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Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1.
J Biol Chem. 2010 Jan 08; 285(2):943-52.JB

Abstract

The East Asian variant of mitochondrial aldehyde dehydrogenase (ALDH2) exhibits significantly reduced dehydrogenase, esterase, and nitroglycerin (GTN) denitrating activities. The small molecule Alda-1 was reported to partly restore low acetaldehyde dehydrogenase activity of this variant. In the present study we compared the wild type enzyme (ALDH2*1) with the Asian variant (ALDH2*2) regarding GTN bioactivation and the effects of Alda-1. Alda-1 increased acetaldehyde oxidation by ALDH2*1 and ALDH2*2 approximately 1.5- and 6-fold, respectively, and stimulated the esterase activities of both enzymes to similar extent as the coenzyme NAD. The effect of NAD was biphasic with pronounced inhibition occurring at > or = 5 mM. In the presence of 1 mM NAD, Alda-1 stimulated ALDH2*2-catalyzed ester hydrolysis 73-fold, whereas the NAD-stimulated activity of ALDH2*1 was inhibited because of 20-fold increased inhibitory potency of NAD in the presence of the drug. Although ALDH2*2 exhibited 7-fold lower GTN denitrating activity and GTN affinity than ALDH2*1, the rate of nitric oxide formation was only reduced 2-fold, and soluble guanylate cyclase (sGC) activation was more pronounced than with wild type ALDH2 at saturating GTN. Alda-1 caused slight inhibition of GTN denitration and did not increase GTN-induced sGC activation in the presence of either variant. The present results indicate that Alda-1 stimulates established ALDH2 activities by improving NAD binding but does not improve the GTN binding affinity of the Asian variant. In addition, our data revealed an unexpected discrepancy between GTN reductase activity and sGC activation, suggesting that GTN denitration and bioactivation may reflect independent pathways of ALDH2-catalyzed GTN biotransformation.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, 8010 Graz, AustriaNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19906643

Citation

Beretta, Matteo, et al. "Characterization of the East Asian Variant of Aldehyde Dehydrogenase-2: Bioactivation of Nitroglycerin and Effects of Alda-1." The Journal of Biological Chemistry, vol. 285, no. 2, 2010, pp. 943-52.
Beretta M, Gorren AC, Wenzl MV, et al. Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1. J Biol Chem. 2010;285(2):943-52.
Beretta, M., Gorren, A. C., Wenzl, M. V., Weis, R., Russwurm, M., Koesling, D., Schmidt, K., & Mayer, B. (2010). Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1. The Journal of Biological Chemistry, 285(2), 943-52. https://doi.org/10.1074/jbc.M109.014548
Beretta M, et al. Characterization of the East Asian Variant of Aldehyde Dehydrogenase-2: Bioactivation of Nitroglycerin and Effects of Alda-1. J Biol Chem. 2010 Jan 8;285(2):943-52. PubMed PMID: 19906643.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1. AU - Beretta,Matteo, AU - Gorren,Antonius C F, AU - Wenzl,M Verena, AU - Weis,Robert, AU - Russwurm,Michael, AU - Koesling,Doris, AU - Schmidt,Kurt, AU - Mayer,Bernd, Y1 - 2009/11/11/ PY - 2009/11/13/entrez PY - 2009/11/13/pubmed PY - 2010/1/27/medline SP - 943 EP - 52 JF - The Journal of biological chemistry JO - J Biol Chem VL - 285 IS - 2 N2 - The East Asian variant of mitochondrial aldehyde dehydrogenase (ALDH2) exhibits significantly reduced dehydrogenase, esterase, and nitroglycerin (GTN) denitrating activities. The small molecule Alda-1 was reported to partly restore low acetaldehyde dehydrogenase activity of this variant. In the present study we compared the wild type enzyme (ALDH2*1) with the Asian variant (ALDH2*2) regarding GTN bioactivation and the effects of Alda-1. Alda-1 increased acetaldehyde oxidation by ALDH2*1 and ALDH2*2 approximately 1.5- and 6-fold, respectively, and stimulated the esterase activities of both enzymes to similar extent as the coenzyme NAD. The effect of NAD was biphasic with pronounced inhibition occurring at > or = 5 mM. In the presence of 1 mM NAD, Alda-1 stimulated ALDH2*2-catalyzed ester hydrolysis 73-fold, whereas the NAD-stimulated activity of ALDH2*1 was inhibited because of 20-fold increased inhibitory potency of NAD in the presence of the drug. Although ALDH2*2 exhibited 7-fold lower GTN denitrating activity and GTN affinity than ALDH2*1, the rate of nitric oxide formation was only reduced 2-fold, and soluble guanylate cyclase (sGC) activation was more pronounced than with wild type ALDH2 at saturating GTN. Alda-1 caused slight inhibition of GTN denitration and did not increase GTN-induced sGC activation in the presence of either variant. The present results indicate that Alda-1 stimulates established ALDH2 activities by improving NAD binding but does not improve the GTN binding affinity of the Asian variant. In addition, our data revealed an unexpected discrepancy between GTN reductase activity and sGC activation, suggesting that GTN denitration and bioactivation may reflect independent pathways of ALDH2-catalyzed GTN biotransformation. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/19906643/Characterization_of_the_East_Asian_variant_of_aldehyde_dehydrogenase_2:_bioactivation_of_nitroglycerin_and_effects_of_Alda_1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)58848-0 DB - PRIME DP - Unbound Medicine ER -