title: Inhibition of succinic semialdehyde dehydrogenase activity by alkenal products of lipid peroxidation.
abstract: Lipid peroxidation causes the generation of the neurotoxic aldehydes acrolein and 4-hydroxy-trans-2-nonenal (HNE). These products are elevated in neurodegenerative diseases and acute CNS trauma. Previous studies demonstrate that mitochondrial class 2 aldehyde dehydrogenase (ALDH2) is susceptible to inactivation by these alkenals. In the liver and brain another mitochondrial aldehyde dehydrogenase, succinic semialdehyde dehydrogenase (SSADH/ALDH5A1), is present. In this study, we tested the hypothesis that aldehyde products of lipid peroxidation inhibit SSADH activity using the endogenous substrate, succinic semialdehyde (SSA, 50 microM). Acrolein potently inhibited SSADH activity (IC(50)=15 microM) in rat brain mitochondrial preparations. This inhibition was of an irreversible and noncompetitive nature. HNE inhibited activity with an IC(50) of 110 microM. Trans-2-hexenal (HEX) and crotonaldehyde (100 microM each) did not inhibit activity. These data suggest that acrolein and HNE disrupt SSA metabolism and may have subsequent effects on CNS neurochemistry.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58203, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Nguyen
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Picklo
mesh_terms: D000171:Acrolein / Q000737:chemistry / Q000494:pharmacology*; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D015227:Lipid Peroxidation; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D050644:Succinate-Semialdehyde Dehydrogenase; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000447:Aldehydes; D005680:gamma-Aminobutyric Acid; D000171:Acrolein; D000445:Aldehyde Oxidoreductases; C493647:Aldh5a1 protein, rat; D050644:Succinate-Semialdehyde Dehydrogenase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; C009338:succinic semialdehyde