davignon, J.; Seidah, N.G.; Laaksonen, R.
Gene Set Enrichment Analysis Reveals Several Globally Affected Pathways due to SKI-1/S1P Inhibition in HepG2 Cells
DNA Cell Biol.
26
765-772
2007
Homo sapiens
Pullikotil, P.; Benjannet, S.; Mayne, J.; Seidah, N.G.
The proprotein convertase SKI-1/S1P: Alternate translation and subcellular localization
J. Biol. Chem.
282
27402-27413
2007
Homo sapiens
Bergeron, E.; Vincent, M.J.; Nichol, S.T.
Crimean-Congo hemorrhagic fever virus glycoprotein processing by the endoprotease SKI-1/S1P is critical for virus infectivity
J. Virol.
81
13271-13276
2007
Homo sapiens
Bodvard, K.; Mohlin, J.; Knecht, W.
Recombinant expression, purification, and kinetic and inhibitor characterisation of human site-1-protease
Protein Expr. Purif.
51
308-319
2007
Homo sapiens
Hawkins, J.L.; Robbins, M.D.; Warren, L.C.; Xia, D.; Petras, S.F.; Valentine, J.J.; Varghese, A.H.; Wang, I.K.; Subashi, T.A.; Shelly, L.D.; Hay, B.A.; Landschulz, K.T.; Geoghegan, K.F.; Harwood, H.J.
Pharmacologic inhibition of site 1 protease activity inhibits sterol regulatory element-binding protein processing and reduces lipogenic enzyme gene expression and lipid synthesis in cultured cells and experimental animals
J. Pharmacol. Exp. Ther.
326
801-808
2008
Homo sapiens (Q14703), Homo sapiens
Rojek, J.M.; Lee, A.M.; Nguyen, N.; Spiropoulou, C.F.; Kunz, S.
Site 1 protease is required for proteolytic processing of the glycoproteins of the South American hemorrhagic fever viruses Junin, Machupo, and Guanarito
J. Virol.
82
6045-6051
2008
Homo sapiens
Basak, A.; Mitra, D.; Das, A.K.; Mohottalage, D.; Basak, A.
C2-Symmetric azobenzene-amino acid conjugates and their inhibition of Subtilisin Kexin Isozyme-1
Bioorg. Med. Chem. Lett.
20
3977-3981
2010
Homo sapiens
Zandberg, W.F.; Benjannet, S.; Hamelin, J.; Pinto, B.M.; Seidah, N.G.
N-glycosylation controls trafficking, zymogen activation and substrate processing of proprotein convertases PC1/3 and subtilisin kexin isozyme-1
Glycobiology
21
1290-1300
2011
Homo sapiens
Urata, S.; Yun, N.; Pasquato, A.; Paessler, S.; Kunz, S.; de la Torre, J.C.
Antiviral activity of a small-molecule inhibitor of arenavirus glycoprotein processing by the cellular site 1 protease
J. Virol.
85
795-803
2011
Homo sapiens
Da Palma, J.; Burri, D.; Oppliger, J.; Salamina, M.; Cendron, L.; De Laureto, P.; Seidah, N.; Kunz, S.; Pasquato, A.
Zymogen activation and subcellular activity of subtilisin kexin isozyme 1/site 1 protease
J. Biol. Chem.
289
35743-35756
2014
Homo sapiens (Q14703)
Weiss, N.; Stegemann, A.; Elsayed, M.A.; Schallreuter, K.U.; Luger, T.A.; Loser, K.; Metze, D.; Weishaupt, C.; Boehm, M.
Inhibition of the prohormone convertase subtilisin-kexin isoenzyme-1 induces apoptosis in human melanoma cells
J. Invest. Dermatol.
134
168-175
2014
Homo sapiens (Q14703), Homo sapiens
Burri, D.; Pasqual, G.; Rochat, C.; Seidah, N.; Pasquato, A.; Kunz, S.
Molecular characterization of the processing of arenavirus envelope glycoprotein precursors by subtilisin kexin isozyme-1/site-1 protease
J. Virol.
86
4935-4946
2012
Homo sapiens (Q14703)
Burri, D.; da Palma, J.; Seidah, N.; Zanotti, G.; Cendron, L.; Pasquato, A.; Kunz, S.
Differential recognition of old world and new world arenavirus envelope glycoproteins by subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P)
J. Virol.
87
6406-6414
2013
Homo sapiens (Q14703), Homo sapiens
Kluender, S.; Heeren, J.; Markmann, S.; Santer, R.; Braulke, T.; Pohl, S.
Site-1 protease-activated formation of lysosomal targeting motifs is independent of the lipogenic transcription control
J. Lipid Res.
56
1625-1632
2015
Homo sapiens, Mus musculus
Schweitzer, G.; Gan, C.; Bucelli, R.; Wegner, D.; Schmidt, R.; Shinawi, M.; Finck, B.; Brookheart, R.
A mutation in Site-1 Protease is associated with a complex phenotype that includes episodic hyperCKemia and focal myoedema
Mol. Genet. Genomic Med.
2019
e733
2019
Homo sapiens
Hyrina, A.; Meng, F.; McArthur, S.J.; Eivemark, S.; Nabi, I.R.; Jean, F.
Human subtilisin kexin isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance A potential target for indirect-acting anti-dengue virus agents
PLoS ONE
12
e0174483
2017
Homo sapiens
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