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Titolo:
Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in A beta-induced cytotoxicity
Autore:
Du Yan, S; Shi, YG; Zhu, AP; Fa, J; Zhu, HJ; Zhu, YC; Gibson, L; Stern, E; Collison, K; Al-Mohanna, F; Ogawa, S; Roher, A; Clarke, SG; Stern, DM;
Indirizzi:
Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA Columbia Univ Coll Phys & Surg New York NY USA 10032 w York, NY 10032 USA Columbia Univ Coll Phys & Surg, Dept Physiol, New York, NY 10032 USA Columbia Univ Coll Phys & Surg New York NY USA 10032 w York, NY 10032 USA Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA ColumbiaUniv Coll Phys & Surg New York NY USA 10032 w York, NY 10032 USA King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia King Faisal Specialist Hosp & Res Ctr Riyadh Saudi Arabia 11211 i Arabia Osaka Univ, Dept Anat & Neurosci, Osaka, Japan Osaka Univ Osaka JapanOsaka Univ, Dept Anat & Neurosci, Osaka, Japan Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA Princeton Univ Princeton NJ USA 08544 t Mol Biol, Princeton, NJ 08544 USA Sun Hlth Res Inst, Haldeman Lab Alzheimers Dis Res, Sun City, AZ 85372 USASun Hlth Res Inst Sun City AZ USA 85372 s Dis Res, Sun City, AZ 85372 USA Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90024 USA Univ Calif Los Angeles Los Angeles CA USA 90024 Los Angeles, CA 90024 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 4, volume: 274, anno: 1999,
pagine: 2145 - 2156
SICI:
0021-9258(19990122)274:4<2145:ROEADT>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
NF-KAPPA-B; ALZHEIMERS-DISEASE; SCAVENGER RECEPTOR; PROTEIN OXIDATION; AMYLOID PROTEIN; BOVINE LIVER; IN-VITRO; PEPTIDE; EXPRESSION; BRAIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Du Yan, S Columbia Univ Coll Phys & Surg, Dept Pathol, P&S 17-410,630 W 168th St, New Columbia Univ Coll Phys & Surg P&S 17-410,630 W 168th St New York NY USA 10020
Citazione:
S. Du Yan et al., "Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in A beta-induced cytotoxicity", J BIOL CHEM, 274(4), 1999, pp. 2145-2156

Abstract

Endoplasmic reticulum-associated amyloid beta-peptide (A beta)-binding protein (ERAB)/L-3-hydroxyacyl-CoA dehydrogenase type II (HADH II) is expressed at high levels in Alzheimer's disease (AD)-affected brain, binds A beta, and contributes to A beta-induced cytotoxicity. Purified recombinant ERAB/HADH II catalyzed the NADH-dependent reduction of S-acetoacetyl-CoA with a K-m of approximate to 68 mu M and a V-max of approximate to 430 mu mol/min/mg. The contribution of ERAB/HADH II enzymatic activity to A beta-mediated cellular dysfunction was studied by site-directed mutagenesis in the catalytic domain (Y168G/K172G). Although COS cells cotransfected to overexpress wild-type ERAB/HADH II and variant beta-amyloid precursor protein (beta APP(V717G)) showed DNA fragmentation, cotransfection with Y168G/K172G-altered ERAB and beta APP(W717G) was without effect. We thus asked whether the enzymemight recognize alcohol substrates of which the aldehyde products could becytotoxic; ERAB/HADH II catalyzed oxidation of a variety of simple alcohols (C2-C10) to their respective aldehydes in the presence of NAD(+) and NAD-dependent oxidation of 17 beta-estradiol. Addition of micromolar levels of synthetic A beta(1-40) to purified ERAB/HADH II inhibited, in parallel, reduction of S-acetoacetyl-CoA (K-i approximate to 1.6 mu M), as web as oxidation of 17 beta-estradiol (K-i approximate to 3.2 mu M) and (-)-2-octanol (K-i approximate to 2.6 mu M). Because micromolar levels of A beta were required to inhibit ERAB/HADH II activity, whereas A beta binding to ERAB/HADH II occurred at much lower concentrations (K-m approximate to 40-70 nM), the latter more closely simulating A beta levels within cells, A beta perturbation of ERAB/HADH II was likely to result from mechanisms other than the direct modulation of enzymatic activity. Cells cotransfected to overexpress ERAB/HADH II and beta APP(V717G) generated malondialdehyde-protein and 4-hydroxynonenal-protein epitopes, which were detectable only at the lowest levels in cells overexpressing either ERAB/HADH II or beta APP(V717G) alone. Generation of such toxic aldehydes was not observed in cells contransfected tooverexpress Y168G/K172G-altered ERAB and beta APP(V717G). We conclude thatthe generalized alcohol dehydrogenase activity of ERAB/HADH II is central to the cytotoxicity observed in an A beta-rich environment.

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Documento generato il 22/01/20 alle ore 12:30:52