Linked Life Data

10098844

Source:http://linkedlifedata.com/resource/pubmed/id/10098844

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
1999-4-13
pubmed:abstractText
The carboxy-terminal ends of the 40- and 42-amino acids amyloid beta-protein (Abeta) may be generated by the action of at least two different proteases termed gamma(40)- and gamma(42)-secretase, respectively. To examine the cleavage specificity of the two proteases, we treated amyloid precursor protein (APP)-transfected cell cultures with several dipeptidyl aldehydes including N-benzyloxycarbonyl-Leu-leucinal (Z-LL-CHO) and the newly synthesized N-benzyloxycarbonyl-Val-leucinal (Z-VL-CHO). All dipeptidyl aldehydes tested inhibited production of both Abeta1-40 and Abeta1-42. Changes in the P1 and P2 residues of these aldehydes, however, indicated that the amino acids occupying these positions are important for the efficient inhibition of gamma-secretases. Peptidyl aldehydes inhibit both cysteine and serine proteases, suggesting that the two gamma-secretases belong to one of these mechanistic classes. To differentiate between the two classes of proteases, we treated our cultures with the specific cysteine protease inhibitor E-64d. This agent inhibited production of secreted Abeta1-40, with a concomitant accumulation of its cellular precursor indicating that gamma(40)-secretase is a cysteine protease. In contrast, this treatment increased production of secreted Abeta1-42. No inhibition of Abeta production was observed with the potent calpain inhibitor I (acetyl-Leu-Leu-norleucinal), suggesting that calpain is not involved. Together, these results indicate that gamma(40)-secretase is a cysteine protease distinct from calpain, whereas gamma(42)-secretase may be a serine protease. In addition, the two secretases may compete for the same substrate. Dipeptidyl aldehyde treatment of cultures transfected with APP carrying the Swedish mutation resulted in the accumulation of the beta-secretase C-terminal APP fragment and a decrease of the alpha-secretase C-terminal APP fragment, indicating that this mutation shifts APP cleavage from the alpha-secretase site to the beta-secretase site.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Aldehydes, http://linkedlifedata.com/resource/pubmed/chemical/Amyloid Precursor Protein Secretases, http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Peptides, http://linkedlifedata.com/resource/pubmed/chemical/Calpain, http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/Dipeptides, http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Leupeptins, http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments, http://linkedlifedata.com/resource/pubmed/chemical/Serine Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/acetylleucyl-leucyl-norleucinal, http://linkedlifedata.com/resource/pubmed/chemical/amyloid beta-protein (1-40), http://linkedlifedata.com/resource/pubmed/chemical/amyloid beta-protein (1-42)
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-3042
pubmed:author
pubmed:issnType
Print
pubmed:volume
72
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1417-22
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Distinct secretases, a cysteine protease and a serine protease, generate the C termini of amyloid beta-proteins Abeta1-40 and Abeta1-42, respectively.
pubmed:affiliation
Department of Biological Sciences, Hunter College, CUNY, New York, NY, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't