Information on EC 3.4.23.45 - memapsin 1

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The expected taxonomic range for this enzyme is: Euteleostomi

EC NUMBER
COMMENTARY hide
3.4.23.45
-
RECOMMENDED NAME
GeneOntology No.
memapsin 1
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-/-Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
cleavage of C-N-linkage
-
-
-
-
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY hide
447457-31-0
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
Mus musculus C57/B16
C57/B16
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
-
the key step in the generation of Abeta is cleavage of APP by beta-secretase
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
(MCA)Glu-Val-Lys-Met-Asp-Ala-Glu-Phe-Lys(DNP) + H2O
(MCA)Glu-Val-Lys-Met + Asp-Ala-Glu-Phe-Lys(DNP)
show the reaction diagram
-
synthetic peptide substrate based on the beta-secretase cleavage site of wild-type APP
-
-
?
amyloid precursor protein + H2O
fragments of amyloid precursor protein
show the reaction diagram
amyloid-alpha pecursor protein + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid-beta precursor protein + H2O
?
show the reaction diagram
beta-amyloid precursor protein APP + H2O
beta-amyloid protein + beta-amyloid precursor protein pre-peptide
show the reaction diagram
DELTA322-IL-1R2 + H2O
fragments of DELTA322-IL-1R2
show the reaction diagram
-
truncated protein cotransfected with the enzyme in HEK 293
cleavage in the same manner as for the full length protein with cleavage between Phe329 and Gln330
-
?
gamma-secretase cleavage site of notch + H2O
?
show the reaction diagram
-
NCH-gamma
-
-
?
IL-1R2 + H2O
?
show the reaction diagram
-
synthetic peptide from Val322 to Ser341
-
-
?
IL-1R2 + H2O
fragments of IL-1R2
show the reaction diagram
insulin B chain + H2O
?
show the reaction diagram
-
only pro-BACE2-T1
-
-
?
kinetensin + H2O
?
show the reaction diagram
-
-
-
-
?
Mastoparan + H2O
?
show the reaction diagram
-
-
-
-
?
neuropetide + H2O
?
show the reaction diagram
-
Met-Lys-Arg-Ser-Arg-Gly-Pro-Ser-Pro-Arg-Arg
-
-
?
pigment cell-specific melanocyte protein + H2O
?
show the reaction diagram
-
-
BACE2 processes pigment cell-specific melanocyte protein to generate functional amyloids. BACE2 cleaves the integral membrane form of pigment cell-specific melanocyte protein within the juxtamembrane domain, releasing the luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis
-
?
preproenkephalin fragment 128-140 + H2O
?
show the reaction diagram
-
-
-
-
?
preproenkephalin fragment 129-138 + H2O
?
show the reaction diagram
-
ENK-1
-
-
?
rhodamine-EVNLDAEFK-quencher + H2O
?
show the reaction diagram
-
FRET-substrate
-
-
?
Swedish amyloid-beta pecursor protein + H2O
?
show the reaction diagram
Tmem27 + H2O
?
show the reaction diagram
-
proliferative plasma membrane protein
BACE2 inactivates Tmem27 by cleavage to release a 25000 Da N-terminal part and a 22000 Da C-terminal fragment
-
?
additional information
?
-
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
amyloid precursor protein + H2O
fragments of amyloid precursor protein
show the reaction diagram
amyloid-beta precursor protein + H2O
?
show the reaction diagram
beta-amyloid precursor protein APP + H2O
beta-amyloid protein + beta-amyloid precursor protein pre-peptide
show the reaction diagram
IL-1R2 + H2O
fragments of IL-1R2
show the reaction diagram
-
cleavage produces fragments which are almost identical to those produced by alpha-sectretase, enzyme might act in an alternative alpha-sectretase like cleavage
cleavage between Phe329 and Gln330
-
?
pigment cell-specific melanocyte protein + H2O
?
show the reaction diagram
-
-
BACE2 processes pigment cell-specific melanocyte protein to generate functional amyloids. BACE2 cleaves the integral membrane form of pigment cell-specific melanocyte protein within the juxtamembrane domain, releasing the luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis
-
?
additional information
?
-
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)-6-methoxy-1Hbenzo[d]imidazole
-
inhibitor of BACE1, EC 3.4.23.46. 150fold more effective on BACE1 than BACE2
6-fluoro-2-(3-(7-fluoroimidazo[1,2-a]pyridin-2-yl)phenyl)-1H-benzo[d]imidazole
-
inhibitor of BACE1, EC 3.4.23.46. 200fold more effective on BACE1 than BACE2
6-fluoro-2-(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)-1H-benzo-[d]imidazole
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inhibitor of BACE1, EC 3.4.23.46. 100fold more effective on BACE1 than BACE2
Asn-Val-Met-Leu-(S)-CH(OH)CH2-Ala-Ala-Ile-Phe
-
-
brefeldin A
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strongly inhibits cleavage of amyloid-beta precursor protein
Cu2+
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70% inhibition at 1 mM
Glu-Glu-Asn-Leu-CH(OH)CH2-Ala-Met-Glu-Phe
-
-
-
Glu-Val-Asn-Leu-(S)-CH(OH)CH2-Ala-Ala-Glu-Phe
-
-
-
Glu-Val-Asn-Leu-CONH-Ala-Ala-Glu-Phe
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inhibitors based on this structure, molecular size is substantially reduced while maintaining comparable enzyme inhibitory potencies
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Lys-Thr-Glu-Glu-Ile-Ser-Glu-Val-Asn-Stat-Val-Ala-Glu-Phe
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P10-P40 StatVal, beta-secretase inhibitor
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}dibenzo[b,f]oxepine-10-carboxamide
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hydroxyethylamine transition-state inhibitor, binding structure at the active site, interaction mode
Zn2+
-
70% inhibition at 1 mM
additional information
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.2
gamma-secretase cleavage site of notch
-
pH 6.5, 37°C
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.003224
2-(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)-6-methoxy-1Hbenzo[d]imidazole
-
pH 4.5, 25°C
0.003568
6-fluoro-2-(3-(7-fluoroimidazo[1,2-a]pyridin-2-yl)phenyl)-1H-benzo[d]imidazole
-
pH 4.5, 25°C
0.003081
6-fluoro-2-(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)-1H-benzo-[d]imidazole
-
pH 4.5, 25°C
0.0000016
Glu-Val-Asn-Leu-(S)-CH(OH)CH2-Ala-Ala-Glu-Phe
-
-
-
0.000036
Glu-Val-Asn-Leu-CONH-Ala-Ala-Glu-Phe
-
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00332
2-(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)-6-methoxy-1Hbenzo[d]imidazole
Homo sapiens
-
pH 4.5, 25°C
0.00367
6-fluoro-2-(3-(7-fluoroimidazo[1,2-a]pyridin-2-yl)phenyl)-1H-benzo[d]imidazole
Homo sapiens
-
pH 4.5, 25°C
0.00317
6-fluoro-2-(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)-1H-benzo-[d]imidazole
Homo sapiens
-
pH 4.5, 25°C
0.000041
Lys-Thr-Glu-Glu-Ile-Ser-Glu-Val-Asn-Stat-Val-Ala-Glu-Phe
Homo sapiens
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pH 4.5, 37°C, substrate concentration 0.015 mM
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.015
-
pro-BACE2-T1
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4.5 - 5.5
-
-
6
-
pro-BACE2-T1 with preproenkephalin fragment 129-138 as substrate
9 - 10
-
pro-BACE2-T2 with gamma-secretase cleavage site of notch as substrate
9.5
-
pro-BACE2-T1 with gamma-secretase cleavage site of notch as substrate
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
of muscle cells
Manually annotated by BRENDA team
low expression; low expression
Manually annotated by BRENDA team
-
transcription control at two sites, tissue-specific expression, overview
Manually annotated by BRENDA team
-
BACE2 mRNA is expressed at much lower levels than in pancreas
Manually annotated by BRENDA team
-
BACE2 mRNA is expressed at much lower levels than in pancreas
Manually annotated by BRENDA team
low expression; low expression
Manually annotated by BRENDA team
low expression; low expression
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
enzyme is poorly reinternalized into membrane
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50000
-
non-glycosylated, SDS-PAGE
55000
non-glycosylated, SDS-PAGE
56000
-
SDS-PAGE
60000
-
glycosylated, SDS-PAGE, present in muscle biopsies, but not in cultured fibers
65000
-
glycosylated, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
proteolytic modification
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
evolutionary trace analysis identifies group-specific residues in the ligand binding sites of BACE1, EC 3.4.23.46, and BACE2.The residues are Pro70, Ile110, Ile126, andAsn233 of BACE1 substituting Lys86, Leu126, Leu142, and Leu246 of BACE2, respectively.These group-specific residues would be the reason for cleavage site selectivity in BACE1 and BACE2 biological function
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purified N- and C-terminally truncated BACE2, residues Ala13-Ala398, in complex with hydroxyethylamine transition-state inhibitor, 0.001 ml of 8.8 mg/ml protein in 10 mM Tris-HCl, pH 6.8, 350 mM NaCl, 2 mM inhibitor, and 2% v/v DMSO, 20°C, is mixed with 0.001 ml of reservoir solution containing 16% w/v PEG 8000, 100 mM CaCl2, and 5% v/v glycerol, equilibration against 0.6 ml reservoir solution, six to eight weeks, X-ray diffraction structure determination and analysis at 3.1 A resolution
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4 - 12
-
stable, over 80% enzyme activity between pH 4 and pH 12
638897
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimethyl sulfoxide
-
assay in 3.3% final concentration
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
two variants of the pro-protease domain: pro-BACE2-T1 and pro-BACE2-T2
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
coexpressed with the Swedish mutant of APP in 20E2 cells, expressed as GFP-fusion protein using lentivirus
-
DNA and amino acid sequence analysis, 5'-flanking region analysis, BACE2 mapping to chromosome 21q22.3, expression analysis, sequence comparison to BACE1
-
DNA and amino acid sequence analysis, expression analysis, sequence comparison to BACE1, functional expression in primary rat cortical cell cultures
-
expressed as C-terminal Myc-His fusion protein in HEK 293 cells
-
expressed in HEK 293 cells
-
expressed together with full length IL-IR2 or truncated form DELTA322-IL-1R2 in HEK 293 cells
-
expression in CHO cell
-
expression of the wild-type and mutated zymogens in Escherichia coli strain BL21(DE3) in inclusion bodies, followed by refolding and autoactivation
-
localization on chromosome 21
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mouse model overexpresing BACE2
-
the encoding gene is located on chromosome 21 in the Down syndrome critical region
two variants of the pro-protease domain: pro-BACE2-T1 and pro-BACE2-T2
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
BACE2 mRNA levels are downregulated at 6, 12, and 24 h exposure to 0.01 mM AlCl3 and 0.002 mM amyloid beta peptide
-
BACE2 mRNA levels are significantly increased after 1 and 3 h exposure to 0.01 mM AlCl3 and 0.002 mM amyloid beta peptide
-
neither treatment with 0.002 mM of the Abeta(25-35) fragment nor with 0.01 mM AlCl3 alone influences BACE2 gene mRNA after 24 h
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
R310Lys
-
mutation interferes with the ability of the enzyme to cleave at the beta site of amyloid-beta precursor protein, but not at their respective cleavage sites internal to amyloid-beta protein
additional information
-
construction of an N- and C-terminally truncated BACE2 lacking the transmembrane and the cytoplasmic domains
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
refolding of recombinant zymogen from Escherichia coli strain BL21(DE3) inclusion bodies followed by autoactivation
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
-
therapeutic interventions that potentiate BACE2 may prevent Alzheimer’s disease
medicine
pharmacology
the enzyme is a potential target for development of inhibitors in Alzheimer's disease therapy and treatment of Down syndrome