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Medium- and short-chain dehydrogenase/reductase gene and protein families: Dual functions of alcohol dehydrogenase 3: implications with focus on formaldehyde dehydrogenese and S-nitrosoglutathione reductase activities
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden.ORCID iD: 0000-0002-1211-7834
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden.ORCID iD: 0000-0001-5257-6261
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden.ORCID iD: 0000-0002-2923-8261
2008 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 65, no 24, p. 3950-3960Article, review/survey (Refereed) Published
Abstract [en]

Alcohol dehydrogenase 3 (ADH3) has emerged as an important regulator of protein S-nitrosation in its function as S-nitrosoglutathione (GSNO) reductase. GSNO depletion is associated with various disease conditions, emphasizing the potential value of a specific ADH3 inhibitor. The present study investigated inhibition of ADH3-mediated GSNO reduction by various substrate analogues, including medium-chain fatty acids and glutathione derivatives. The observed inhibition type was non-competitive. Similar to the Michaelis constants for the corresponding ω-hydroxy fatty acids, the inhibition constants for fatty acids were in the micromolar range and showed a clear dependency on chain length with optimal inhibitory capacity for eleven and twelve carbons. The most efficient inhibitors found were undecanoic acid, dodecanoic acid and dodecanedioic acid, with no significant difference in inhibition constant. All glutathione-derived inhibitors displayed inhibition constants in the millimolar range, at least three orders of magnitudes higher than the Michaelis constants of the high-affinity substrates GSNO and S-hydroxymethylglutathione. The experimental results as well as docking simulations with GSNO and S-methylglutathione suggest that for ADH3 ligands with a glutathione scaffold, in contrast to fatty acids, a zinc-binding moiety is imperative for correct orientation and stabilization of the hydrophilic glutathione scaffold within a predominantly hydrophobic active site.

Place, publisher, year, edition, pages
Springer, 2008. Vol. 65, no 24, p. 3950-3960
Keywords [en]
Alcohol dehydrogenase, Formaldehyde, Metabolic interaction, Protein S-nitrosation, S-nitrosoglutathione
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-109970DOI: 10.1007/s00018-008-8592-2ISI: 000261987400007PubMedID: 19011746Scopus ID: 2-s2.0-58149141583OAI: oai:DiVA.org:oru-109970DiVA, id: diva2:1815925
Funder
Cancer and Allergy FoundationKarolinska InstituteAvailable from: 2023-11-30 Created: 2023-11-30 Last updated: 2023-12-01Bibliographically approved

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Hellgren, Mikko

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