The Janus face of alcohol dehydrogenase 3

Claudia A. Staab, Johan Ålander, Ralf Morgenstern, Roland Grafström, Jan-Olov Höög (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Many carbonyl metabolizing enzymes are equally involved in xenobiotic and endogenous metabolism, but few have been investigated in terms of substrate competition and interference between different cellular pathways. Mammalian alcohol dehydrogenase 3 (ADH3) represents the key enzyme in the formaldehyde detoxification pathway by oxidation of S-hydroxymethylglutathione [HMGSH; the glutathione (GSH) adduct of formaldehyde]. In addition, several studies have established ADH3 as S-nitrosoglutathione (GSNO) reductase in endogenous NO homeostasis during the last decade. GSNO depletion associates with various diseases including asthma, and evidence for a causal relationship between ADH3 and asthma pathology has been put forward. In a recent study, we showed that ADH3-mediated alcohol oxidation, including HMGSH oxidation, is accelerated in presence of GSNO which is concurrently reduced under immediate cofactor recycling [C.A. Staab, J. Ålander, M. Brandt, J. Lengqvist, R. Morgenstern, R.C. Grafström, J.-O. Höög, Reduction of S-nitrosoglutathione by alcohol dehydrogenase 3 is facilitated by substrate alcohols via direct cofactor recycling and leads to GSH-controlled formation of glutathione transferase inhibitors, Biochem. J. 413 (2008) 493–504]. Thus, considering the usually low cytosolic free NADH/NAD+ ratio, formaldehyde may trigger and promote GSNO reduction by enzyme-bound cofactor recycling. These findings provided evidence for formaldehyde-induced, ADH3-mediated GSNO depletion with potential direct implications for asthma. Furthermore, analysis of product formation as a function of GSH concentrations suggested that, under conditions of oxidative stress, GSNO reduction can lead to the formation of glutathione sulfinamide and its hydrolysis product glutathione sulfinic acid, both potent inhibitors of glutathione transferase activity.
Original languageEnglish
Pages (from-to)29-35
JournalChemico-Biological Interactions
Volume178
Issue number1-3
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed
Event14th International Workshop on the Enzymology and Molecular Biology of Carbonyl Metabolism - Kranjska Gora, Slovenia
Duration: 8 Jul 200812 Jul 2008

Fingerprint

Alcohol Dehydrogenase
Formaldehyde
Recycling
Asthma
glutathione-independent formaldehyde dehydrogenase
Glutathione Transferase
NAD
Oxidation
Glutathione
Enzymes
Sulfinic Acids
Alcohols
S-Nitrosoglutathione
Detoxification
Oxidative stress
Coenzymes
Pathology
Xenobiotics
Substrates
Metabolism

Keywords

  • Asthma
  • Alcohol dehydrogenase
  • Formaldehyde dehydrogenase
  • Glutathione
  • Metabolic interaction
  • S-nitrosoglutathione

Cite this

Staab, C. A., Ålander, J., Morgenstern, R., Grafström, R., & Höög, J-O. (2009). The Janus face of alcohol dehydrogenase 3. Chemico-Biological Interactions, 178(1-3), 29-35. https://doi.org/10.1016/j.cbi.2008.10.050
Staab, Claudia A. ; Ålander, Johan ; Morgenstern, Ralf ; Grafström, Roland ; Höög, Jan-Olov. / The Janus face of alcohol dehydrogenase 3. In: Chemico-Biological Interactions. 2009 ; Vol. 178, No. 1-3. pp. 29-35.
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abstract = "Many carbonyl metabolizing enzymes are equally involved in xenobiotic and endogenous metabolism, but few have been investigated in terms of substrate competition and interference between different cellular pathways. Mammalian alcohol dehydrogenase 3 (ADH3) represents the key enzyme in the formaldehyde detoxification pathway by oxidation of S-hydroxymethylglutathione [HMGSH; the glutathione (GSH) adduct of formaldehyde]. In addition, several studies have established ADH3 as S-nitrosoglutathione (GSNO) reductase in endogenous NO homeostasis during the last decade. GSNO depletion associates with various diseases including asthma, and evidence for a causal relationship between ADH3 and asthma pathology has been put forward. In a recent study, we showed that ADH3-mediated alcohol oxidation, including HMGSH oxidation, is accelerated in presence of GSNO which is concurrently reduced under immediate cofactor recycling [C.A. Staab, J. {\AA}lander, M. Brandt, J. Lengqvist, R. Morgenstern, R.C. Grafstr{\"o}m, J.-O. H{\"o}{\"o}g, Reduction of S-nitrosoglutathione by alcohol dehydrogenase 3 is facilitated by substrate alcohols via direct cofactor recycling and leads to GSH-controlled formation of glutathione transferase inhibitors, Biochem. J. 413 (2008) 493–504]. Thus, considering the usually low cytosolic free NADH/NAD+ ratio, formaldehyde may trigger and promote GSNO reduction by enzyme-bound cofactor recycling. These findings provided evidence for formaldehyde-induced, ADH3-mediated GSNO depletion with potential direct implications for asthma. Furthermore, analysis of product formation as a function of GSH concentrations suggested that, under conditions of oxidative stress, GSNO reduction can lead to the formation of glutathione sulfinamide and its hydrolysis product glutathione sulfinic acid, both potent inhibitors of glutathione transferase activity.",
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Staab, CA, Ålander, J, Morgenstern, R, Grafström, R & Höög, J-O 2009, 'The Janus face of alcohol dehydrogenase 3', Chemico-Biological Interactions, vol. 178, no. 1-3, pp. 29-35. https://doi.org/10.1016/j.cbi.2008.10.050

The Janus face of alcohol dehydrogenase 3. / Staab, Claudia A.; Ålander, Johan; Morgenstern, Ralf; Grafström, Roland; Höög, Jan-Olov (Corresponding Author).

In: Chemico-Biological Interactions, Vol. 178, No. 1-3, 2009, p. 29-35.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - The Janus face of alcohol dehydrogenase 3

AU - Staab, Claudia A.

AU - Ålander, Johan

AU - Morgenstern, Ralf

AU - Grafström, Roland

AU - Höög, Jan-Olov

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N2 - Many carbonyl metabolizing enzymes are equally involved in xenobiotic and endogenous metabolism, but few have been investigated in terms of substrate competition and interference between different cellular pathways. Mammalian alcohol dehydrogenase 3 (ADH3) represents the key enzyme in the formaldehyde detoxification pathway by oxidation of S-hydroxymethylglutathione [HMGSH; the glutathione (GSH) adduct of formaldehyde]. In addition, several studies have established ADH3 as S-nitrosoglutathione (GSNO) reductase in endogenous NO homeostasis during the last decade. GSNO depletion associates with various diseases including asthma, and evidence for a causal relationship between ADH3 and asthma pathology has been put forward. In a recent study, we showed that ADH3-mediated alcohol oxidation, including HMGSH oxidation, is accelerated in presence of GSNO which is concurrently reduced under immediate cofactor recycling [C.A. Staab, J. Ålander, M. Brandt, J. Lengqvist, R. Morgenstern, R.C. Grafström, J.-O. Höög, Reduction of S-nitrosoglutathione by alcohol dehydrogenase 3 is facilitated by substrate alcohols via direct cofactor recycling and leads to GSH-controlled formation of glutathione transferase inhibitors, Biochem. J. 413 (2008) 493–504]. Thus, considering the usually low cytosolic free NADH/NAD+ ratio, formaldehyde may trigger and promote GSNO reduction by enzyme-bound cofactor recycling. These findings provided evidence for formaldehyde-induced, ADH3-mediated GSNO depletion with potential direct implications for asthma. Furthermore, analysis of product formation as a function of GSH concentrations suggested that, under conditions of oxidative stress, GSNO reduction can lead to the formation of glutathione sulfinamide and its hydrolysis product glutathione sulfinic acid, both potent inhibitors of glutathione transferase activity.

AB - Many carbonyl metabolizing enzymes are equally involved in xenobiotic and endogenous metabolism, but few have been investigated in terms of substrate competition and interference between different cellular pathways. Mammalian alcohol dehydrogenase 3 (ADH3) represents the key enzyme in the formaldehyde detoxification pathway by oxidation of S-hydroxymethylglutathione [HMGSH; the glutathione (GSH) adduct of formaldehyde]. In addition, several studies have established ADH3 as S-nitrosoglutathione (GSNO) reductase in endogenous NO homeostasis during the last decade. GSNO depletion associates with various diseases including asthma, and evidence for a causal relationship between ADH3 and asthma pathology has been put forward. In a recent study, we showed that ADH3-mediated alcohol oxidation, including HMGSH oxidation, is accelerated in presence of GSNO which is concurrently reduced under immediate cofactor recycling [C.A. Staab, J. Ålander, M. Brandt, J. Lengqvist, R. Morgenstern, R.C. Grafström, J.-O. Höög, Reduction of S-nitrosoglutathione by alcohol dehydrogenase 3 is facilitated by substrate alcohols via direct cofactor recycling and leads to GSH-controlled formation of glutathione transferase inhibitors, Biochem. J. 413 (2008) 493–504]. Thus, considering the usually low cytosolic free NADH/NAD+ ratio, formaldehyde may trigger and promote GSNO reduction by enzyme-bound cofactor recycling. These findings provided evidence for formaldehyde-induced, ADH3-mediated GSNO depletion with potential direct implications for asthma. Furthermore, analysis of product formation as a function of GSH concentrations suggested that, under conditions of oxidative stress, GSNO reduction can lead to the formation of glutathione sulfinamide and its hydrolysis product glutathione sulfinic acid, both potent inhibitors of glutathione transferase activity.

KW - Asthma

KW - Alcohol dehydrogenase

KW - Formaldehyde dehydrogenase

KW - Glutathione

KW - Metabolic interaction

KW - S-nitrosoglutathione

U2 - 10.1016/j.cbi.2008.10.050

DO - 10.1016/j.cbi.2008.10.050

M3 - Article

VL - 178

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JO - Chemico-Biological Interactions

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Staab CA, Ålander J, Morgenstern R, Grafström R, Höög J-O. The Janus face of alcohol dehydrogenase 3. Chemico-Biological Interactions. 2009;178(1-3):29-35. https://doi.org/10.1016/j.cbi.2008.10.050