Statistical studies have demonstrated that various agents may reduce the risk of cancer’s development. One of them is activity of flavin-dependent enzymes such as flavin-containing monooxygenase (FMO) GS-OX1, FAD-dependent 5,10-methylenetetrahydrofolate reductase and flavin-dependent monoamine oxidase. In the last decade, many papers concerning their structure, reaction mechanism and role in the cancer prevention were published. In our work, we provide a more in-depth analysis of flavin-dependent enzymes and their contribution to the cancer prevention. We present the actual knowledge about the glucosinolate synthesized by flavin-containing monooxygenase (FMO) GS-OX1 and its role in cancer prevention, discuss the influence of mutations in FAD-dependent 5,10-methylenetetrahydrofolate reductase on the cancer risk, and describe FAD as an important cofactor for the demethylation of histons. We also present our views on the role of riboflavin supplements in the prevention against cancer.
References
[1]
Powers, H.J. Riboflavin (vitamin B-2) and health. Am. J. Clin. Nutr 2003, 77, 1352–1360.
[2]
Basset, J.K.; Severi, G.; Hodge, A.M.; Baglietto, L.; Hopper, J.L.; English, D.R.; Giles, G.G. Dietary intake of B vitamins and methionine and prostate cancer incidence and mortality. Cancer Causes Control 2012, 23, 855–863.
[3]
Kimura, M.; Umegaki, K.; Higuchi, M.; Thomas, P. Methylenetetrahydrofolate reductase C677T polymorphism, folic acid and riboflavin are important determinants of genome stability in culture human lymphocytes. J. Nutr 2004, 134, 48–56.
[4]
Powers, H.J. Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer. J. Nutr 2005, 135, 2960S–2966S.
[5]
Powers, H.J.; Hill, M.H.; Welfare, M.; Spiers, A.; Bal, W.; Russell, J.; Duckworth, Y.; Gibney, E.; Williams, E.A.; Mathers, J.C. Responses of biomarkers of folate and riboflavin status to folate and riboflavin supplementation in healthy and colorectal polyp patients (The FAB2 study). Cancer Epidemiol. Biomarkers Prev 2007, 16, 2128–2135.
[6]
Premkumar, V.G.; Yuvaraj, S.; Shanthi, P.; Sachdanandam, P. Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy. Br. J. Nutr 2008, 100, 1179–1182.
[7]
Vergara, F.; Wenzler, M.; Hansen, B.G.; Kliebenstein, D.J.; Halkier, B.A.; Gersgenzon, J.; Schneider, B. Determination of the absolute configuration of the glucosinolate methyl sulfoxide group reveals a stereospecific biosynthesis of the side chain. Phytochemistry 2008, 69, 2737–2742.
[8]
S?nderby, I.E.; Geu-Flores, F.; Halkier, B.A. Biosynthesis of glucosinolates-gene discovery and beyond. Trends Plant Sci 2010, 15, 283–290.
Katchamart, S.; Stresser, D.M.; Dehal, S.S.; Kupfer, D.; Williams, D.E. Concurrent flavin-containing monooxygenase down-regulation and cytochrome P-450 induction by dietary indoles in rat: implications for drug-drug interaction. Drug Metab. Dispos 2000, 28, 930–936.
[11]
Hansen, B.G.; Kliebenstein, D.J.; Halkier, B.A. Identification of a flavin-monooxygenase as the S-oxygenating enzyme in aliphatic glucosinolate biosynthesis in Arabidopsis. Plant J 2007, 50, 902–910.
Mikkelsen, M.D.; Olsen, C.E.; Halkier, B.A. Production of the cancer-preventive glucoraphanin in tobacco. Mol. Plant 2010, 4, 751–759.
[14]
Li, J.; Kristiansen, K.A.; Hansen, B.G.; Halkier, B.A. Cellular and subcellular localization of flavin-monooxygenases involved in glucosinolate biosynthesis. J. Exp. Bot 2010, 62, 1337–1346.
[15]
Verhoeven, D.T.H.; Goldbohm, R.A.; van Poppel, G.; Verhagen, H.; van den Brandt, P.A. Epidemiological studies on Brassica vegetables and cancer risk. Cancer Epidemiol. Biomark. Prev 1996, 5, 733–748.
[16]
Fahey, J.W.; Zhang, Y.; Talalay, P. Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc. Natl. Acad. Sci. USA 1997, 94, 10367–10372.
[17]
Talalay, P.; Fahey, J.W. Phytochemicals from Cruciferous plants protect against cancer by modulating carcinogen metabolism. J. Nutr 2001, 131, 3027S–3033S.
Eswaramoorthy, S.; Bonanno, J.B.; Burley, S.K.; Swaminathan, S. Mechanism of action of a flavin-containing monooxygenase. Proc. Natl. Acad. Sci. USA 2006, 103, 9832–9837.
[20]
Palfey, B.A.; McDonald, C.A. Control of catalysis in flavin-depndent monooxygenases. Arch. Biochem. Biophys 2010, 493, 26–36.
[21]
Varalakshmi, K.; Savithri, H.S.; Rao, A. Purification and kinetic mechanism of 5,10-metliyienetetrahydrofolate reductase from sheep liver. J. Biosci 1983, 5, 287–299.
[22]
Viel, A.; Dall’Agnese, L.; Simone, F.; Canzonieri, V.; Capozzi, E.; Visentin, M.C.; Valle, R.; Boiocchi, M. Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas. Br. J. Cancer 1997, 75, 1105–1110.
[23]
Roje, S.; Wang, H.; McNeil, S.D.; Raymond, R.K.; Appling, D.R.; Shachar-Hill, Y.; Bohnert, H.J.; Hanson, A.D. Isolation, characterization, and functional expression of cDNAs encoding NADH-dependent methylenetetrahydrofolate reductase from higher plants. J. Biol. Chem 1999, 274, 36089–36096.
[24]
Sheppard, C.A.; Trimmer, E.E.; Matthews, R.G. Purification and properties of NADH-depndent 5,10-methylenetetrahydrofolate reductase (MetF) from Escherichia coli. J. Bacteriol 1999, 181, 718–725.
[25]
Chen, J.; Gammon, M.D.; Chan, W.; Palomeque, C.; Wetmur, J.G.; Kabat, G.C.; Teitelbaum, S.L.; Britton, J.A.; Terry, M.B.; Neugut, A.I.; et al. One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res 2005, 65, 1606–1614.
[26]
Pejchal, R.; Sargeant, R.; Ludwig, M.L. Structures of NADH and CH3-H4 folate complex of Escherichia coli methylenetetrahydrofolate reductase reveal a Spartan strategy for a ping-pong reaction. Biochemistry 2005, 44, 11447–11457.
[27]
Igari, S.; Ohtaki, A.; Yamanaka, Y.; Sato, Y.; Yohda, M.; Odaka, M.; Noguchi, K.; Yamada, K. Properties and crystal structure of methylenetetrahydrofolate reductase from Thermus thermophilus HB8. PLoS One 2011, 6, e23716.
[28]
Matthews, R.G.; Sheppard, S.; Goulding, C. Methylenetetrahydrofolate reductase and methionine synthase: Biochemistry and molecular biology. Eur. J. Pediatr 1998, 157, S54–S59.
[29]
Ronien, K.; Ulrich, C.M. 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: A HuGE minireview. Am. J. Epidemiol 2003, 157, 571–582.
[30]
Linnebank, M.; Semmler, A.; Moskau, S.; Smulders, Y.; Blom, H.; Simon, M. The methylenetetrahydrofolate reductase (MTHFR) variant c.677C > T (A222V) influences overall survival of patients with glioblastoma multifore. Neuro-Oncology 2008, 10, 548–552.
[31]
Jacques, P.F.; Kalmbach, R.; Bagley, P.J.; Russo, G.T.; Rogers, G.; Wilson, P.W.F.; Rosenberg, I.H.; Selhub, J. The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring Cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J. Nutr 2002, 132, 283–288.
[32]
Forges, T.; Chery, C.; Audonnet, S.; Feillet, F.; Gueant, J.L. Life-treatening methylenetetrahydrofolate reductase (MTHFR) deficiency with extremely early onset: characterization of two novel mutations in compound heterozygous patients. Mol. Genet. Metab 2010, 100, 143–148.
[33]
Hosseini, M.; Houshmand, M.; Ebrahimi, A. MTHFR polymorphisms and breast cancer risk. Arch. Med. Sci 2011, 7, 134–137.
[34]
Chiuve, S.E.; Giovannucci, E.L.; Hankinson, S.E.; Hunter, D.J.; Stampfer, M.J.; Willett, W.C.; Rimm, E.B. Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine. Am. J. Clin. Nutr 2005, 82, 155–162.
[35]
Kafadar, A.M.; Yilmaz, H.; Kafadar, D.; Ergen, A.; Zeybek, U.; Bozkurt, N.; Kuday, C.; Isbir, T. C677T gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) in meningiomas and high-grade gliomas. Anticancer Res 2006, 26, 2445–2450.
[36]
Hustad, S.; Nedreb?, B.G.; Ueland, P.M.; Schneede, J.; Vollset, S.E.; Ulvik, A.; Lien, E.A. Phenotypic expression of the methylenetetrahydrofolate reductase 677C→T polymorphism and flavin cofactor availability in thyroid dysfunction. Am. J. Clin. Nutr 2004, 80, 1050–1057.
[37]
McNulty, H.; McKinley, M.C.; Wilson, B.; McPartlin, J.; Strain, J.J.; Weir, D.G.; Scott, J.M. Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. Am. J. Clin. Nutr 2002, 76, 436–441.
[38]
Hustad, S.; Midttun, ?.; Schneede, J.; Vollset, S.E.; Grotmol, T.; Ueland, P.M. The methylenetetrahydrofolate reductase 677C→T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Am. J. Hum. Genet. 2007, 80, 846–855.
[39]
Ferroni, P.; Palmirotta, R.; Martini, F.; Riondino, S.; Savonarola, A.; Spila, A.; Ciatti, S.; Sini, V.; Mariotti, S.; Del Monte, G.; et al. Determinants of homocysteine levels in colorectal and breast cancer patients. Anticancer Res 2009, 29, 4131–4138.
[40]
Wu, L.L.; Wu, J.T. Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clin. Chim. Acta 2002, 322, 21–28.
[41]
Lin, J.; Lee, I.M.; Song, Y.; Cook, N.R.; Selhub, J.; Manson, J.E.; B Uring, J.E.; Zhang, S.M. Plasma homocysteine and cysteine and risk of breast cancer in woman. Cancer Res 2010, 70, 2397–2405.
[42]
Jakubowski, H. Metabolism of homocysteine thiolactone in human cell cultures. J. Biol. Chem 1997, 272, 1935–1942.
[43]
Vinukonda, G. Plasma homocysteine and methylenetetrahydrofolate reductase gene polymorphism in human health and disease: An update. Int. J. Hum. Genet 2008, 8, 171–179.
[44]
Ueland, P.M.; Hustad, S.; Schneede, J.; Refsum, H.; Vollset, S.E. Biological and clinical implications of the MTFR C677T polymorphism. Trends Pharmacol. Sci 2001, 22, 195–201.
[45]
Moat, S.J.; Ashfield-Watt, P.A.L.; Powers, H.J.; Newcombe, R.G.; McDowell, I.F.W. Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype. Clin. Chem 2003, 49, 295–302.
[46]
Hustad, S.; Ueland, P.M.; Vollset, S.E.; Zhang, Y.; Bj?rke-Monsen, A.L.; Schneede, J. Riboflavin as a determinant of plasma total homocysteine: Effect modification by the methylenetetrahydrofolate reductase C667T polymorphism. Clin. Chem 2000, 46, 1065–1071.
[47]
Forneris, F.; Binda, C.; Vanoni, M.A.; Mattevi, A.; Battaglioli, E. Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process. FEBS Lett 2005, 579, 2203–2207.
[48]
Cloos, P.A.C.; Christensen, J.; Agger, K.; Helin, K. Erasing the methyl mark: Histone demethylases at the center of cellular differentiation and disease. Genes Dev 2008, 22, 1115–1140.
[49]
Forneris, F.; Battaglioli, E.; Mattevi, A.; Binda, C. New roles of flavoproteins in molecular cell biology: histone demethylase LSD1 and chromatin. FEBS J 2009, 276, 4304–4312.
[50]
Karytinos, A.; Forneris, F.; Profumo, A.; Ciossani, G.; Battaglioli, E.; Binda, C.; Mattevi, A. A novel mammalian flavin-dependent histone demethylase. J. Biol. Chem 2009, 284, 17775–17782.
Culhane, J.C.; Cole, P.A. LSD1 and the chemistry of histone demethylation. Curr. Opin. Biol. Chem 2007, 11, 561–568.
[53]
Schmidt, D.M.Z.; McCafferty, D.G. trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 2007, 46, 4408–4416.
[54]
Wang, Y.; Zhang, H.; Chen, Y.; Sun, Y.; Yang, F.; Yu, W.; Liang, J.; Sun, L.; Yang, X.; Shi, L.; et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 2009, 138, 660–672.
[55]
Binda, C.; Valente, S.; Romanenghi, M.; Pilotto, S.; Cirilli, R.; karytinos, A.; Ciossani, G.; Botrugno, O.A.; Forneris, F.; Tardugno, M.; et al. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J. Am. Chem. Soc 2010, 132, 6827–6833.
[56]
Upadhyay, A.K.; Horton, J.R.; Zhang, X.; Cheng, X. Coordinated methyl-lysine erasure: Structural and functional linkage of a Jumonji demethylase domain and a reader domain. Curr. Opin. Struct. Biol 2011, 21, 750–760.
[57]
Heightman, T.D. Chemical biology of lysine demethylases. Curr. Chem. Genomics 2011, 5, 62–71.
[58]
Baron, R.; Binda, C.; Tortorici, M.; McCammon, J.A.; Mattevi, A. Molecular mimicry and ligand recognition in binding and catalysis by the histone demethylase LSD1-CoREST complex. Structure 2011, 19, 212–220.
[59]
Forneris, F.; Binda, C.; Battaglioli, E.; Mattevi, A. LSD1: Oxidative chemistry for multifaceted functions in chromatin regulation. Trends Biochem. Sci 2008, 33, 181–189.
[60]
Chen, Y.; Yang, Y.; Wang, F.; Wan, K.; Yamane, K.; Zhang, Y.; Lei, M. Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc. Natl. Acad. Sci. USA 2006, 103, 13956–13961.
[61]
Fang, R.; Barbera, A.J.; Xu, Y.; Rutenberg, M.; Leonor, T.; Bi, Q.; Lan, F.; Mei, P.; Yuan, G.C.; Lian, C.; et al. Human LSD2/KDM1b/AOF1 regulates gene transcription by modulating intragenic H3K4me2 methylation. Mol. Cell 2010, 39, 222–233.
[62]
Kong, X.; Ouyang, S.; Liang, Z.; Lu, J.; Chen, L.; Shen, B.; Li, D.; Zheng, M.; Li, K.K.; Luo, C.; et al. Catalytic mechanism investigation of lysine-specific demethylase 1 (LSD1): A computational study. PLoS One 2011, 6, e25444.
[63]
Kurtz, K.A.; Rishavy, M.A.; Cleland, W.W.; Fitzpatrick, P.F. Nitrogen isotope effects as probes of the mechanism of D-amino acid oxidase. J. Am. Chem. Soc 2000, 122, 12896–12897.
[64]
Edmondson, D.E.; Binda, C.; Mattevi, A. Structural insights into the mechanism of amine oxidation by monoamine oxidases A and B. Arch. Biochem. Biophys 2007, 464, 269–276.
[65]
Shi, Y.; Whetstine, J.R. Dynamic regulation of histone lysine methylation by demethylases. Mol. Cell 2007, 25, 1–13.
[66]
Yang, M.; Culhane, J.C.; Szewczuk, L.M.; Jalili, P.; Ball, H.L.; Machius, M.; Cole, P.A.; Yu, H. Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry 2007, 46, 8058–8065.
[67]
Baron, R.; Vellore, N.A. LSD1/CoREST in an allosteric nanoscale clamp regulated by H3-histone-tail molecular recognition. Proc. Natl. Acad. Sci. USA 2012, doi:10.1073/pnas.1207892109.
[68]
Huang, J.; Sengupta, R.; Espejo, A.B.; Lee, M.G.; Dorsey, J.A.; Richter, M.; Opravil, S.; Shiekhattar, R.; Bedford, M.T.; Jenuwein, T.; et al. p53 is regulated by the lysine demethylase LSD1. Nature 2007, 449, 105–109.
[69]
He, Y.; Korboukh, I.; Jin, J.; Huang, J. Targeting protein lysine methylation and demethylation in cancer. Acta Biochim. Biophys. Sin 2012, 44, 70–79.
[70]
Culhane, J.C.; Szewczuk, L.M.; Liu, X.; Da, G.; Marmorstein, R.; Cole, P.A. A mechanizm-based inactivator for histone demethylase LSD1. J. Am. Chem. Soc 2006, 128, 4536–4537.
[71]
Culhane, J.C.; Wang, D.; Yen, P.M.; Cole, P.A. Comparative analysis of small molecules and histone substrate analogs as LSD1 lysine demethylase inhibitors. J. Am. Chem. Soc 2010, 132, 3164–3176.
[72]
Schulte, J.H.; Lim, S.; Schramm, A.; Friedrichs, N.; Koster, J.; Versteeg, R.; Ora, I.; Pajtler, K.; Klein-Hitpass, L.; kuhfitting-Kulle, S.; et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: Implications for therapy. Cancer Res 2009, 69, 2065–2071.
[73]
Lukaski, H.C. Vitamin and mineral status: Effects on physical performance. Nutrition 2004, 20, 632–644.
[74]
Mannion, C.A.; Gray-Donald, K.; Koski, K.G. Association of low intake of milk and vitamin D during pregnancy with decreased birth weight. CMAJ 2006, 174, 1273–1277.
[75]
He, Y.; Ye, L.; Shan, B.; Song, G.; Meng, F.; Wang, S. Effect of riboflavin-fortified salt nutrition intervention on esophaheal squamous call carcinoma in a high incidence area, China. Asian Pac. J. Cancer Prev 2009, 10, 619–622.
[76]
Wang, G.Q.; Dawsey, S.M.; Li, J.Y.; Taylor, P.R.; Li, B.; Blot, W.J.; Weinstein, W.M.; Liu, F.S.; Lewin, K.J.; Wang, H.; et al. Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: Results from the general population trial in Linxian, China. Cancer Epidemiol. Biomark. Prev 1994, 3, 161–166.
[77]
de Vogel, S.; Dindore, V.; van Engeland, M.; Goldbohm, R.A.; van den Brandt, P.A.; Weijenberg, M.P. Dietary folate, methionine, riboflavin, and vitamin B-6 and risk of sporadic colorectal cancer. J. Nutr 2008, 138, 2372–2378.