Nomenclature: presenilin 1

Family: A22: Presenilin

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing. 

Contents

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 467 14q24.3 PSEN1 presenilin 1
Mouse - 467 12 D1 Psen1 presenilin 1
Rat - 468 6q31 Psen1 presenilin 1
Previous and Unofficial Names
AD3
Ad3h
FAD
presenilin-1
PS-1
PS1
S182
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
ExplorEnz
GeneCards
GenitoUrinary Development Molecular Anatomy Project
InterPro
KEGG BRITE Hierarchy
KEGG Gene
MEROPS
OMIM
Orphanet Gene
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Enzyme Reaction
EC Number: 3.4.23.-
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
begacestat Hs Inhibition 7.83 pEC50 4
pEC50 7.83 (EC50 1.48x10-8 M) [4]
CHF-5074 Hs Binding 4.4 pEC50 6
pEC50 4.4 (EC50 4x10-5 M) [6]
avagacestat Hs Inhibition 9.5 pIC50 7
pIC50 9.5 (IC50 3x10-10 M) [7]
ELND006 Hs Inhibition 9.47 pIC50 5
pIC50 9.47 (IC50 3.4x10-10 M) [5]
Description: A-beta release assay
RO4929097 Hs Inhibition 8.4 pIC50 2
pIC50 8.4 (IC50 4x10-9 M) [2]
semagacestat Hs Inhibition 7.82 pIC50 1
pIC50 7.82 (IC50 1.5x10-8 M) [1]
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Cx3cr1+|Cx3cr1tm1Litt|Psen1tm1Mpm|Tg(APPSwe,tauP301L)1Lfa|Tg(Thy1-YFPH)2Jrs Cx3cr1tm1Litt/Cx3cr1+,Psen1tm1Mpm/Psen1tm1Mpm,Tg(APPSwe,tauP301L)1Lfa/0,Tg(Thy1-YFPH)2Jrs/0
involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1202717  MGI:1333815  MGI:2684637  MGI:3497950  MP:0000136 abnormal microglial cell morphology PMID: 20305648 
Cx3cr1+|Cx3cr1tm1Litt|Psen1tm1Mpm|Tg(APPSwe,tauP301L)1Lfa|Tg(Thy1-YFPH)2Jrs Cx3cr1tm1Litt/Cx3cr1+,Psen1tm1Mpm/Psen1tm1Mpm,Tg(APPSwe,tauP301L)1Lfa/0,Tg(Thy1-YFPH)2Jrs/0
involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1202717  MGI:1333815  MGI:2684637  MGI:3497950  MP:0003691 abnormal microglial cell physiology PMID: 20305648 
Cx3cr1+|Cx3cr1tm1Litt|Psen1tm1Mpm|Tg(APPSwe,tauP301L)1Lfa|Tg(Thy1-YFPH)2Jrs Cx3cr1tm1Litt/Cx3cr1+,Psen1tm1Mpm/Psen1tm1Mpm,Tg(APPSwe,tauP301L)1Lfa/0,Tg(Thy1-YFPH)2Jrs/0
involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1202717  MGI:1333815  MGI:2684637  MGI:3497950  MP:0003224 neuron degeneration PMID: 20305648 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Alzheimer disease, 3
OMIM:  607822
Orphanet:  1020
References: 
Mutations not determined
Disease:  Frontotemporal dementia; semantic dementia
OMIM:  600274
Orphanet:  100069
References: 
Mutations not determined
Disease:  Progressive non-fluent aphasia
Orphanet:  100070
References:  3
Click column headers to sort
Type Species Molecular location Description Reference
Nonsynonymous point mutation Human P264L Nucleotide transition 49976C > T causes amino acid substitution proline > leucine at position 246 3
Disease:  Cardiomyopathy, dilated, 1U
OMIM:  613694
Orphanet:  154
References: 
Mutations not determined
Disease:  Behavioral variant of frontotemporal dementia
Orphanet:  275864
References: 
Mutations not determined
Disease:  Acne inversa, familial, 3
OMIM:  613737
References: 
Mutations not determined

IUPHAR-DB (through the Guide to PHARMACOLOGY portal) curates quantitative bioactivity mappings for all approved, clinical and selected actively pursued research targets. Data for additional protein mappings from medicinal chemistry papers and selected PubChem Bioassays can be found in the ChEMBL links.

REFERENCES

1. Kreft AF, Martone R, Porte A. (2009) Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer's disease. J. Med. Chem.52 (20): 6169-88. [PMID:19694467]

2. Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H et al.. (2009) Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res.69 (19): 7672-80. [PMID:19773430]

3. Mahoney CJ, Downey LE, Beck J, Liang Y, Mead S, Perry RJ, Warren JD. (2013) The presenilin 1 P264L mutation presenting as non-fluent/agrammatic primary progressive aphasia. J. Alzheimers Dis.36 (2): 239-43. [PMID:23579325]

4. Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, Gong X, Jin M, Kreft A, Harrison B et al.. (2009) Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J. Pharmacol. Exp. Ther.331 (2): 598-608. [PMID:19671883]

5. Probst G, Aubele DL, Bowers S, Dressen D, Garofalo AW, Hom RK, Konradi AW, Marugg JL, Mattson MN, Neitzel ML et al.. (2013) Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch. J. Med. Chem.56 (13): 5261-74. [PMID:23713656]

6. Xin Z, Peng H, Zhang A, Talreja T, Kumaravel G, Xu L, Rohde E, Jung MY, Shackett MN, Kocisko D et al.. (2011) Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach. Bioorg. Med. Chem. Lett.21 (24): 7277-80. [PMID:22061640]

7. DRUGS IN CLINICAL TRIALS: BMS-708163. Accessed on 06/09/2013. Modified on 06/09/2013. Alzheimer Research Forum, http://www.alzforum.org/drg/drc/detail.asp?id=124

To cite this database page, please use the following:

A22: Presenilin: presenilin 1. Last modified on 25/03/2014. Accessed on 25/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=2402.

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