Oxidation of 4-hydroxy-2-nonenal by succinic semialdehyde dehydrogenase (ALDH5A).
Elevated levels of 4-hydroxy-trans-2-nonenal (HNE) are implicated in the pathogenesis of numerous neurodegenerative disorders. Although well-characterized in the periphery, the mechanisms of detoxification of HNE in the CNS are unclear. HNE is oxidized to a non-toxic metabolite in the rat cerebral cortex by mitochondrial aldehyde dehydrogenases (ALDHs). Two possible ALDH enzymes which might oxidize HNE in CNS mitochondria are ALDH2 and succinic semialdehyde dehydrogenase (SSADH/ALDH5A). It was previously established that hepatic ALDH2 can oxidize HNE. In this work, we tested the hypothesis that SSADH oxidizes HNE. SSADH is critical in the detoxification of the GABA metabolite, succinic semialdehyde (SSA). Recombinant rat SSADH oxidized HNE and other alpha,beta-unsaturated aldehydes. Inhibition and competition studies in rat brain mitochondria showed that SSADH was the predominant oxidizing enzyme for HNE but only contributed a portion of the total oxidizing activity in liver mitochondria. In vivo administration of diethyldithiocarbamate (DEDC) effectively inhibited (86%) ALDH2 activity but not HNE oxidation in liver mitochondria. The data suggest that a relationship between the detoxification of SSA and the neurotoxic aldehyde HNE exists in the CNS. Furthermore, these studies show that multiple hepatic aldehyde dehydrogenases are able to oxidize HNE.
Murphy
Tonya C
TC
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, USA.
Amarnath
Venkataraman
V
Gibson
K Michael
KM
Picklo
Matthew J
MJ
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000445:Aldehyde Oxidoreductases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001542:Benomyl / Q000494:pharmacology; D001923:Brain Chemistry; D004050:Ditiocarb / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050644:Succinate-Semialdehyde Dehydrogenase; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000447:Aldehydes; D004791:Enzyme Inhibitors; C045934:4-hydroxy-2-hexenal; C013166:2-nonenal; C051750:2-hexenal; D005680:gamma-Aminobutyric Acid; D004050:Ditiocarb; D000445:Aldehyde Oxidoreductases; C493647:Aldh5a1 protein, rat; D050644:Succinate-Semialdehyde Dehydrogenase; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C027576:4-hydroxy-2-nonenal; C009338:succinic semialdehyde; D001542:Benomyl