Inhibition of succinic semialdehyde dehydrogenase activity by alkenal products of lipid peroxidation.
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.
Nguyen
Ethan
E
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.
Picklo
Matthew J
MJ
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
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