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Titolo:
How an inhibitor of the HIV-I protease modulates proteasome activity
Autore:
Schmidtke, G; Holzhutter, HG; Bogyo, M; Kairies, N; Groll, M; de Giuli, R; Emch, S; Groettrup, M;
Indirizzi:
Cantonal Hosp St Gall, Res Dept, CH-9007 St Gallen, Switzerland Cantonal Hosp St Gall St Gallen Switzerland CH-9007 Gallen, Switzerland Humboldt Univ, Fac Med Charite, Inst Biochem, D-10117 Berlin, Germany Humboldt Univ Berlin Germany D-10117 st Biochem, D-10117 Berlin, Germany Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA Univ Calif San Francisco San Francisco CA USA 94143 ancisco, CA 94143 USA Max Planck Inst Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem Martinsried Germany D-82152 Martinsried, Germany
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 50, volume: 274, anno: 1999,
pagine: 35734 - 35740
SICI:
0021-9258(199912)274:50<35734:HAIOTH>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
MAJOR HISTOCOMPATIBILITY COMPLEX; 20S PROTEASOME; INTERFERON-GAMMA; BETA-SUBUNITS; INCREMENTAL CONSTRUCTION; ANTIGEN PRESENTATION; PEPTIDE; YEAST; DEGRADATION; SITE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Groettrup, M Kantonsspital, Lab Forsch Abt, Haus 09, CH-9007 St Gallen, Switzerland Kantonsspital Haus 09 St Gallen Switzerland CH-9007 tzerland
Citazione:
G. Schmidtke et al., "How an inhibitor of the HIV-I protease modulates proteasome activity", J BIOL CHEM, 274(50), 1999, pp. 35734-35740

Abstract

The human immunodeficiency virus, type I protease inhibitor Ritonavir has been used successfully in AIDS therapy for 4 years. Clinical observations suggested that Ritonavir may exert a direct effect on the immune system unrelated to inhibition of the human immunodeficiency virus, type I protease. In fact, Ritonavir inhibited the major histocompatibility complex class I restricted presentation of several viral antigens at therapeutically relevantconcentrations (5 mu M). In search of a molecular target we found that Ritonavir inhibited the chymotrypsin-like activity of the proteasome whereas the tryptic activity was enhanced. In this study we kinetically analyzed howRitonavir modulates proteasome activity and what consequences this has on cellular functions of the proteasome. Ritonavir is a reversible effector ofproteasome activity that protected the subunits MB-1 (X) and/or LMP7 from covalent active site modification with the vinyl sulfone inhibitor(125)I-NLVS, suggesting that they are the prime targets for competitive inhibition by Ritonavir. At low concentrations of Ritonavir (5 mu M) cells were more sensitive to canavanine but proliferated normally whereas at higher concentrations (50 mu M) protein degradation was affected, and the cell cycle was arrested in the G(1)/S phase, Ritonavir thus modulates antigen processing at concentrations at which vital cellular functions of the proteasome are not yet severely impeded. Proteasome modulators may hence qualify as therapeutics for the control of the cytotoxic immune response.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/12/20 alle ore 09:29:55