The Janus face of alcohol dehydrogenase 3.
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. Alander, 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.
Staab
Claudia A
CA
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Alander
Johan
J
Morgenstern
Ralf
R
Grafström
Roland C
RC
Höög
Jan-Olov
JO
D000426:Alcohol Dehydrogenase / Q000302:isolation & purification / Q000378:metabolism*; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D051379:Mice
D004791:Enzyme Inhibitors; D000426:Alcohol Dehydrogenase; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent; D005982:Glutathione Transferase; D053612:Janus Kinases