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Information on EC 3.4.23.46 - memapsin 2 and Organism(s) Mus musculus and UniProt Accession P56818
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- 3.4.23.46
- alzheimer
-
presenilins
- plaque
- abeta
- notch
- amyloid-beta
- tau
- deficit
- cerebral
- neurodegenerative
- dementia
- hippocampus
-
early-onset
-
amyloidogenic
-
neuropathological
- adam10
- beta-peptide
-
intramembrane
-
neurofibrillary
- synaptic
-
neuritic
- tangle
- neuroblastoma
- cortical
-
nicastrin
- psen1
-
neurotoxic
-
senile
-
neuroprotective
- csf
-
sh-sy5y
-
epsilon4
-
hyperphosphorylation
-
endoproteolysis
-
anti-ad
-
maze
-
ad-related
-
disintegrin
- analysis
- ectodomain
-
holoproteins
-
anti-alzheimer
- beta-protein
- dapt
-
insulin-degrading
- medicine
-
swedish
-
ad-like
- pharmacology
- abeta1-42
- neprilysin
-
amyloidogenesis
- angiopathy
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-/-Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein
Synonyms
bace1, gamma-secretase, presenilin 1, presenilin-1, bace-1, alpha-secretase, presenilin-2, memapsin 2, bace 1, beta-site amyloid precursor protein cleaving enzyme, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
amyloid precursor protein secretase
-
-
-
-
APP secretase
-
-
-
-
aspartic protease BACE
-
-
-
-
aspartic protease BACE1
-
-
-
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aspartic proteinase BACE1
-
-
-
-
beta protein amyloidogenase
-
-
-
-
beta-amyloid protein precursor secretase
-
-
-
-
beta-secretase
beta-site Alzheimer's amyloid precursor protein cleaving enzyme 1 (BACE1)
-
-
-
-
beta-site APP-cleaving enzyme 1
-
-
-
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D-aspartyl-beta-amyloid secretase
-
-
-
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memapsin 1
-
-
-
-
membrane-bound aspartic protease
-
-
-
-
protease Asp2
-
-
-
-
proteinase BACE1
-
-
-
-
beta-secretase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
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
mechanism for enzyme regulation
-
CAS REGISTRY NUMBER
COMMENTARY
158736-49-3
-
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
7-amido-4-methylcoumarin-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-(Lys-2,4-dinitrophenyl)-OH + H2O
?
-
-
-
-
?
7-amido-4-methylcoumarin-Glu-Val-Lys-Met-Asp-Ala-Glu-Phe-(Lys-2,4-dinitrophenyl)-OH + H2O
?
-
-
-
-
?
amyloid beta-precursor protein + H2O
?
-
BACE1 and the amyloid beta-precursor protein processing pathway are critical for cognitive, emotional and synaptic functions
-
-
?
Z-Val-Asn-Leu-7-amido-4-methylcoumarin + H2O
Z-Val-Asn-Leu + 7-amino-4-methylcoumarin
-
-
-
-
?
beta2 subunit of voltage-gated sodium channel + H2O
?
substrate cleavage investigated, cleavage products beta2-CTFbeta and beta2-ICD characterized, multiple roles in regulating neuronal function through regulating of neuronal BACE1 substrate proteins discussed
-
-
?
amyloid precursor protein + H2O
fragments of amyloid precursor protein
-
-
-
-
?
amyloid precursor protein + H2O
fragments of amyloid precursor protein
-
BACE1 cleaves APP at the N-terminal end of the Abeta sequence, producing a 14000 Da C-terminal fragment beta or C99
-
-
?
additional information
?
-
BACE1 expression shown to be stimulated by oxidative stress, mechanism of transcriptional induction of BACE1 by oxidative stress discussed as a contribution to production of pathological levels of amyloid beta protein in Alzheimer disease
-
-
?
additional information
?
-
BACE1 function in regulation of myelination and myelin sheath thickness in the central and peripheral nerves determined, abolishment of BACE1 shown to be associated with altered neurological behaviors such as elevated pain sensitivity and reduced grip strength, altered neuregulin-AKT kinase signalling pathway in BACE1-null mice shown
-
-
?
additional information
?
-
influence of combination of ovariectomy and chronic stress on BACE1 activity analyzed
-
-
?
additional information
?
-
-
influence of combination of ovariectomy and chronic stress on BACE1 activity analyzed
-
-
?
additional information
?
-
properties of memapsin 2 inhibitors analyzed by cellular assay
-
-
?
additional information
?
-
screen for substrate proteins in pancreatic beta cells by proteomic approach reveals non-redundant roles of BACE1 and BACE2 in ectodomain shedding, with BACE1 regulating a broader and BACE2 a more distinct set of beta-cell-enriched substrates including two proteins of the seizure 6 protein family, SEZ6L and SEZ6L2
-
-
?
additional information
?
-
-
BACE1 is required for myelination and correct bundling of axons by Schwann cell most likely via processing of type III neuregulin 1
-
-
?
additional information
?
-
-
BACE 1 does not cleave Z-Val-Lys-Met-7-amido-4-methylcoumarin
-
-
?
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
amyloid beta-precursor protein + H2O
?
-
BACE1 and the amyloid beta-precursor protein processing pathway are critical for cognitive, emotional and synaptic functions
-
-
?
additional information
?
-
-
BACE1 is required for myelination and correct bundling of axons by Schwann cell most likely via processing of type III neuregulin 1
-
-
?
amyloid precursor protein + H2O
fragments of amyloid precursor protein
-
-
-
-
?
amyloid precursor protein + H2O
fragments of amyloid precursor protein
-
BACE1 cleaves APP at the N-terminal end of the Abeta sequence, producing a 14000 Da C-terminal fragment beta or C99
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(4S)-4-(2,4-difluorophenyl)-6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine
-
(4S)-4-[2,4-difluoro-5-(pyrimidin-5-yl)phenyl]-6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine
-
(4S,6R)-4-(2,4-difluorophenyl)-4-methyl-6-(pyrimidin-5-yl)-5,6-dihydro-4H-1,3-thiazin-2-amine
-
4-fluoro-1-(pyridin-4-yl)-1-[3-(pyrimidin-5-yl)phenyl]-1H-isoindol-3-amine
i.e. AZ2000. Inhibitor with improved brain disposition, reduces amyloid beta levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE1, display a 62% reduction in plasma amyloid beta40 levels, whereas brain amyloid beta40 is only lowered by 11%
(1S,2R)-N-{1-benzyl-2-hydroxy-3-(S)-[2-(1-benzylpiperidin-4-yl)ethylamino]-propyl}-5-[methyl(methylsulfonyl)amino]-N'-[(R)-1-phenylethyl]isophthalamide
-
dual inhibitor of both beta-secretase and acetylcholinesterase. Intracerebroventricular injection of into amyloid precursor protein transgenic mice causes a 29% reduction of amyloid beta1-40 production
(2S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-5-(propylsulfonyl)pyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide
-
decreases amyloid beta1-40 in wild-type mice and has excellent blood/brain barrier penetration in the absence of P-glycoprotein, P-glycoprotein is the main factor limiting efficacy of this compound
(3S,14R,16S)-16-[(1R)-1-hydroxy-2-([3-(1-methylethyl)benzyl]amino)ethyl]-3,4,14-trimethyl-1,4-diazacyclohexadecane-2,5-dione
-
inhibition of beta-secretase in the brain of amyloid precursor protein 51/16 transgenic mice after intravenous application
(3S,14R,16S)-16-[(1S)-2-[[(1R)-3,3-dimethyl-7-(1-methylethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]-1-hydroxyethyl]-3,4,14-trimethyl-1,4-diazacyclohexadecane-2,5-dione
-
inhibition of beta-secretase in the brain of amyloid precursor protein 51/16 transgenic mice after oral application
(5S)-2-amino-5-[3-fluoro-5-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one
-
aminohydantoin inhibitor, EC50 value in ELISA-assay 20 nM, and demonstrates more than 100fold selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. Acute oral administration at 100 mg/kg results in a 69% reduction of plasma amyloid beta40 at 8 h in a Tg2576 mouse
CA074Me
-
treatment of London APP transgenic mouse model of Alzheimer's disease that expresses human amyloid precursor protein containing the wild-type beta-secretase site results in substantial improvement in memory deficit assessed by the Morris water maze test. Improved memory function is accompanied by reduced amyloid plaque load, decreased amyloid beta40 and amyloid beta42, and reduced C-terminal beta-secretase fragment derived from amyloid precursor protein by beta-secretase. Inhibitor has no effects on any of these parameters in mice expressing the Swedish mutant beta-secretase site of amyloid precursor protein
E64d
-
treatment of London APP transgenic mouse model of Alzheimer's disease that expresses human amyloid precursor protein containing the wild-type beta-secretase site results in substantial improvement in memory deficit assessed by the Morris water maze test. Improved memory function is accompanied by reduced amyloid plaque load, decreased amyloid beta40 and amyloid beta42, and reduced C-terminal beta-secretase fragment derived from amyloid precursor protein by beta-secretase. Inhibitor has no effects on any of these parameters in mice expressing the Swedish mutant beta-secretase site of amyloid precursor protein
EVNLAAEF
-
Leu in the transition state isostere, i.e. OM99-2, IC50: 0.0000014 mM
N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-ethoxybenzyl)amino]propyl]-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide
-
up to 65% reduction of plasma amyloid beta in transgenic mice
additional information
-
murine BACE1 in amyloid precursor protein transgenic mouse models should exhibit similar pharmacological and enzymatic profiles to those of human BACE1 and should thus be useful in the development of BACE inhibitors for the treatment of Alzheimer's disease
-
additional information
-
CP-681301 treatment leads to significant reduction of BACE1 mRNA and protein
-
additional information
-
gamma-secretase affects BACE1 expression and induces an increase in protein levels in Alzheimer's disease
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4-hydroxynonenal
induction of BACE1 expression under oxidative stress determined
sphingosine 1-phosphate
-
treatment by sphingosine kinase inhibitor, RNA interference knockdown of sphingosine kinase, or overexpression of sphingosine 1-phosphate degrading enzymes decrease BACE1 activity, which reduces amyloid beta production. Sphingosine-1-phosphate specifically binds to full-length BACE1 and increases its proteolytic activity, suggesting that cellular sphingosine 1-phosphate directly modulates BACE1 activity
additional information
-
BACE1 is increased by oxidative stress, oxidative stress fails to induce BACE1 expression in presenilin-1 (gamma-secretase)-deficient cells and in normal cells treated with gamma-secretase inhibitors, 4-hydroxy-2,3-nonenal enhances the expression of BACE1 in a gamma-secretase-dependent manner
-
additional information
-
overexpression of peptide p25 leads to increased levels of BACE1 mRNA and protein in vitro and in vivo
-
additional information
-
thiamine deficiency causes amyloid beta accumulation in the brain, which is reversed by thiamine supplementation. Thiamine deficiency can promote beta-secretase activity, and the accumulation of amyloid beta subsequently exacerbates thiamine deficiency-induced oxidative stress
-
additional information
-
upon exposure to various cell stressors including amyloid-beta 1-42, expression of BACE1-antisense transcript becomes elevated leading to increased BACE1 mRNA stability. BACE1 expression by BACE1-antisense transcript does not occur only at the mRNA but also at the protein level. BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology.
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00015
(4S)-4-(2,4-difluorophenyl)-6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine
Mus musculus
pH and temperature not specified in the publication
0.000008
(4S)-4-[2,4-difluoro-5-(pyrimidin-5-yl)phenyl]-6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine
Mus musculus
pH and temperature not specified in the publication
0.00031
(4S,6R)-4-(2,4-difluorophenyl)-4-methyl-6-(pyrimidin-5-yl)-5,6-dihydro-4H-1,3-thiazin-2-amine
Mus musculus
pH and temperature not specified in the publication
0.0000014
EVNLAAEF
Mus musculus
-
Leu in the transition state isostere, i.e. OM99-2, IC50: 0.0000014 mM
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
beta2 subunit of voltage-gated sodium channel analyzed as substrate of BACE1, increase of mRNA and protein levels of pore-forming alpha subunit of sodium channel after cleavage observed, regulation of alpha subunit of voltage-gated sodium channel mediated through BACE1, association between BACE1 and cell-surface sodium current densities shown
additional information
genetic deletion of BACE1 causes hypomyelination, elevated pain sensitivity and reduced grip strength shown in BACE1-null mice, neuregulin-1 expression increased and cleavage products and phosphorylated AKT protein kinase shown to be decreased in BACE1-null mice, neuregulin-1 cleavage by BACE1 shown, processed neuregulin-1 regulates myelination by means of phosphorylation of AKT protein kinase in myelin-forming cells
additional information
increased BACE1 activity determined in hippocampal CA1 and CA3 regions of mice tretated by combination of ovariectomy and chronic stress, condition shown to evoke an impairment of hippocampus-dependent memory, association between stressful life after menopause and Alzheimer disease-related molecules suggested, BACE1 discussed as the most sensitive molecule
additional information
-
increased BACE1 activity determined in hippocampal CA1 and CA3 regions of mice tretated by combination of ovariectomy and chronic stress, condition shown to evoke an impairment of hippocampus-dependent memory, association between stressful life after menopause and Alzheimer disease-related molecules suggested, BACE1 discussed as the most sensitive molecule
additional information
oxidative stress measured in cytosolic fractions, antibodies and immunoblot analysis performed, RNA interference and Luciferase reporter gene assay applied, stimulation of BACE1 expression by oxidative stress determined, mechanism shown to require gamma-secretase activity involving the c-jun N-terminal kinase (JNK)/c-jun pathway, inceased BACE1 levels identified in normal cells, but not in cells lacking presenilins or amyloid precursor protein, correlation with activation of JNK and c-jun determined
additional information
synthesis, structure and potencies of memapsin 2 inhibitors shown, up to 65% reduction of plasma amyloid-beta peptide in transgenic mice indicated
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4.5
cleavage of beta2 subunit of voltage-gated sodium channel by BACE1 observed at pH 4.5 but not at pH 7
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
female ICR mice, ovariectomized or sham-operated, treated with or without daily restraint stress conditions for 6 h per day over 3 weeks
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
expression of BACE1 in CA1 and C3 regions analyzed under combination of chronic stress and ovariectomy
cleavage products of BACE1 determined, sodium-current densities reduced in neuroblastoma cells and hippocampal cells of transgenic mice
-
immortalized mouse embryonic fibroblasts from wild-type, and presenilin-deficient PS1-/-, PS2-/-, PS1-/-/PS2-/- mice. Oxidative stress fails to induce BACE1 expression in presenilin-1 deficient cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
loss of enzyme in the dentate gyrus leads to increased granule cell excitability, indicated by enhanced efficiency of synaptic potentials to generate granule cell spikes. The increase in granule cell excitability is accompanied by prolonged paired-pulse inhibition, altered network gamma oscillations, and impaired synaptic plasticity at entorhinal-dentate synapses of the perforant path
physiological function
malfunction
-
BACE1 heterozygous deletion rescues conditioned taste aversion memory deficits in 5XFAD mice
physiological function
-
BACE1 knock-out and wild-type nerves degenerate at a similar rate after axotomy and to a similar extent in the experimental neuropathies produced by administration of paclitaxel and acrylamide. BACE1 knock-out mice have markedly enhanced clearance of axonal and myelin debris from degenerated fibers, accelerated axonal regeneration, and earlier reinnervation of neuromuscular junctions, compared with littermate controls
physiological function
BACE1-/- mice develop significant retinal pathology including retinal thinning, apoptosis, reduced retinal vascular density and an increase in the age pigment, lipofuscin. BACE1 expression is highest in the neural retina. Pigment epithelial-derived factor, a regulator of gamma-secretase, inhibits vascular endothelial growth factor-induced in vitro and in vivo angiogenesis and this is abolished by BACE1 inhibition. Intravitreal administration of BACE1 inhibitor or BACE1 small interfering RNA increases choroidal neovascularization in mice. BACE1 induces ectodomain shedding of vascular endothelial growth factor receptor VEGFR1 which is a prerequisite for gamma-secretase release of a 100 kDa intracellular domain. The increase in lipofuscin following BACE1 inhibition and RNAI knockdown is associated with lysosomal perturbations
physiological function
selective inhibition of peripheral BACE1 activity in wild-type mice or mice over-expressing amyloid precursor protein reduces amyloid beta levels in the periphery but not in the brain, not even after chronic treatment over several months. BACE1 inhibitor 4-fluoro-1-(pyridin-4-yl)-1-[3-(pyrimidin-5-yl)phenyl]-1H-isoindol-3-amine with improved brain disposition reduces amyloid beta levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE1, display a 62% reduction in plasma amyloid beta40 levels, whereas brain amyloid beta40 is only lowered by 11%
physiological function
enzyme activity levels have an inverse effect on peripheral nerve repair after injury. Neuronal enzyme activity levels impact peripheral nerve regeneration. Enzyme overexpression impairs axonal regeneration as early as 3 days after injury and leads to impaired axonal regeneration 10 days after injury
physiological function
the enzyme is important for normal dentate gyrus network function
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). BACE1_MOUSE
501
1
55748
Swiss-Prot
Secretory Pathway (Reliability: 2)
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with inhibitor (2S)-2-((3R)-3-acetamido-3-isobutyl-2-oxo-1-pyrrolidinyl)-N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-2-(1,2,3,4-tetrahydro-3-isoquinolinyl)ethyl)-4-phenylbutanamide
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
BACE1 knockout mice instrumental in validating BACE1 as regulator of voltage-gated sodium channels and neuronal activity
additional information
BACE1-null mice instrumental in validating roles of BACE1 in regulation of myelination
additional information
-
BACE1 knockout mice, evidence that neither beta-secretase nor Abeta plays a vital role in mouse physiology
additional information
-
the BACE1-antisense transcript regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-beta 1-42 , expression of BACE1-antisense becomes elevated, increasing BACE1 mRNA stability and generating additional amyloid beta 142 through a post-transcriptional feed-forward mechanism. BACE1-antisense concentrations are elevated in amyloid precursor protein transgenic mice
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
BACE1 levels in 5XFAD mice are significantly increased up to 200% of those found in wild type mice
-
endogenous testosterone, independent of estrogen, downregulates BACE1 activities at transcriptional level. Heterozygous transgenic APP23/aromatase male mice exhibit decreased BACE1 protein expression and activity compared with control mice at age of 12 and 18 months
-
mRNAand activity level of BACE1 in the cortex and hippocampus remain unchanged by dietary quercetin supplementation. Supplementing primary cortical neurons with 0.00001, 0.0001 and 0.001 mM quercetin does not result in any significant change in mRNA level of BACE
-
oligemia/mild hypoperfusion produces a long lasting effect on Alzheimers disease related proteins, increasing amyloid-beta levels via enhanced BACE1 expression
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
pharmacology
development of inhibitor drugs for the treatment of Alzheimer disease
medicine
pharmacology
-
treatment of London APP transgenic mouse model of Alzheimer's disease that expresses human amyloid precursor protein containing the wild-type beta-secretase site with inhibitors CA074Me or E64d results in substantial improvement in memory deficit assessed by the Morris water maze test. Improved memory function is accompanied by reduced amyloid plaque load, decreased amyloid beta40 and amyloid beta42, and reduced C-terminal beta-secretase fragment derived from amyloid precursor protein by beta-secretase. Inhibitor hHas no effects on any of these parameters in mice expressing the Swedish mutant beta-secretase site of amyloid precursor protein
medicine
roles of BACE1 in regulation postmenopausal memory effects analyzed
medicine
-
the BACE1-antisense transcript regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-beta 1-42 , expression of BACE1-antisense becomes elevated, increasing BACE1 mRNA stability and generating additional amyloid beta 142 through a post-transcriptional feed-forward mechanism. BACE1-antisense concentrations are elevated in amyloid precursor protein transgenic mice
medicine
-
BACE1 knock-out mice have markedly enhanced clearance of axonal and myelin debris from degenerated fibers, accelerated axonal regeneration, and earlier reinnervation of neuromuscular junctions, compared with littermate controls. data suggest BACE1 inhibition as a therapeutic approach to accelerate regeneration and recovery after peripheral nerve damage
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Luo, Y.; Bolon, B.; Damore, M.A.; Fitzpatrick, D.; Liu, H.; Zhang, J.; Yan, Q.; Vassar, R.; Citron, M.
BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time
Neurobiol. Dis.
14
81-88
2003
Mus musculus
Yan, R.; Han, P.; Miao, H.; Greengard, P.; Xu, H.
The transmembrane domain of the Alzheimer's b-secretase (BACE1) determines its late Golgi localization and access to beta-amyloid precursor protein (APP) substrate
J. Biol. Chem.
276
36788-36796
2001
Homo sapiens, Mus musculus
Wong, H.K.; Sakurai, T.; Oyama, F.; Kaneko, K.; Wada, K.; Miyazaki, H.; Kurosawa, M.; De Strooper, B.; Saftig, P.; Nukina, N.
beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase
J. Biol. Chem.
280
23009-23017
2005
Mus musculus
Yang, H.C.; Chai, X.; Mosior, M.; Kohn, W.; Boggs, L.N.; Erickson, J.A.; McClure, D.B.; Yeh, W.K.; Zhang, L.; Gonzalez-DeWhitt, P.; Mayer, J.P.; Martin, J.A.; Hu, J.; Chen, S.H.; Bueno, A.B.; Little, S.P.; McCarthy, J.R.; May, P.C.
Biochemical and kinetic characterization of BACE1: investigation into the putative species-specificity for beta- and beta-cleavage sites by human and murine BACE1
J. Neurochem.
91
1249-1259
2004
Homo sapiens, Mus musculus
Laird, F.M.; Cai, H.; Savonenko, A.V.; Farah, M.H.; He, K.; Melnikova, T.; Wen, H.; Chiang, H.C.; Xu, G.; Koliatsos, V.E.; Borchelt, D.R.; Price, D.L.; Lee, H.K.; Wong, P.C.
BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions
J. Neurosci.
25
11693-11709
2005
Mus musculus
Willem, M.; Garratt, A.N.; Novak, B.; Citron, M.; Kaufmann, S.; Rittger, A.; Destrooper, B.; Saftig, P.; Birchmeier, C.; Haass, C.
Control of peripheral nerve myelination by the {beta}-secretase BACE1
Science
314
664-666
2006
Mus musculus
Ghosh, A.K.; Kumaragurubaran, N.; Hong, L.; Koelsh, G.; Tang, J.
Memapsin 2 (beta-secretase) inhibitors: drug development
Curr. Alzheimer Res.
5
121-131
2008
Homo sapiens (P56817), Mus musculus (P56818)
Tamagno, E.; Guglielmotto, M.; Aragno, M.; Borghi, R.; Autelli, R.; Giliberto, L.; Muraca, G.; Danni, O.; Zhu, X.; Smith, M.A.; Perry, G.; Jo, D.G.; Mattson, M.P.; Tabaton, M.
Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein
J. Neurochem.
104
683-695
2008
Mus musculus (P56818), Mus musculus BalbC (P56818)
Kim, D.Y.; Carey, B.W.; Wang, H.; Ingano, L.A.; Binshtok, A.M.; Wertz, M.H.; Pettingell, W.H.; He, P.; Lee, V.M.; Woolf, C.J.; Kovacs, D.M.
BACE1 regulates voltage-gated sodium channels and neuronal activity
Nat. Cell Biol.
9
755-764
2007
Homo sapiens (P56817), Homo sapiens, Mus musculus (P56818)
Hu, X.; Hicks, C.W.; He, W.; Wong, P.; Macklin, W.B.; Trapp, B.D.; Yan, R.
BACE1 modulates myelination in the central and peripheral nervous system
Nat. Neurosci.
9
1520-1525
2006
Mus musculus (P56818)
Fukuzaki, E.; Takuma, K.; Himeno, Y.; Yoshida, S.; Funatsu, Y.; Kitahara, Y.; Mizoguchi, H.; Ibi, D.; Koike, K.; Inoue, M.; Yamada, K.
Enhanced activity of hippocampal BACE1 in a mouse model of postmenopausal memory deficits
Neurosci. Lett.
433
141-145
2008
Mus musculus (P56818), Mus musculus
Zhu, Y.; Xiao, K.; Ma, L.; Xiong, B.; Fu, Y.; Yu, H.; Wang, W.; Wang, X.; Hu, D.; Peng, H.; Li, J.; Gong, Q.; Chai, Q.; Tang, X.; Zhang, H.; Li, J.; Shen, J.
Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase
Bioorg. Med. Chem.
17
1600-1613
2009
Homo sapiens, Mus musculus
Ghosh, A.K.; Kumaragurubaran, N.; Hong, L.; Kulkarni, S.; Xu, X.; Miller, H.B.; Reddy, D.S.; Weerasena, V.; Turner, R.; Chang, W.; Koelsch, G.; Tang, J.
Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation
Bioorg. Med. Chem. Lett.
18
1031-1036
2008
Homo sapiens, Mus musculus
Machauer, R.; Laumen, K.; Veenstra, S.; Rondeau, J.M.; Tintelnot-Blomley, M.; Betschart, C.; Jaton, A.L.; Desrayaud, S.; Staufenbiel, M.; Rabe, S.; Paganetti, P.; Neumann, U.
Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo
Bioorg. Med. Chem. Lett.
19
1366-1370
2009
Mus musculus, Homo sapiens (P56817)
Hook, V.Y.; Kindy, M.; Hook, G.
Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein
J. Biol. Chem.
283
7745-7753
2008
Mus musculus
Faghihi, M.A.; Modarresi, F.; Khalil, A.M.; Wood, D.E.; Sahagan, B.G.; Morgan, T.E.; Finch, C.E.; St Laurent, G.; Kenny, P.J.; Wahlestedt, C.
Expression of a noncoding RNA is elevated in Alzheimers disease and drives rapid feed-forward regulation of beta-secretase
Nat. Med.
14
723-730
2008
Homo sapiens, Mus musculus
Jo, D.G.; Arumugam, T.V.; Woo, H.N.; Park, J.S.; Tang, S.C.; Mughal, M.; Hyun, D.H.; Park, J.H.; Choi, Y.H.; Gwon, A.R.; Camandola, S.; Cheng, A.; Cai, H.; Song, W.; Markesbery, W.R.; Mattson, M.P.
Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimers disease
Neurobiol. Aging
31
917-925
2008
Homo sapiens, Mus musculus, Rattus norvegicus
Zhang, Q.; Yang, G.; Li, W.; Fan, Z.; Sun, A.; Luo, J.; Ke, Z.J.
Thiamine deficiency increases beta-secretase activity and accumulation of beta-amyloid peptides
Neurobiol. Aging
32
42-53
2011
Homo sapiens, Mus musculus
Wen, Y.; Yu, W.H.; Maloney, B.; Bailey, J.; Ma, J.; Marie, I.; Maurin, T.; Wang, L.; Figueroa, H.; Herman, M.; Krishnamurthy, P.; Liu, L.; Planel, E.; Lau, L.F.; Lahiri, D.K.; Duff, K.
Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing
Neuron
57
680-690
2008
Mus musculus
Koike, M.A.; Green, K.N.; Blurton-Jones, M.; Laferla, F.M.
Oligemic hypoperfusion differentially affects Tau and amyloid-beta
Am. J. Pathol.
177
300-310
2010
Mus musculus
Devi, L.; Ohno, M.
Genetic reductions of beta-site amyloid precursor protein-cleaving enzyme 1 and amyloid-beta ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimers disease model mice
Eur. J. Neurosci.
31
110-118
2010
Mus musculus
Malamas, M.S.; Erdei, J.; Gunawan, I.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Chopra, R.; Olland, A.; Bard, J.; Jacobsen, S.; Magolda, R.L.; Pangalos, M.; Robichaud, A.J.
Design and synthesis of 5,5-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors
J. Med. Chem.
53
1146-1158
2010
Homo sapiens, Homo sapiens (P56817), Mus musculus
McAllister, C.; Long, J.; Bowers, A.; Walker, A.; Cao, P.; Honda, S.; Harada, N.; Staufenbiel, M.; Shen, Y.; Li, R.
Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment
J. Neurosci.
30
7326-7334
2010
Mus musculus
Huebbe, P.; Wagner, A.E.; Boesch-Saadatmandi, C.; Sellmer, F.; Wolffram, S.; Rimbach, G.
Effect of dietary quercetin on brain quercetin levels and the expression of antioxidant and Alzheimers disease relevant genes in mice
Pharmacol. Res.
61
242-246
2010
Mus musculus
Thompson, L.A.; Shi, J.; Decicco, C.P.; Tebben, A.J.; Olson, R.E.; Boy, K.M.; Guernon, J.M.; Good, A.C.; Liauw, A.; Zheng, C.; Copeland, R.A.; Combs, A.P.; Trainor, G.L.; Camac, D.M.; Muckelbauer, J.K.; Lentz, K.A.; Grace, J.E.; Burton, C.R.; Toyn, J.H.; Barten, D.M.; Marcinkeviciene, J.; Meredith, J.E.; Albright, C.F.
Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors
Bioorg. Med. Chem. Lett.
21
6909-6915
2011
Mus musculus, Homo sapiens (P56817)
Farah, M.H.; Pan, B.H.; Hoffman, P.N.; Ferraris, D.; Tsukamoto, T.; Nguyen, T.; Wong, P.C.; Price, D.L.; Slusher, B.S.; Griffin, J.W.
Reduced BACE1 activity enhances clearance of myelin debris and regeneration of axons in the injured peripheral nervous system
J. Neurosci.
31
5744-5754
2011
Mus musculus
Takasugi, N.; Sasaki, T.; Suzuki, K.; Osawa, S.; Isshiki, H.; Hori, Y.; Shimada, N.; Higo, T.; Yokoshima, S.; Fukuyama, T.; Lee, V.M.; Trojanowski, J.Q.; Tomita, T.; Iwatsubo, T.
BACE1 activity is modulated by cell-associated sphingosine-1-phosphate
J. Neurosci.
31
6850-6857
2011
Homo sapiens, Mus musculus
Cai, J.; Qi, X.; Kociok, N.; Skosyrski, S.; Emilio, A.; Ruan, Q.; Han, S.; Liu, L.; Chen, Z.; Bowes Rickman, C.; Golde, T.; Grant, M.B.; Saftig, P.; Serneels, L.; de Strooper, B.; Joussen, A.M.; Boulton, M.E.
beta-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment
EMBO Mol. Med.
4
980-991
2012
Mus musculus (P56818)
Stuetzer, I.; Selevsek, N.; Esterhazy, D.; Schmidt, A.; Aebersold, R.; Stoffel, M.
Systematic proteomic analysis identifies beta-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic beta-cells
J. Biol. Chem.
288
10536-10547
2013
Mus musculus (P56818)
Georgievska, B.; Gustavsson, S.; Lundkvist, J.; Neelissen, J.; Eketjaell, S.; Ramberg, V.; Bueters, T.; Agerman, K.; Jureus, A.; Svensson, S.; Berg, S.; Faelting, J.; Lendahl, U.
Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter beta-amyloid levels in the CNS
J. Neurochem.
132
477-486
2015
Mus musculus (P56818), Mus musculus
Vnencak, M.; Schoelvinck, M.L.; Schwarzacher, S.W.; Deller, T.; Willem, M.; Jedlicka, P.
Lack of beta-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo
Brain Struct. Funct.
224
1279-1290
2019
Mus musculus (P56818)
Wu, Y.J.; Guernon, J.; Shi, J.; Marcin, L.; Higgins, M.; Rajamani, R.; Muckelbauer, J.; Lewis, H.; Chang, C.; Camac, D.; Toyn, J.H.; Ahlijanian, M.K.; Albright, C.F.; Macor, J.E.; Thompson, L.A.
Discovery of S3-truncated, C-6 heteroaryl substituted aminothiazine beta-site APP cleaving enzyme-1 (BACE1) inhibitors
J. Med. Chem.
59
8593-8600
2016
Mus musculus (P56818)
Dislich, B.; Wohlrab, F.; Bachhuber, T.; Mueller, S.A.; Kuhn, P.H.; Hogl, S.; Meyer-Luehmann, M.; Lichtenthaler, S.F.
Label-free quantitative proteomics of mouse cerebrospinal fluid detects beta-site APP cleaving enzyme (BACE1) protease substrates in vivo
Mol. Cell. Proteomics
14
2550-2563
2015
Mus musculus (P56818), Mus musculus
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