Linear non-competitive inhibition of solubilized human gamma-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines.

Tian G; Sobotka-Briner CD; Zysk J; Liu X; Birr C; Sylvester MA; Edwards PD; Scott CD; Greenberg BD

doi:10.1074/jbc.m112328200

Linear non-competitive inhibition of solubilized human gamma-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines.

Tian G ¹,

Sobotka-Briner CD ,

Zysk J ,

Liu X ,

Birr C ,

Affiliations

1. Department of Lead Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware 19850, USA.
Authors
Tian G¹
(1 author)

ORCIDs linked to this article

Liu X | 0009-0000-2114-5784

The Journal of Biological Chemistry, 18 Jun 2002, 277(35):31499-31505
https://doi.org/10.1074/jbc.m112328200 PMID: 12072428

Abstract

Cerebral deposition of amyloid beta-protein (A beta) is believed to play a key role in the pathogenesis of Alzheimer's disease. Because A beta is produced from the processing of amyloid beta-protein precursor (APP) by beta- and gamma-secretases, these enzymes are considered important therapeutic targets for identification of drugs to treat Alzheimer's disease. Unlike beta-secretase, which is a monomeric aspartyl protease, gamma-secretase activity resides as part of a membrane-bound, high molecular weight, macromolecular complex. Pepstatin and L685458 are among several structural classes of gamma-secretase inhibitors identified so far. These compounds possess a hydroxyethylene dipeptide isostere of aspartyl protease transition state analogs, suggesting gamma-secretase may be an aspartyl protease. However, the mechanism of inhibition of gamma-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 gamma-secretase. Sulfonamides and benzodiazepines, which do not resemble transition state analogs of aspartyl proteases, also displayed potent, non-competitive inhibition of gamma-secretase. Models to rationalize how transition state analogs inhibit their targets by non-competitive inhibition are discussed.

Full text links

Read article at publisher's site: https://doi.org/10.1074/jbc.m112328200

Read article for free, from open access legal sources, via Unpaywall: http://www.jbc.org/article/S0021925820699987/pdf

References

Articles referenced by this article (33)

Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein.
Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J
Proc Natl Acad Sci U S A, (4):1456-1460 2000
MED: 10677483
Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity.
Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME
Nature, (6761):533-537 1999
MED: 10591213
Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, [...] Citron M
Science, (5440):735-741 1999
MED: 10531052
Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor.
Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J
Science, (5489):150-153 2000
MED: 11021803
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
Nature, (6665):387-390 1998
MED: 9450754
Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants.
Ye Y, Lukinova N, Fortini ME
Nature, (6727):525-529 1999
MED: 10206647
Title not supplied
AUTHOR UNKNOWN
A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R
Nature, (6727):518-522 1999
MED: 10206645
Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations.
Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA
Proc Natl Acad Sci U S A, (12):6959-6963 1999
MED: 10359821
gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase.
Ni CY, Murphy MP, Golde TE, Carpenter G
Science, (5549):2179-2181 2001
MED: 11679632

Show 10 more references (10 of 33)

Citations & impact

Impact metrics

Citations

Jump to Citations

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/42106638

Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/42106638

Article citations

Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors.
Pesaresi A
Comput Struct Biotechnol J, 23:34-42, 14 Nov 2023
Cited by: 0 articles | PMID: 38089466 | PMCID: PMC10711399
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC
Inhibition on α-Glucosidase Activity and Non-Enzymatic Glycation by an Anti-Oxidative Proteoglycan from Ganoderma lucidum.
Zhang Y, Pan Y, Li J, Zhang Z, He Y, Yang H, Zhou P
Molecules, 27(5):1457, 22 Feb 2022
Cited by: 6 articles | PMID: 35268560 | PMCID: PMC8912016
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC
Directing Cholangiocyte Morphogenesis in Natural Biomaterial Scaffolds.
Smith Q, Bays J, Li L, Shareef H, Chen CS, Bhatia SN
Adv Sci (Weinh), 9(3):e2102698, 16 Nov 2021
Cited by: 1 article | PMID: 34786888 | PMCID: PMC8787431
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC
Design of Transmembrane Mimetic Structural Probes to Trap Different Stages of γ-Secretase-Substrate Interaction.
Bhattarai S, Devkota S, Wolfe MS
J Med Chem, 64(20):15367-15378, 14 Oct 2021
Cited by: 2 articles | PMID: 34647731 | PMCID: PMC8918029
Free full text in Europe PMC
Design of Substrate Transmembrane Mimetics as Structural Probes for γ-Secretase.
Bhattarai S, Devkota S, Meneely KM, Xing M, Douglas JT, Wolfe MS
J Am Chem Soc, 142(7):3351-3355, 04 Feb 2020
Cited by: 6 articles | PMID: 31999444 | PMCID: PMC7359870
Free full text in Europe PMC

Go to all (78) article citations

Search life-sciences literature (45,103,589 articles, preprints and more)