Staab Claudia A, Alander Johan, Morgenstern Ralf, Grafström Roland C, Höög Jan-Olov
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Chem Biol Interact. 2009 Mar 16;178(1-3):29-35. doi: 10.1016/j.cbi.2008.10.050. Epub 2008 Nov 6.
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.
许多羰基代谢酶在异源生物和内源性代谢中发挥着同等作用，但在不同细胞途径之间的底物竞争和干扰方面，鲜有研究。哺乳动物乙醇脱氢酶3（ADH3）是甲醛解毒途径中的关键酶，可氧化S-羟甲基谷胱甘肽[HMGSH；甲醛的谷胱甘肽（GSH）加合物]。此外，在过去十年中，多项研究证实ADH3是内源性一氧化氮（NO）稳态中的S-亚硝基谷胱甘肽（GSNO）还原酶。GSNO耗竭与包括哮喘在内的多种疾病相关，并且已有证据表明ADH3与哮喘病理之间存在因果关系。在最近的一项研究中，我们发现，在GSNO存在的情况下，ADH3介导的酒精氧化（包括HMGSH氧化）会加速，同时在直接的辅因子循环作用下，GSNO会被还原[C.A. Staab、J. Alander、M. Brandt、J. Lengqvist、R. Morgenstern、R.C. Grafström、J.-O. Höög，底物醇类通过直接的辅因子循环促进乙醇脱氢酶3对S-亚硝基谷胱甘肽的还原，并导致谷胱甘肽转移酶抑制剂的GSH控制形成，《生物化学杂志》413（2008）493 - 504]。因此，考虑到通常较低的胞质游离NADH/NAD(+)比率，甲醛可能通过酶结合的辅因子循环触发并促进GSNO的还原。这些发现为甲醛诱导的、ADH3介导的GSNO耗竭提供了证据，这可能对哮喘有直接影响。此外，对产物形成与GSH浓度关系的分析表明，在氧化应激条件下，GSNO的还原可导致谷胱甘肽亚磺酰胺及其水解产物谷胱甘肽亚磺酸的形成，这两种物质都是谷胱甘肽转移酶活性的有效抑制剂。
