title: Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal.
abstract: 4-Hydroxy-2-nonenal (4HNE) and acrolein (ACR) are highly reactive neurotoxic products of lipid peroxidation that are implicated in the pathogenesis and progression of Alzheimer's and Parkinson's diseases. Conjugation with glutathione (GSH) initiates the 4HNE and ACR detoxification pathway, which generates the mercapturates of 4HNE and ACR that can be excreted. Prior work has shown that the efficiency of the GSH-dependent renal detoxification of haloalkene derived mercapturates is significantly decreased upon their deacetylation because of rapid transformation of the deacetylated products into toxic compounds mediated by β-lyase. The enzymes of the GSH-conjugation pathway and β-lyases are expressed in the brain, and we hypothesized that a similar toxicity mechanism may be initiated in the brain by the deacetylation of 4HNE- and ACR-mercapturate. The present study was performed to identify an enzyme(s) involved in 4HNE- and ACR-mercapturate deacetylation, characterize the brain expression of this enzyme and determine whether its inhibition decreases 4HNE and 4HNE-mercapturate neurotoxicity. We demonstrated that of two candidate deacetylases, aminoacylases 1 (AA1) and 3 (AA3), only AA3 efficiently deacetylates both 4HNE- and ACR-mercapturate. AA3 was further localized to neurons and blood vessels. Using a small molecule screen we generated high-affinity AA3 inhibitors. Two of them completely protected rat brain cortex neurons expressing AA3 from the toxicity of 4HNE-mercapturate. 4HNE-cysteine (4HNE-Cys) was also neurotoxic and its toxicity was mostly prevented by a β-lyase inhibitor, aminooxyacetate. The results suggest that the AA3 mediated deacetylation of 4HNE-mercapturate may be involved in the neurotoxicity of 4HNE.
authors: Department of Medicine, University of California at Los Angeles, CA 90095-1689, USA.
authors: Kirill
authors: K
authors: Tsirulnikov
authors: Natalia
authors: N
authors: Abuladze
authors: Anatol
authors: A
authors: Bragin
authors: Kym
authors: K
authors: Faull
authors: Duilio
authors: D
authors: Cascio
authors: Robert
authors: R
authors: Damoiseaux
authors: Matthew J
authors: MJ
authors: Schibler
authors: Alexander
authors: A
authors: Pushkin
mesh_terms: D000107:Acetylation; D000111:Acetylcysteine / Q000737:chemistry; D000171:Acrolein / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000544:Alzheimer Disease / Q000503:physiopathology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000473:pathology*; D010300:Parkinson Disease / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D000625:Aminooxyacetic Acid; D000171:Acrolein; D000581:Amidohydrolases; C575983:aminoacylase III, rat; C019672:aminoacylase I; C027576:4-hydroxy-2-nonenal; D000111:Acetylcysteine