TY - JOUR
T1 - Linear non-competitive inhibition of solubilized human γ-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines
AU - Tian, Gaochao
AU - Sobotka-Briner, Cynthia D.
AU - Zysk, John
AU - Liu, Xiaodong
AU - Birr, Cynthia
AU - Sylvester, Mark A.
AU - Edwards, Philip D.
AU - Scott, Clay D.
AU - Greenberg, Barry D.
PY - 2002/8/30
Y1 - 2002/8/30
N2 - Cerebral deposition of amyloid β-protein (Aβ) is believed to play a key role in the pathogenesis of Alzheimer's disease. Because Aβ is produced from the processing of amyloid β-protein precursor (APP) by β- and γ-secretases, these enzymes are considered important therapeutic targets for identification of drugs to treat Alzheimer's disease. Unlike β-secretase, which is a monomeric aspartyl protease, γ-secretase activity resides as part of a membrane-bound, high molecular weight, macromolecular complex. Pepstatin and L685458 are among several structural classes of γ-secretase inhibitors identified so far. These compounds possess a hydroxyethylene dipeptide isostere of aspartyl protease transition state analogs, suggesting γ-secretase may be an aspartyl protease. However, the mechanism of inhibition of γ-secretase by pepstatin and L685458 has not been elucidated. In this study, we report that pepstatin A methylester and L685458 unexpectedly displayed linear non-competitive inhibition of γ-secretase. Sulfonamides and benzodiazepines, which do not resemble transition state analogs of aspartyl proteases, also displayed potent, non-competitive inhibition of γ-secretase. Models to rationalize how transition state analogs inhibit their targets by non-competitive inhibition are discussed.
AB - Cerebral deposition of amyloid β-protein (Aβ) is believed to play a key role in the pathogenesis of Alzheimer's disease. Because Aβ is produced from the processing of amyloid β-protein precursor (APP) by β- and γ-secretases, these enzymes are considered important therapeutic targets for identification of drugs to treat Alzheimer's disease. Unlike β-secretase, which is a monomeric aspartyl protease, γ-secretase activity resides as part of a membrane-bound, high molecular weight, macromolecular complex. Pepstatin and L685458 are among several structural classes of γ-secretase inhibitors identified so far. These compounds possess a hydroxyethylene dipeptide isostere of aspartyl protease transition state analogs, suggesting γ-secretase may be an aspartyl protease. However, the mechanism of inhibition of γ-secretase by pepstatin and L685458 has not been elucidated. In this study, we report that pepstatin A methylester and L685458 unexpectedly displayed linear non-competitive inhibition of γ-secretase. Sulfonamides and benzodiazepines, which do not resemble transition state analogs of aspartyl proteases, also displayed potent, non-competitive inhibition of γ-secretase. Models to rationalize how transition state analogs inhibit their targets by non-competitive inhibition are discussed.
UR - http://www.scopus.com/inward/record.url?scp=0037200036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037200036&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112328200
DO - 10.1074/jbc.M112328200
M3 - Article
C2 - 12072428
AN - SCOPUS:0037200036
SN - 0021-9258
VL - 277
SP - 31499
EP - 31505
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -