ArticleThe Journal of biological chemistry2009
Role of the general base Glu-268 in nitroglycerin bioactivation and superoxide formation by aldehyde dehydrogenase-2.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 34 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
- Energy metabolism disturbance in migraine: From a mitochondrial point of view.Frontiers in physiology · 2023Review
- Modulation of Glia Activation by TRPA1 Antagonism in Preclinical Models of Migraine.International journal of molecular sciences · 2022Article
- Aldehyde Dehydrogenase 2 as a Therapeutic Target in Oxidative Stress-Related Diseases: Post-Translational Modifications Deserve More Attention.International journal of molecular sciences · 2022Review
- Glyceryl Trinitrate: History, Mystery, and Alcohol Intolerance.Molecules (Basel, Switzerland) · 2021Review
- Insulin-like growth factor-1 inhibits nitroglycerin-induced trigeminal activation of oxidative stress, calcitonin gene-related peptide and c-Fos expression.Neuroscience letters · 2021Article
- TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice.Brain : a journal of neurology · 2018Article
- Formation of Nitric Oxide by Aldehyde Dehydrogenase-2 Is Necessary and Sufficient for Vascular Bioactivation of Nitroglycerin.The Journal of biological chemistry · 2016Article
- Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress.Antioxidants & redox signaling · 2015Review
- Aldehyde dehydrogenase-independent bioactivation of nitroglycerin in porcine and bovine blood vessels.Biochemical pharmacology · 2015Article
- Effect of overexpression of human aldehyde dehydrogenase 2 in LLC-PK1 cells on glyceryl trinitrate biotransformation and cGMP accumulation.British journal of pharmacology · 2013Article
- Vascular bioactivation of nitroglycerin by aldehyde dehydrogenase-2: reaction intermediates revealed by crystallography and mass spectrometry.The Journal of biological chemistry · 2012Article
- Nitroglycerin use in myocardial infarction patients.Circulation journal : official journal of the Japanese Circulation Society · 2012Review
- Changes in aldehyde dehydrogenase 2 expression in rat blood vessels during glyceryl trinitrate tolerance development and reversal.British journal of pharmacology · 2011Article
- Regulation of human mitochondrial aldehyde dehydrogenase (ALDH-2) activity by electrophiles in vitro.The Journal of biological chemistry · 2011Article
- Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1.The Journal of biological chemistry · 2010Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays an essential role in nitroglycerin (GTN) bioactivation, resulting in formation of NO or a related activator of soluble guanylate cyclase. ALDH2 denitrates GTN to 1,2-glyceryl dinitrate and nitrite but also catalyzes reduction of GTN to NO. To elucidate the relationship between ALDH2-catalyzed GTN bioconversion and established ALDH2 activities (dehydrogenase, esterase), we compared the function of the wild type (WT) enzyme with mutants lacking either the reactive Cys-302 (C302S) or the general base Glu-268 (E268Q). Although the C302S mutation led to >90% loss of all enzyme activities, the E268Q mutant exhibited virtually unaffected rates of GTN denitration despite low dehydrogenase and esterase activities. The nucleotide co-factor NAD caused a pronounced increase in the rates of 1,2-glyceryl dinitrate formation by WT-ALDH2 but inhibited the reaction catalyzed by the E268Q mutant. GTN bioactivation measured as activation of purified soluble guanylate cyclase or release of NO in the presence of WT- or E268Q-ALDH2 was markedly potentiated by superoxide dismutase, suggesting that bioavailability of GTN-derived NO is limited by co-generation of superoxide. Formation of superoxide was confirmed by determination of hydroethidine oxidation that was inhibited by superoxide dismutase and the ALDH2 inhibitor chloral hydrate. E268Q-ALDH2 exhibited approximately 50% lower rates of superoxide formation than the WT enzyme. Our results suggest that Glu-268 is involved in the structural organization of the NAD-binding pocket but is not required for GTN denitration. ALDH2-catalyzed superoxide formation may essentially contribute to oxidative stress in GTN-exposed blood vessels.
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