title: Amyloid beta -peptide-binding alcohol dehydrogenase is a component of the cellular response to nutritional stress.
abstract: Amyloid beta-peptide-binding alcohol dehydrogenase (ABAD) is a member of the family of short chain dehydrogenase/reductases whose distinctive properties include the capacity to bind amyloid beta-peptide and enzymatic activity toward a broad array of substrates including n-isopropanol and beta-estradiol. In view of the wide substrate specificity of ABAD and its high activity on l-beta-hydroxyacyl-CoA derivatives, we asked whether it might also catalyze the oxidation of the ketone body d-3-hydroxybutyrate. This was indeed the case, and oxidation proceeded with K(m) of approximately 4.5 mm and V(max) of approximately 4 nmol/min/mg protein. When placed in medium with d-beta-hydroxybutyrate as the principal energy substrate, COS cells stably transfected to overexpress wild-type ABAD (COS/wtABAD) better maintained 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, cellular energy charge, and morphologic phenotype compared with COS/vector cells. Using a severe model of metabolic perturbation, transgenic mice with targeted neuronal expression of ABAD subjected to transient middle cerebral artery occlusion showed strokes of smaller volume and lower neurologic deficit scores in parallel with increased brain ATP and decreased lactate, compared with nontransgenic controls. These data suggest that ABAD contributes to the protective response to metabolic stress, especially in the setting of ischemia.
authors.affiliation: Departments of Pathology, Surgery, Physiology & Cellular Biophysics, Neurosurgery and Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. sdy1@columbia.edu
authors.forename: S
authors.initials: S
authors.lastname: Du Yan
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: E D
authors.initials: ED
authors.lastname: Stern
authors.forename: Y C
authors.initials: YC
authors.lastname: Hwang
authors.forename: O
authors.initials: O
authors.lastname: Hori
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.forename: M P
authors.initials: MP
authors.lastname: Frosch
authors.forename: E S
authors.initials: ES
authors.lastname: Connolly
authors.forename: R
authors.initials: R
authors.lastname: McTaggert
authors.forename: D J
authors.initials: DJ
authors.lastname: Pinsky
authors.forename: S
authors.initials: S
authors.lastname: Clarke
authors.forename: D M
authors.initials: DM
authors.lastname: Stern
authors.forename: R
authors.initials: R
authors.lastname: Ramasamy
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D000426:Alcohol Dehydrogenase; D020155:3-Hydroxybutyric Acid