ArticleBiochemistry2010
Substrate specificity combined with stereopromiscuity in glutathione transferase A4-4-dependent metabolism of 4-hydroxynonenal.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 44 citations in OpenAlex.
- The role of glutathione S-transferases in human disease pathogenesis and their current inhibitors.Genes & diseases · 2025Review
- Reversibility and Low Commitment to Forward Catalysis in the Conjugation of Lipid Alkenals by Glutathione Transferase A4-4.Biomolecules · 2023Article
- Mechanisms of promiscuity among drug metabolizing enzymes and drug transporters.The FEBS journal · 2020Review
- GSTA4 mediates reduction of cisplatin ototoxicity in female mice.Nature communications · 2019Article
- Signaling by 4-hydroxy-2-nonenal: Exposure protocols, target selectivity and degradation.Archives of biochemistry and biophysics · 2017Review
- Using Domestic and Free-Ranging Arctic Canid Models for Environmental Molecular Toxicology Research.Environmental science & technology · 2016Article
- Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling.Toxicology and applied pharmacology · 2015Review
- Epsilon glutathione transferases possess a unique class-conserved subunit interface motif that directly interacts with glutathione in the active site.Bioscience reports · 2015Article
- 4-Hydroxy-nonenal-A Bioactive Lipid Peroxidation Product.Biomolecules · 2015Review
- High-fat diet induces changes in adipose tissue trans-4-oxo-2-nonenal and trans-4-hydroxy-2-nonenal levels in a depot-specific manner.Free radical biology & medicine · 2013Article
- Cloning, expression and analysis of the olfactory glutathione S-transferases in coho salmon.Biochemical pharmacology · 2013Article
- Article
- A glutathione transferase from Agrobacterium tumefaciens reveals a novel class of bacterial GST superfamily.PloS one · 2012Article
- Interactions of glutathione transferases with 4-hydroxynonenal.Drug metabolism reviews · 2011Review
- Glutathione s-transferases in pediatric cancer.Frontiers in oncology · 2011Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Conjugation to glutathione (GSH) by glutathione transferase A4-4 (GSTA4-4) is a major route of elimination for the lipid peroxidation product 4-hydroxynonenal (HNE), a toxic compound that contributes to numerous diseases. Both enantiomers of HNE are presumed to be toxic, and GSTA4-4 has negligible stereoselectivity toward them, despite its high catalytic chemospecificity for alkenals. In contrast to the highly flexible, and substrate promiscuous, GSTA1-1 isoform that has poor catalytic efficiency with HNE, GSTA4-4 has been postulated to be a rigid template that is preorganized for HNE metabolism. However, the combination of high substrate chemoselectivity and low substrate stereoselectivity is intriguing. The mechanism by which GSTA4-4 achieves this combination is important, because it must metabolize both enantiomers of HNE to efficiently detoxify the biologically formed mixture. The crystal structures of GSTA4-4 and an engineered variant of GSTA1-1 with high catalytic efficiency toward HNE, cocrystallized with a GSH-HNE conjugate analogue, demonstrate that GSTA4-4 undergoes no enantiospecific induced fit; instead, the active site residue Arg15 is ideally located to interact with the 4-hydroxyl group of either HNE enantiomer. The results reveal an evolutionary strategy for achieving biologically useful stereopromiscuity toward a toxic racemate, concomitant with high catalytic efficiency and substrate specificity toward an endogenously formed toxin.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.