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Open AccessArticle

Stereoselectivity of Aldose Reductase in the Reduction of Glutathionyl-Hydroxynonanal Adduct

1
Biochemistry Unit, Department of Biology, University of Pisa, via S. Zeno 51, 56127 Pisa, Italy
2
Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, 56124 Pisa, Italy
3
Proteomics & Mass Spectrometry Laboratory, ISPAAM-CNR, Via Argine 1085, 80147 Napoli, Italy
4
Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy
5
Department of Chemistry and Industrial Chemistry, University of Pisa, via G. Moruzzi, 13, 56124 Pisa, Italy
*
Author to whom correspondence should be addressed.
Present address: Pathology Department, IRCCS, CRO Aviano, National Cancer Institute, 33081 Aviano, (PN), Italy.
Antioxidants 2019, 8(10), 502; https://doi.org/10.3390/antiox8100502
Received: 23 September 2019 / Revised: 18 October 2019 / Accepted: 21 October 2019 / Published: 22 October 2019
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
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. View Full-Text
Keywords: aldose reductase; 4-hydroxy-2-nonenal; 3-glutathionyl-4-hydroxynonenal; inflammation aldose reductase; 4-hydroxy-2-nonenal; 3-glutathionyl-4-hydroxynonenal; inflammation
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Balestri, F.; Barracco, V.; Renzone, G.; Tuccinardi, T.; Pomelli, C.S.; Cappiello, M.; Lessi, M.; Rotondo, R.; Bellina, F.; Scaloni, A.; Mura, U.; Del Corso, A.; Moschini, R. Stereoselectivity of Aldose Reductase in the Reduction of Glutathionyl-Hydroxynonanal Adduct. Antioxidants 2019, 8, 502.

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