ArticleThe Journal of biological chemistry2012
Vascular bioactivation of nitroglycerin by aldehyde dehydrogenase-2: reaction intermediates revealed by crystallography and mass spectrometry.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 37 citations in OpenAlex.
- Influence of the aldehyde dehydrogenase 2 polymorphism on the vasodilatory effect of nitroglycerin in infants with congenital heart disease and pulmonary arterial hypertension.European journal of clinical pharmacology · 2019Trial
- Mass Spectrometry- and Structural Biology-Based Investigation of Proteins.Advances in experimental medicine and biology · 2026Review
- Nitroglycerin-responsive gene switch for the on-demand production of therapeutic proteins.Nature biomedical engineering · 2025Article
- Modeling predicts facile release of nitrite but not nitric oxide from the thionitrate CHScientific reports · 2024Article
- Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer.Cancers · 2023Review
- Thiol and HJournal of the American Chemical Society · 2023Article
- Nitroglycerin: a comprehensive review in cancer therapy.Cell death & disease · 2023Review
- Activation of aldehyde dehydrogenase-2 improves ischemic random skin flap survival in rats.Frontiers in immunology · 2023Article
- The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management.International journal of molecular sciences · 2022Review
- Biochemical and clinical studies of putative allergens to assess what distinguishes them from other non-allergenic proteins in the same family.Transgenic research · 2022Article
- Glyceryl Trinitrate: History, Mystery, and Alcohol Intolerance.Molecules (Basel, Switzerland) · 2021Review
- Evolutionary, computational, and biochemical studies of the salicylaldehyde dehydrogenases in the naphthalene degradation pathway.Scientific reports · 2017Article
- Structure and biochemistry of phenylacetaldehyde dehydrogenase from the Pseudomonas putida S12 styrene catabolic pathway.Archives of biochemistry and biophysics · 2017Article
- Modeling of the Bioactivation of an Organic Nitrate by a Thiol to Form a Thionitrate Intermediate.Molecules (Basel, Switzerland) · 2016Article
- Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons.DNA repair · 2016Article
- Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress.Antioxidants & redox signaling · 2015Review
- Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.Journal of medicinal chemistry · 2014Article
- Expression, crystallization and preliminary X-ray crystallographic analysis of cellobiose 2-epimerase from Dictyoglomus turgidum DSM 6724.Acta crystallographica. Section F, Structural biology and crystallization communications · 2013Article
- Expression, crystallization and preliminary X-ray crystallographic analysis of alcohol dehydrogenase (ADH) from Kangiella koreensis.Acta crystallographica. Section F, Structural biology and crystallization communications · 2013Article
- Expression, crystallization and preliminary X-ray crystallographic analysis of aldehyde dehydrogenase (ALDH) from Bacillus cereus.Acta crystallographica. Section F, Structural biology and crystallization communications · 2013Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Aldehyde dehydrogenase-2 (ALDH2) catalyzes the bioactivation of nitroglycerin (glyceryl trinitrate, GTN) in blood vessels, resulting in vasodilation by nitric oxide (NO) or a related species. Because the mechanism of this reaction is still unclear we determined the three-dimensional structures of wild-type (WT) ALDH2 and of a triple mutant of the protein that exhibits low denitration activity (E268Q/C301S/C303S) in complex with GTN. The structure of the triple mutant showed that GTN binds to the active site via polar contacts to the oxyanion hole and to residues 268 and 301 as well as by van der Waals interactions to hydrophobic residues of the catalytic pocket. The structure of the GTN-soaked wild-type protein revealed a thionitrate adduct to Cys-302 as the first reaction intermediate, which was also found by mass spectrometry (MS) experiments. In addition, the MS data identified sulfinic acid as the irreversibly inactivated enzyme species. Assuming that the structures of the triple mutant and wild-type ALDH2 reflect binding of GTN to the catalytic site and the first reaction step, respectively, superposition of the two structures indicates that denitration of GTN is initiated by nucleophilic attack of Cys-302 at one of the terminal nitrate groups, resulting in formation of the observed thionitrate intermediate and release of 1,2-glyceryl dinitrate. Our results shed light on the molecular mechanism of the GTN denitration reaction and provide useful information on the structural requirements for high affinity binding of organic nitrates to the catalytic site of ALDH2.
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