Stereoselectivity of Aldose Reductase in the Reduction of Glutathionyl-Hydroxynonanal Adduct.
3-glutathionyl-4-hydroxynonenal
4-hydroxy-2-nonenal
aldose reductase
inflammation
Journal
Antioxidants (Basel, Switzerland)
ISSN: 2076-3921
Titre abrégé: Antioxidants (Basel)
Pays: Switzerland
ID NLM: 101668981
Informations de publication
Date de publication:
22 Oct 2019
22 Oct 2019
Historique:
received:
23
09
2019
revised:
18
10
2019
accepted:
21
10
2019
entrez:
27
10
2019
pubmed:
28
10
2019
medline:
28
10
2019
Statut:
epublish
Résumé
The formation of the adduct between the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) and glutathione, which leads to the generation of 3-glutathionyl-4-hydroxynonane (GSHNE), is one of the main routes of HNE detoxification. The aldo-keto reductase AKR1B1 is involved in the reduction of the aldehydic group of both HNE and GSHNE. In the present study, the effect of chirality on the recognition by aldose reductase of HNE and GSHNE was evaluated. AKR1B1 discriminates very modestly between the two possible enantiomers of HNE as substrates. Conversely, a combined kinetic analysis of the glutathionyl adducts obtained starting from either 4R- or 4S-HNE and mass spectrometry analysis of GSHNE products obtained from racemic HNE revealed that AKR1B1 possesses a marked preference toward the 3S,4R-GSHNE diastereoisomer. Density functional theory and molecular modeling studies revealed that this diastereoisomer, besides having a higher tendency to be in an open aldehydic form (the one recognized by AKR1B1) in solution than other GSHNE diastereoisomers, is further stabilized in its open form by a specific interaction with the enzyme active site. The relevance of this stereospecificity to the final metabolic fate of GSHNE is discussed.
Identifiants
pubmed: 31652566
pii: antiox8100502
doi: 10.3390/antiox8100502
pmc: PMC6827081
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : University of Pisa
ID : PRA 2017
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