NDLI: Characterization of the East Asian Variant of Aldehyde Dehydrogenase-2

Content Provider	PubMed Central
Author	Beretta, Matteo Gorren, Antonius C. F. Wenzl, M. Verena Weis, Robert Russwurm, Michael Doris, Koesling Schmidt, Kurt Mayer, Bernd
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 (ALDH21) with the Asian variant (ALDH22) regarding GTN bioactivation and the effects of Alda-1. Alda-1 increased acetaldehyde oxidation by ALDH21 and ALDH22 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 ≥5 mm. In the presence of 1 mm NAD, Alda-1 stimulated ALDH22-catalyzed ester hydrolysis 73-fold, whereas the NAD-stimulated activity of ALDH21 was inhibited because of 20-fold increased inhibitory potency of NAD in the presence of the drug. Although ALDH22 exhibited 7-fold lower GTN denitrating activity and GTN affinity than ALDH21, 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.
Related Links	http://dx.doi.org/10.1074/jbc.M109.014548
Starting Page	943
File Format	PDF
ISSN	1083351X
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	2
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-01-08
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Bioactivation of nitroglycerin by the East Asian variant of aldehyde dehydrogenase-2

Bioactivation of nitroglycerin by the East Asian variant of aldehyde dehydrogenase-2

Bioactivation of nitroglycerin by the East Asian variant of aldehyde dehydrogenase-2

Bioactivation of nitroglycerin by the East Asian variant of aldehyde dehydrogenase-2

Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase ‘Asian’ variant.

Characterization of the East Asian Variant of Aldehyde Dehydrogenase-2 BIOACTIVATION OF NITROGLYCERIN AND EFFECTS OF Alda-1

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