A human brain L-3-hydroxyacyl coenzyme A dehydrogenase is identical to an amyloid p-peptide-binding protein involved in Alzheimer's disease

被引:111
作者
He, XY
Schulz, H
Yang, SY
机构
[1] New York State Inst Basic Res Dev Disabil, Dept Pharmacol, Staten Isl, NY 10314 USA
[2] CUNY City Coll, Dept Chem, New York, NY 10031 USA
关键词
D O I
10.1074/jbc.273.17.10741
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A novel L-3-hydroxyacyl-CoA dehydrogenase from human brain has been cloned, expressed, purified, and characterized. This enzyme is a homotetramer with a molecular mass of 108 kDa. Its subunit consists of 261 amino acid residues and has structural features characteristic of short chain dehydrogenases. It was found that the amino acid sequence of this human brain enzyme is identical to that of an endoplasmic reticulum amyloid beta-peptide-binding protein (ERAB), which mediates neurotoxicity in Alzheimer's disease (Yan, S. D., Fu, J., Soto, C., Chen, X, Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A, Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A, and Stern, D. (1997) Nature 389, 689-695). The purification of human brain short chain L-3-hydroxyacyl-CoA dehydrogenase made it possible to characterize the structural and catalytic properties of ERAB. This NAD(+)-dependent dehydrogenase catalyzes the reversible oxidation of L-3-hydroxyacyl-CoAs to form 3-ketoacyl-CoAs, but it does not act on the D-isomers. The catalytic rate constant of the purified enzyme was estimated to be 37 s(-1) with apparent K-m values of 89 and 20 mu M for aceto-acetyl-CoA and NADH, respectively. The activity ratio of this enzyme for substrates with chain lengths of C-4, C-8, and C-16 was similar to 1:2:2. The human short chain L-5-hydroxyacyl-CoA dehydrogenase gene is organized into six exons and five introns and maps to chromosome Xp11.2. The amino-terminal NAD-binding region of the dehydrogenase is encoded by the first three exons, whereas the other exons code for the carboxyl-terminal substrate-binding region harboring putative catalytic residues. The results of this study lead to the conclusion that ERAB involved in neuronal dysfunction is encoded by the human short chain L-3-hydroxyacyl-CoA dehydrogenase gene.
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页码:10741 / 10746
页数:6
相关论文
共 37 条
[1]   Gapped BLAST and PSI-BLAST: a new generation of protein database search programs [J].
Altschul, SF ;
Madden, TL ;
Schaffer, AA ;
Zhang, JH ;
Zhang, Z ;
Miller, W ;
Lipman, DJ .
NUCLEIC ACIDS RESEARCH, 1997, 25 (17) :3389-3402
[2]   THE NH2-TERMINAL 14-16 AMINO-ACIDS OF MITOCHONDRIAL AND BACTERIAL THIOLASES CAN DIRECT MATURE ORNITHINE CARBAMOYLTRANSFERASE INTO MITOCHONDRIA [J].
ARAKAWA, H ;
AMAYA, Y ;
MORI, M .
JOURNAL OF BIOCHEMISTRY, 1990, 107 (01) :160-164
[3]   Alzheimer's disease - The ins and outs of amyloid-beta [J].
Beyreuther, K ;
Masters, CL .
NATURE, 1997, 389 (6652) :677-678
[4]  
Binstock J F, 1981, Methods Enzymol, V71 Pt C, P403
[5]   STRUCTURE OF L-3-HYDROXYACYL-COENZYME-A DEHYDROGENASE - PRELIMINARY CHAIN TRACING AT 2.8-A RESOLUTION [J].
BIRKTOFT, JJ ;
HOLDEN, HM ;
HAMLIN, R ;
XUONG, NH ;
BANASZAK, LJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (23) :8262-8266
[6]  
BLACKSHEAR PJ, 1984, METHOD ENZYMOL, V104, P237
[7]   OVALBUMIN GENE - EVIDENCE FOR A LEADER SEQUENCE IN MESSENGER-RNA AND DNA SEQUENCES AT EXON-INTRON BOUNDARIES [J].
BREATHNACH, R ;
BENOIST, C ;
OHARE, K ;
GANNON, F ;
CHAMBON, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1978, 75 (10) :4853-4857
[8]   SITE-SPECIFIC MUTAGENESIS OF DROSOPHILA ALCOHOL-DEHYDROGENASE - EVIDENCE FOR INVOLVEMENT OF TYROSINE-152 AND LYSINE-156 IN CATALYSIS [J].
CHEN, Z ;
JIANG, JC ;
LIN, ZG ;
LEE, WR ;
BAKER, ME ;
CHANG, SH .
BIOCHEMISTRY, 1993, 32 (13) :3342-3346
[9]   ONE-STEP PREPARATION OF COMPETENT ESCHERICHIA-COLI - TRANSFORMATION AND STORAGE OF BACTERIAL-CELLS IN THE SAME SOLUTION [J].
CHUNG, CT ;
NIEMELA, SL ;
MILLER, RH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (07) :2172-2175
[10]  
Cornish-Bowden A., 1995, ANAL ENZYME KINETIC