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2018 | 65 | 1 | 125-132
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Is aldehyde dehydrogenase inhibited by sulfur compounds? In vitro and in vivo studies

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Aldehyde dehydrogenase (ALDH) catalyzes the critical step of ethanol metabolism, i.e. transformation of toxic acetaldehyde to acetic acid. It is a redox sensitive protein with the key Cys in its active site. Recently, it has been documented that activity of some proteins can be modified by sulfur-containing molecules called reactive sulfur species leading to the formation of hydro- persulfides. The aim of the present study was to examine whether ALDH activity can be modified in this way. Studies were performed in vitro using yeast ALDH and various reactive sulfur species, including Na2S, GSSH, K2Sx, Na2S2O3, and garlic-derived allyl sulfides. The effect of garlic-derived trisulfide on ALDH activity was also studied in vivo in the rat liver. The obtained results clearly demonstrated that ALDH could be regulated by sulfur species which inhibited its enzymatic activity. The results also suggested that not H2S but polysulfides or hydropersulfides were the oxidizing species responsible for this modification. This process was easily reversible by reducing agents. After the treatment with polysulfides or hydropersulfides the level of protein-bound sulfur increased, while the activity of the enzyme dramatically decreased. Moreover, the study demonstrated that ALDH activity was inhibited in vivo in the rat liver after garlic-derived trisulfide administration. This is the first study reporting the regulation of ALDH activity by sulfane sulfur species and the results suggest that it leads to the inhibition of the enzyme.
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  • Chair of Medical Biochemistry, Jagiellonian University, Medical College Kraków, Poland
  • Chair of Medical Biochemistry, Jagiellonian University, Medical College Kraków, Poland
  • Chair of Medical Biochemistry, Jagiellonian University, Medical College Kraków, Poland
  • Chair of Medical Biochemistry, Jagiellonian University, Medical College Kraków, Poland
  • Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D (2014) Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev 94: 1-34. doi: 10.1152/physrev.00017.2013.
  • Chen Z, Foster MW, Zhang J, Mao L, Rockman HA, Kawamoto T, Kitagawa K, Nakayama KI, Hess DT, Stamler JS (2005) An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. Proc Natl Acad Sci USA 102: 12159-12164.
  • Edenberg HJ (2007) The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 30: 5-13.
  • Greiner R, Pálinkás Z, Bäsell K, Becher D, Antelmann H, Nagy P, Dick TP (2013) Polysulfides link H2S to protein thiol oxidation. Antioxid Redox Signal 19: 1749-1765. doi: 10.1089/ars.2012.5041.
  • Grimsrud P, Xie H, Griffin T, Bernlohr D (2008) Oxidative stress and covalent modification of protein with bioactive aldehydes. J Biol Chem 283: 21837-21841. doi: 10.1074/jbc.R700019200.
  • Hao PP, Chen YG, Wang JL, Wang XL, Zhang Y (2011) Meta-analysis of aldehyde dehydrogenase 2 gene polymorphism and Alzheimer's disease in East Asians. Can J Neurol Sci 38: 500-506.
  • Iciek M, Bilska-Wilkosz A, Górny M, Sokołowska-Jeżewicz M, Kowalczyk-Pachel D (2016) The effects of different garlic-derived allyl sulfides on anaerobic sulfur metabolism in the mouse kidney. Antioxidants 5: E46.
  • Iciek M, Kowalczyk-Pachel D, Bilska-Wilkosz A, Kwiecień I, Górny M, Włodek L (2015) S-sulfhydration as a cellular redox regulation. Biosci Rep 36: e00304. doi: 10.1042/BSR20150147.
  • Iciek M, Kowalczyk-Pachel D, Kwiecień I, Dudek M (2012) Effects of different garlic-derived allyl sulfides on peroxidative processes and anaerobic sulfur metabolism in mouse liver. Phytother Res 26: 425-431. doi: 10.1002/ptr.3572.
  • Jarosz AP, Wei W, Gauld JW, Auld J, Özcan F, Aslan M, Mutus B (2015) Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is inactivated by S-sulfuration in vitro. Free Radic Biol Med 89: 512-521. doi: 10.1016/j.freeradbiomed.2015.09.007.
  • Ju Y, Untereiner A, Wu L, Yang G (2015) H2S-induced S-sulfhydration of pyruvate carboxylase contributes to gluconeogenesis in liver cells. Biochim Biophys Acta 1850: 2293-2303. doi: 10.1016/j.bbagen.2015.08.003.
  • Kim SH, Kaschula CH, Priedigkeit N, Lee AV, Singh SV (2016) Forkhead Box Q1 is a novel target of breast cancer stem cell inhibition by diallyl trisulfide. J Biol Chem 291: 13495-13508. doi: 10.1074/jbc.M116.715219.
  • Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasiliou V (2012) Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev 64: 520-539. doi: 10.1124/pr.111.005538.
  • Liu Y, Yamanaka M, Abe-Kanoh N, Liu X, Zhu B, Munemasa S, Nakamura T, Murata Y, Nakamura Y (2017) Benzyl isothiocyanate ameliorates acetaldehyde-induced cytotoxicity by enhancing aldehyde dehydrogenase activity in murine hepatoma Hepa1c1c7 cells. Food Chem Toxicol 108: 305-313. doi: 10.1016/j.fct.2017.08.016.
  • Lowry OH, Rosebrough NJ, Farr AL, Randall RI (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265-275.
  • Luo XJ, Liu B, Ma QL, Peng J (2014) Mitochondrial aldehyde dehydrogenase, a potential drug target for protection of heart and brain from ischemia/reperfusion injury. Curr Drug Targets 15: 948-955. doi: 10.2174/1389450115666140828142401.
  • Mikami Y, Shibuya N, Kimura Y, Nagahara N, Ogasawara Y, Kimura H (2011) Thioredoxin and dihydrolipoic acid are required for 3-mercaptopyruvate sulfurtransferase to produce hydrogen sulfide. Biochem J 439: 479-485. doi: 10.1042/BJ20110841.
  • Motohashi H, Yamamoto M (2004) Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 10: 549-557.
  • Módis K, Ju Y, Ahmad A, Untereiner AA, Altaany Z, Wu L, Szabo C, Wang R (2016) S-Sulfhydration of ATP synthase by hydrogen sulfide stimulates mitochondrial bioenergetics. Pharmacol Res 113: 116-124. doi: 10.1016/j.phrs.2016.08.023.
  • Moon KH, Kim BJ, Song BJ (2005) Inhibition of mitochondrial aldehyde dehydrogenase by nitric oxide-mediated S-nitrosylation. FEBS Lett 579: 6115-6120. doi: 10.1016/j.febslet.2005.09.082.
  • Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, Barrow RK, Yang G, Wang R, Snyder SH (2009) H2S signals through protein S-sulfhydration. Sci Signal 2: ra72. doi: 10.1126/scisignal.2000464.
  • Ogasawara Y, Isoda S, Tanabe S (1994) Tissue and subcellular distribution of bound and acid labile sulfur, and the enzymic capacity for sulfide production in the rat. Biol Pharm Bull 17: 1535-1542.
  • Orywal K, Jelski W, Werel T, Szmitkowski M (2017) The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in the sera of bladder cancer patients. Acta Biochim Pol 64: 81-84. doi: 10.18388/abp.2016_1289.
  • Orywal K, Szmitkowski M (2017) Alcohol dehydrogenase and aldehyde dehydrogenase in malignant neoplasms. Clin Exp Med 17: 131-139. doi: 10.1007/s10238-016-0408-3.
  • Pang JJ, Barton LA, Chen YG, Ren J (2015) Mitochondrial aldehyde dehydrogenase in myocardial ischemia-reperfusion injury: from bench to bedside. Sheng Li Xue Bao 67: 535-544. doi: 10.13294/j.aps.2015.0067.
  • Paul BD, Snyder SH (2012) H2S signalling through protein sulfhydration and beyond. Nat Rev Mol Cell Biol 13: 499-507. doi: 10.1016/j.niox.2014.01.002.
  • Sladek NE (2003) Human aldehyde dehydrogenases: Potential pathological, pharmacological, and toxicological impact. J Biochem Mol Toxicol 17: 7-23. doi: 10.1002/jbt.10057.
  • Song BJ, Abdelmegeed MA, Yoo SH, Kim BJ, Jo SA, Jo I, Moon KH (2011) Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications. J Proteomics 74: 2691-2702. doi: 10.1016/j.jprot.2011.05.013.
  • Toohey JI (2011) Sulfur signaling: is the agent sulfide or sulfane? Anal Biochem 413: 1-7.
  • Toohey JI, Cooper AJ (2014) Thiosulfoxide (sulfane) sulfur: new chemistry and new regulatory roles in biology. Molecules 19: 12789-12813. doi: 10.3390/molecules190812789.
  • Tottmar SO, Pettersson H, Kiessling KH (1975) The subcellular distribution and properties of aldehyde dehydrogenases in rat liver. Biochem J 135: 577-586.
  • Ushida Y, Talalay P (2013) Sulforaphane accelerates acetaldehyde metabolism by inducing aldehyde dehydrogenases: relevance to ethanol intolerance. Alcohol Alcohol 48: 526-534. doi: 10.1093/alcalc/agt063.
  • Wenzel P, Hink U, Oelze M, Schuppan S, Schaeuble K, Schildknecht S, Ho KK, Weiner H, Bachschmid M, Münzel T, Daiber A (2007) Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity. Implications for mitochondrial oxidative stress and nitrate tolerance. J Biol Chem 282: 792-799.
  • Wey MC, Fernandez E, Martinez PA, Sullivan P, Goldstein DS, Strong R (2012) Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson's disease. PLoS One 7: e31522. doi: 10.1371/journal.pone.0031522.
  • Williams TI, Lynn BC, Markesbery WR, Lovell MA (2006) Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer's disease. Neurobiol Aging 27: 1094-1099.
  • Wood JL (1987) Sulfane sulfur. Methods Enzymol 143: 25-29.
  • Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I (2010) Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis. Nat Med 16: 1024-1028. doi: 10.1038/nm.2200..
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