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 language | English |
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Pages (from-to) | 29-35 |
Journal | Chemico-Biological Interactions |
Volume | 178 |
Issue number | 1-3 |
DOIs | |
Publication status | Published - 2009 |
MoE publication type | A1 Journal article-refereed |
Event | 14th International Workshop on the Enzymology and Molecular Biology of Carbonyl Metabolism - Kranjska Gora, Slovenia Duration: 8 Jul 2008 → 12 Jul 2008 |
Keywords
- Asthma
- Alcohol dehydrogenase
- Formaldehyde dehydrogenase
- Glutathione
- Metabolic interaction
- S-nitrosoglutathione