PMID- 10591214
OWN - NLM
STAT- MEDLINE
DCOM- 19991216
LR  - 20091119
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 402
IP  - 6761
DP  - 1999 Dec 2
TI  - Purification and cloning of amyloid precursor protein beta-secretase from human
      brain.
PG  - 537-40
AB  - Proteolytic processing of the amyloid precursor protein (APP) generates amyloid
      beta (Abeta) peptide, which is thought to be causal for the pathology and
      subsequent cognitive decline in Alzheimer's disease. Cleavage by beta-secretase
      at the amino terminus of the Abeta peptide sequence, between residues 671 and 672
      of APP, leads to the generation and extracellular release of beta-cleaved soluble
      APP, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of
      the C-terminal fragment by gamma-secretase(s) leads to the formation of Abeta.
      The pathogenic mutation K670M671-->N670L671 at the beta-secretase cleavage site
      in APP, which was discovered in a Swedish family with familial Alzheimer's
      disease, leads to increased beta-secretase cleavage of the mutant substrate. Here
      we describe a membrane-bound enzyme activity that cleaves full-length APP at the 
      beta-secretase cleavage site, and find it to be the predominant beta-cleavage
      activity in human brain. We have purified this enzyme activity to homogeneity
      from human brain using a new substrate analogue inhibitor of the enzyme activity,
      and show that the purified enzyme has all the properties predicted for
      beta-secretase. Cloning and expression of the enzyme reveals that human brain
      beta-secretase is a new membrane-bound aspartic proteinase.
FAU - Sinha, S
AU  - Sinha S
AD  - Elan Pharmaceuticals, South San Francisco, California 94080, USA.
      ssinha@elanpharama.com
FAU - Anderson, J P
AU  - Anderson JP
FAU - Barbour, R
AU  - Barbour R
FAU - Basi, G S
AU  - Basi GS
FAU - Caccavello, R
AU  - Caccavello R
FAU - Davis, D
AU  - Davis D
FAU - Doan, M
AU  - Doan M
FAU - Dovey, H F
AU  - Dovey HF
FAU - Frigon, N
AU  - Frigon N
FAU - Hong, J
AU  - Hong J
FAU - Jacobson-Croak, K
AU  - Jacobson-Croak K
FAU - Jewett, N
AU  - Jewett N
FAU - Keim, P
AU  - Keim P
FAU - Knops, J
AU  - Knops J
FAU - Lieberburg, I
AU  - Lieberburg I
FAU - Power, M
AU  - Power M
FAU - Tan, H
AU  - Tan H
FAU - Tatsuno, G
AU  - Tatsuno G
FAU - Tung, J
AU  - Tung J
FAU - Schenk, D
AU  - Schenk D
FAU - Seubert, P
AU  - Seubert P
FAU - Suomensaari, S M
AU  - Suomensaari SM
FAU - Wang, S
AU  - Wang S
FAU - Walker, D
AU  - Walker D
FAU - Zhao, J
AU  - Zhao J
FAU - McConlogue, L
AU  - McConlogue L
FAU - John, V
AU  - John V
LA  - eng
SI  - GENBANK/AF201468
PT  - Journal Article
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Recombinant Fusion Proteins)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.45 (BACE2 protein, human)
RN  - EC 3.4.23.46 (BACE1 protein, human)
RN  - EC 3.4.23.46 (Bace1 protein, mouse)
SB  - IM
CIN - Nature. 1999 Dec 2;402(6761):471-2. PMID: 10591201
MH  - Amino Acid Sequence
MH  - Amyloid Precursor Protein Secretases
MH  - Amyloid beta-Protein Precursor/metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases/antagonists & inhibitors/genetics/*isolation &
      purification/metabolism
MH  - Brain/*enzymology
MH  - CHO Cells
MH  - Cell Line
MH  - Cell Membrane/enzymology
MH  - Cloning, Molecular
MH  - Cricetinae
MH  - Endopeptidases
MH  - Enzyme Inhibitors/pharmacology
MH  - Escherichia coli
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Recombinant Fusion Proteins/genetics/metabolism
MH  - Sequence Homology, Amino Acid
MH  - Tissue Distribution
MH  - Transfection
EDAT- 1999/12/11 09:00
MHDA- 2001/03/23 10:01
CRDT- 1999/12/11 09:00
PHST- 1999/12/11 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/12/11 09:00 [entrez]
AID - 10.1038/990114 [doi]
PST - ppublish
SO  - Nature. 1999 Dec 2;402(6761):537-40. doi: 10.1038/990114.