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Medium-chain fatty acids and glutathione derivatives as inhibitors of S-nitrosoglutathione reduction mediated by alcohol dehydrogenase 3
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.ORCID iD: 0000-0002-1211-7834
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.ORCID iD: 0000-0001-5257-6261
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; VTT Technical Research Center of Finland, Medical Biotechnology, Turku, Finland.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
2009 (English)In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 180, no 1, p. 113-118Article in journal (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 omega-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
Elsevier, 2009. Vol. 180, no 1, p. 113-118
Keywords [en]
Alcohol dehydrogenase, computer modelling, formaldehyde dehydrogenase, inhibitors, S-nitrosoglutathione, transnitrosation
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:oru:diva-109906DOI: 10.1016/j.cbi.2009.01.008ISI: 000266659300014PubMedID: 19428350Scopus ID: 2-s2.0-67349222284OAI: oai:DiVA.org:oru-109906DiVA, id: diva2:1815328
Funder
Cancer and Allergy FoundationSwedish Cancer SocietySwedish Fund for Research Without Animal ExperimentsKarolinska InstituteAvailable from: 2023-11-28 Created: 2023-11-28 Last updated: 2023-11-28Bibliographically approved

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