Abstract
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.
Highlights
IntroductionLipid peroxidation is one of the well-known toxic consequences of cell oxidative stress [1]
Lipid peroxidation is one of the well-known toxic consequences of cell oxidative stress [1].This process generates hydrophobic aldehydic compounds such as alkanals, alkenals and hydroxyalkenals that are able to induce cellular damage through the irreversible modification of proteins and nucleic acids [2]
Stereoselective synthesis of the two HNE enantiomers allowed suitable chiral substrates to be assayed for their Human recombinant AKR1B1 (hAKR1B1)-catalyzed reduction
Summary
Lipid peroxidation is one of the well-known toxic consequences of cell oxidative stress [1] This process generates hydrophobic aldehydic compounds such as alkanals, alkenals and hydroxyalkenals that are able to induce cellular damage through the irreversible modification of proteins and nucleic acids [2]. Recent evidence clearly indicates that the beneficial effects exerted by various antioxidants, both in vivo and in vitro, can derive from a decrease of HNE-protein adducts [9,10]. All these considerations suggest that the removal of HNE is relevant to human health [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
