Flavins and Flavoproteins: Applications in Medicine

  • Esther Jortzik
  • Lihui Wang
  • Jipeng Ma
  • Katja BeckerEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1146)


The potential of flavoproteins as targets of pharmacological treatments is immense. In this review we present an overview of the current research progress on medical interventions based on flavoproteins with a special emphasis on cancer, infectious diseases, and neurological disorders.

Key words

Lysine-specific demethylase 1 Thioredoxin reductase NAD(P)H:quinone oxidoreductase Monoamine oxidase d-amino acid oxidase Xanthine oxidase NADPH oxidase 

List of abbreviations




Amyotrophic lateral sclerosis


Androgen receptor




d-amino acid oxidase


Dihydroorotate dehydrogenase


Estrogen receptor


Flavin adenine dinucleotide


Flavin mononucleotide


Glutathione reductase




Reduced glutathione


Oxidized glutathione


Histone deacetylase


Lipoamide dehydrogenase


Lysine specific demethylase


Monoamine oxidase


Motexafin gadolinium


NAD(P)H:quinone oxidoreductase 1




N-methyl d-aspartate receptor


NADPH oxidases


Mi-2/nucleosome remodeling and deacetylase complex






Reversible inhibitors of MAO-A


Ribonucleotide reductase


Reactive oxygen species




Selenium compromised thioredoxin reductase-derived apoptotic proteins


Transforming growth factor-β1


Thioredoxin glutathione reductase


Thymidylate synthase


Trypanothione reductase




Thioredoxin reductase


Xanthine oxidase



The authors wish to thank the Deutsche Forschungsgemeinschaft (DFG, BE1540/15-1) for supporting their work.


  1. 1.
    Massey V (1994) Activation of molecular oxygen by flavins and flavoproteins. J Biol Chem 269:22459–22462PubMedGoogle Scholar
  2. 2.
    Mansoorabadi SO, Thibodeaux CJ, Liu HW (2007) The diverse roles of flavin coenzymes: nature’s most versatile thespians. J Org Chem 72:6329–6342PubMedCentralPubMedGoogle Scholar
  3. 3.
    Miura R (2001) Versatility and specificity in flavoenzymes: control mechanisms of flavin reactivity. Chem Rec 1:183–194PubMedGoogle Scholar
  4. 4.
    Mathews FS, Cunane L, Durley RC (2000) Flavin electron transfer proteins. Subcell Biochem 35:29–72PubMedGoogle Scholar
  5. 5.
    Macheroux P, Kappes B, Ealick SE (2011) Flavogenomics: a genomic and structural view of flavin-dependent proteins. FEBS J 278:2625–2634PubMedGoogle Scholar
  6. 6.
    Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068PubMedGoogle Scholar
  7. 7.
    Shi Y, Whetstine JR (2007) Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25:1–14PubMedGoogle Scholar
  8. 8.
    Heightman TD (2011) Chemical biology of lysine demethylases. Curr Chem Genomics 5:62–71PubMedCentralPubMedGoogle Scholar
  9. 9.
    Chi P, Allis CD, Wang GG (2010) Covalent histone modifications: miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10:457–469PubMedCentralPubMedGoogle Scholar
  10. 10.
    Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953PubMedGoogle Scholar
  11. 11.
    Metzger E, Wissmann M, Yin N, Müller JM, Schneider R, Peters AHFM, Günther T, Buettner R, Schüle R (2005) LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437:436–439PubMedGoogle Scholar
  12. 12.
    Forneris F, Binda C, Vanoni MA, Battaglioli E, Mattevi A (2005) Human histone demethylase LSD1 reads the histone code. J Biol Chem 280:41360–41365PubMedGoogle Scholar
  13. 13.
    Lan F, Collins RE, De Cegli R, Alpatov R, Horton JR, Shi X, Gozani O, Cheng X, Shi Y (2007) Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature 448:718–722PubMedCentralPubMedGoogle Scholar
  14. 14.
    Lee MG, Wynder C, Bochar DA, Hakimi MA, Cooch N, Shiekhattar R (2006) Functional interplay between histone demethylase and deacetylase enzymes. Mol Cell Biol 26:6395–6402PubMedCentralPubMedGoogle Scholar
  15. 15.
    Varier RA, Timmers HT (2011) Histone lysine methylation and demethylation pathways in cancer. Biochim Biophys Acta 1815:75–89PubMedGoogle Scholar
  16. 16.
    Pedersen MT, Helin K (2010) Histone demethylases in development and disease. Trends Cell Biol 20:662–671PubMedGoogle Scholar
  17. 17.
    Shi Y (2007) Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8:829–833PubMedGoogle Scholar
  18. 18.
    Manuyakorn A, Paulus R, Farrell J, Dawson NA, Tze S, Cheung-Lau G, Hines OJ, Reber H, Seligson DB, Horvath S, Kurdistani SK, Guha C, Dawson DW (2010) Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704. J Clin Oncol 28:1358–1365PubMedCentralPubMedGoogle Scholar
  19. 19.
    Magerl C, Ellinger J, Braunschweig T, Kremmer E, Koch LK, Höller T, Büttner R, Lüscher B, Gütgemann I (2010) H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1. Hum Pathol 41:181–189PubMedGoogle Scholar
  20. 20.
    Lim S, Janzer A, Becker A, Zimmer A, Schüle R, Buettner R, Kirfel J (2010) Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis 31:512–520PubMedGoogle Scholar
  21. 21.
    Ellinger J, Kahl P, von der Gathen J, Rogenhofer S, Heukamp LC, Gütgemann I, Walter B, Hofstädter F, Büttner R, Müller SC, Bastian PJ, von Ruecker A (2010) Global levels of histone modifications predict prostate cancer recurrence. Prostate 70:61–69PubMedGoogle Scholar
  22. 22.
    Seligson DB, Horvath S, McBrian MA, Mah V, Yu H, Tze S, Wang Q, Chia D, Goodglick L, Kurdistani SK (2009) Global levels of histone modifications predict prognosis in different cancers. Am J Pathol 174:1619–1628PubMedCentralPubMedGoogle Scholar
  23. 23.
    Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA et al (2009) Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res 69:3802–3809PubMedGoogle Scholar
  24. 24.
    Barlesi F, Giaccone G, Gallegos-Ruiz MI, Loundou A, Span SW et al (2007) Global histone modifications predict prognosis of resected non small-cell lung cancer. J Clin Oncol 25:4358–4364PubMedGoogle Scholar
  25. 25.
    Seligson DB, Horvath S, Shi T, Yu H, Tze S et al (2005) Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435:1262–1266PubMedGoogle Scholar
  26. 26.
    Schildhaus HU, Riegel R, Hartmann W, Steiner S, Wardelmann E et al (2011) Lysine-specific demethylase 1 is highly expressed in solitary fibrous tumors, synovial sarcomas, rhabdomyosarcomas, desmoplastic small round cell tumors, and malignant peripheral nerve sheath tumors. Hum Pathol 42:1667–1675PubMedGoogle Scholar
  27. 27.
    Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J et al (2009) Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res 69:2065–2071PubMedGoogle Scholar
  28. 28.
    Huang Y, Stewart TM, Wu Y, Baylin SB, Marton LJ et al (2009) Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin Cancer Res 15:7217–7228PubMedCentralPubMedGoogle Scholar
  29. 29.
    Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA et al (2007) p53 is regulated by the lysine demethylase LSD1. Nature 449:105–108PubMedGoogle Scholar
  30. 30.
    Cho HS, Suzuki T, Dohmae N, Hayami S, Unoki M et al (2011) Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res 71:655–660PubMedGoogle Scholar
  31. 31.
    Wang Y, Zhang H, Chen Y, Sun Y, Yang F et al (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138:660–672PubMedGoogle Scholar
  32. 32.
    Spannhoff A, Hauser AT, Heinke R, Sippl W, Jung M (2009) The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem 4:1568–1582PubMedGoogle Scholar
  33. 33.
    Schmidt DM, McCafferty DG (2007) Trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46:4408–4416PubMedGoogle Scholar
  34. 34.
    Yang M, Culhane JC, Szewczuk LM, Jalili P, Ball HL et al (2007) Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry 46:8058–8065PubMedGoogle Scholar
  35. 35.
    Binda C, Valente S, Romanenghi M, Pilotto S, Cirilli R et al (2010) Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J Am Chem Soc 132:6827–6833PubMedGoogle Scholar
  36. 36.
    Ueda R, Suzuki T, Mino K, Tsumoto H, Nakagawa H et al (2009) Identification of cell-active lysine specific demethylase 1-selective inhibitors. J Am Chem Soc 131:17536–17537PubMedGoogle Scholar
  37. 37.
    Singh MM, Manton CA, Bhat KP, Tsai WW, Aldape K et al (2011) Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol 13:894–903PubMedCentralPubMedGoogle Scholar
  38. 38.
    Huang Y, Vasilatos SN, Boric L, Shaw PG, Davidson NE (2011) Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Res Treat 131:777–789PubMedCentralPubMedGoogle Scholar
  39. 39.
    Culhane JC, Szewczuk LM, Liu X, Da G, Marmorstein R et al (2006) A mechanism-based inactivator for histone demethylase LSD1. J Am Chem Soc 128:4536–4537PubMedGoogle Scholar
  40. 40.
    Huang Y, Greene E, Murray Stewart T, Goodwin AC, Baylin SB et al (2007) Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci USA 104:8023–8028PubMedCentralPubMedGoogle Scholar
  41. 41.
    Zhu Q, Huang Y, Marton LJ, Woster PM, Davidson NE, Casero RA (2011) Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells. Amino Acids 42:887–898PubMedCentralPubMedGoogle Scholar
  42. 42.
    Sharma SK, Wu Y, Steinbergs N, Crowley ML, Hanson AS et al (2010) (Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. J Med Chem 53:5197–5212PubMedCentralPubMedGoogle Scholar
  43. 43.
    Wang J, Lu F, Ren Q, Sun H, Xu Z, Lan R, Liu Y, Ward D, Quan J, Ye T, Zhang H (2011) Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res 71:7238–7249PubMedCentralPubMedGoogle Scholar
  44. 44.
    Arner ES (2009) Focus on mammalian thioredoxin reductases: important selenoproteins with versatile functions. Biochim Biophys Acta 1790:495–526PubMedGoogle Scholar
  45. 45.
    Gromer S, Urig S, Becker K (2004) The thioredoxin system: from science to clinic. Med Res Rev 24:40–89PubMedGoogle Scholar
  46. 46.
    Lee SR, Kim JR, Kwon KS, Yoon HW, Levine RL et al (1999) Molecular cloning and characterization of a mitochondrial selenocysteine-containing thioredoxin reductase from rat liver. J Biol Chem 274:4722–4734PubMedGoogle Scholar
  47. 47.
    Turanov AA, Su D, Gladyshev VN (2006) Characterization of alternative cytosolic forms and cellular targets of mouse mitochondrial thioredoxin reductase. J Biol Chem 281:22953–22963PubMedGoogle Scholar
  48. 48.
    Sun QA, Kirnarsky L, Sherman S, Gladyshev VN (2001) Selenoprotein oxidoreductase with specificity for thioredoxin and glutathione systems. Proc Natl Acad Sci USA 98:3673–3678PubMedCentralPubMedGoogle Scholar
  49. 49.
    Zhong L, Arner ES, Ljung J, Aslund F, Holmgren A (1998) Rat and calf thioredoxin reductase are homologous to glutathione reductase with a carboxyl-terminal elongation containing a conserved catalytically active penultimate selenocysteine residue. J Biol Chem 273:8581–8591PubMedGoogle Scholar
  50. 50.
    Sandalova T, Zhong L, Lindqvist Y, Holmgren A, Schneider G (2001) Three-dimensional structure of a mammalian thioredoxin reductase: implications for mechanism and evolution of a selenocysteine-dependent enzyme. Proc Natl Acad Sci USA 98:9533–9538PubMedCentralPubMedGoogle Scholar
  51. 51.
    Zhong L, Arner ES, Holmgren A (2000) Structure and mechanism of mammalian thioredoxin reductase: the active site is a redox-active selenolthiol/selenenylsulfide formed from the conserved cysteine-selenocysteine sequence. Proc Natl Acad Sci USA 97:5854–5859PubMedCentralPubMedGoogle Scholar
  52. 52.
    Gromer S, Johansson L, Bauer H, Arscott LD, Rauch S et al (2003) Active sites of thioredoxin reductases: why selenoproteins? Proc Natl Acad Sci USA 100:12618–12623PubMedCentralPubMedGoogle Scholar
  53. 53.
    Fritz-Wolf K, Kehr S, Stumpf M, Rahlfs S, Becker K (2011) Crystal structure of the human thioredoxin reductase-thioredoxin complex. Nat Commun 2 Article-No. 383Google Scholar
  54. 54.
    Nordberg J, Arner ES (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31:1287–1312PubMedGoogle Scholar
  55. 55.
    Bjornstedt M, Hamberg M, Kumar S, Xue J, Holmgren A (1995) Human thioredoxin reductase directly reduces lipid hydroperoxides by NADPH and selenocystine strongly stimulates the reaction via catalytically generated selenols. J Biol Chem 270:11761–11764PubMedGoogle Scholar
  56. 56.
    Johansson C, Lillig CH, Holmgren A (2004) Human mitochondrial glutaredoxin reduces S-glutathionylated proteins with high affinity accepting electrons from either glutathione or thioredoxin reductase. J Biol Chem 279:7537–7543PubMedGoogle Scholar
  57. 57.
    Lundstrom-Ljung J, Birnbach U, Rupp K, Soling HD, Holmgren A (1995) Two resident ER-proteins, CaBP1 and CaBP2, with thioredoxin domains, are substrates for thioredoxin reductase: comparison with protein disulfide isomerase. FEBS Lett 357:305–308PubMedGoogle Scholar
  58. 58.
    May JM, Mendiratta S, Hill KE, Burk RF (1997) Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. J Biol Chem 272:22607–22610PubMedGoogle Scholar
  59. 59.
    Xia L, Nordman T, Olsson JM, Damdimopoulos A, Bjorkhem-Bergman L et al (2003) The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. J Biol Chem 278:2141–2146PubMedGoogle Scholar
  60. 60.
    Lu J, Berndt C, Holmgren A (2009) Metabolism of selenium compounds catalyzed by the mammalian selenoprotein thioredoxin reductase. Biochim Biophys Acta 1790:1513–1519PubMedGoogle Scholar
  61. 61.
    Rhee SG, Chae HZ, Kim K (2005) Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med 38:1543–1552PubMedGoogle Scholar
  62. 62.
    Oien DB, Moskovitz J (2008) Substrates of the methionine sulfoxide reductase system and their physiological relevance. Curr Top Dev Biol 80:93–133PubMedGoogle Scholar
  63. 63.
    Klaunig JE, Kamendulis LM, Hocevar BA (2010) Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol 38:96–109PubMedGoogle Scholar
  64. 64.
    Ganther HE (1999) Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. Carcinogenesis 20:1657–1666PubMedGoogle Scholar
  65. 65.
    Gallegos A, Berggren M, Gasdaska JR, Powis G (1997) Mechanisms of the regulation of thioredoxin reductase activity in cancer cells by the chemopreventive agent selenium. Cancer Res 57:4965–4970PubMedGoogle Scholar
  66. 66.
    Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z et al (2006) Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10:241–252PubMedGoogle Scholar
  67. 67.
    Tonissen KF, Di Trapani G (2009) Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy. Mol Nutr Food Res 53:87–103PubMedGoogle Scholar
  68. 68.
    Arner ES, Holmgren A (2006) The thioredoxin system in cancer. Semin Cancer Biol 16:420–426PubMedGoogle Scholar
  69. 69.
    Nordlund P, Reichard P (2006) Ribonucleotide reductases. Annu Rev Biochem 75:681–706PubMedGoogle Scholar
  70. 70.
    Lincoln DT, Ali Emadi EM, Tonissen KF, Clarke FM (2003) The thioredoxin-thioredoxin reductase system: over-expression in human cancer. Anticancer Res 23:2425–2433PubMedGoogle Scholar
  71. 71.
    Singh SS, Li Y, Ford OH, Wrzosek CS, Mehedint DC et al (2008) Thioredoxin reductase 1 expression and castration-recurrent growth of prostate cancer. Transl Oncol 1:153–157PubMedCentralPubMedGoogle Scholar
  72. 72.
    Eriksson SE, Prast-Nielsen S, Flaberg E, Szekely L, Arner ES (2009) High levels of thioredoxin reductase 1 modulate drug-specific cytotoxic efficacy. Free Radic Biol Med 47:1661–1671PubMedGoogle Scholar
  73. 73.
    Iwasawa S, Yamano Y, Takiguchi Y, Tanzawa H, Tatsumi K et al (2011) Upregulation of thioredoxin reductase 1 in human oral squamous cell carcinoma. Oncol Rep 25:637–644PubMedGoogle Scholar
  74. 74.
    Soini Y, Kahlos K, Napankangas U, Kaarteenaho-Wiik R, Saily M et al (2001) Widespread expression of thioredoxin and thioredoxin reductase in non-small cell lung carcinoma. Clin Cancer Res 7:1750–1757PubMedGoogle Scholar
  75. 75.
    Berggren M, Gallegos A, Gasdaska JR, Gasdaska PY, Warneke J et al (1996) Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. Anticancer Res 16:3459–3466PubMedGoogle Scholar
  76. 76.
    Shao L, Diccianni MB, Tanaka T, Gribi R, Yu AL et al (2001) Thioredoxin expression in primary T-cell acute lymphoblastic leukemia and its therapeutic implication. Cancer Res 61:7333–7338PubMedGoogle Scholar
  77. 77.
    Lincoln DT, Al-Yatama F, Mohammed FM, Al-Banaw AG, Al-Bader M et al (2010) Thioredoxin and thioredoxin reductase expression in thyroid cancer depends on tumour aggressiveness. Anticancer Res 30:767–775PubMedGoogle Scholar
  78. 78.
    Cadenas C, Franckenstein D, Schmidt M, Gehrmann M, Hermes M et al (2010) Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer. Breast Cancer Res 12 Article-No. R44Google Scholar
  79. 79.
    Smart DK, Ortiz KL, Mattson D, Bradbury CM, Bisht KS et al (2004) Thioredoxin reductase as a potential molecular target for anticancer agents that induce oxidative stress. Cancer Res 64:6716–6724PubMedGoogle Scholar
  80. 80.
    Yoo MH, Xu XM, Carlson BA, Gladyshev VN, Hatfield DL (2006) Thioredoxin reductase 1 deficiency reverses tumor phenotype and tumorigenicity of lung carcinoma cells. J Biol Chem 281:13005–13008PubMedGoogle Scholar
  81. 81.
    Yoo MH, Xu XM, Carlson BA, Patterson AD, Gladyshev VN et al (2007) Targeting thioredoxin reductase 1 reduction in cancer cells inhibits self-sufficient growth and DNA replication. PLoS One 2:e1112PubMedCentralPubMedGoogle Scholar
  82. 82.
    Lu J, Chew EH, Holmgren A (2007) Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci USA 104:12288–12293PubMedCentralPubMedGoogle Scholar
  83. 83.
    Gromer S, Arscott LD, Williams CH Jr, Schirmer RH, Becker K (1998) Human placenta thioredoxin reductase. Isolation of the selenoenzyme, steady state kinetics, and inhibition by therapeutic gold compounds. J Biol Chem 273:20096–20101PubMedGoogle Scholar
  84. 84.
    Pennington JD, Jacobs KM, Sun L, Bar-Sela G, Mishra M et al (2007) Thioredoxin and thioredoxin reductase as redox-sensitive molecular targets for cancer therapy. Curr Pharm Des 13:3368–3377PubMedGoogle Scholar
  85. 85.
    Urig S, Becker K (2006) On the potential of thioredoxin reductase inhibitors for cancer therapy. Semin Cancer Biol 16:452–465PubMedGoogle Scholar
  86. 86.
    Nguyen P, Awwad RT, Smart DD, Spitz DR, Gius D (2006) Thioredoxin reductase as a novel molecular target for cancer therapy. Cancer Lett 236:164–174PubMedGoogle Scholar
  87. 87.
    Anestal K, Prast-Nielsen S, Cenas N, Arner ES (2008) Cell death by SecTRAPs: thioredoxin reductase as a prooxidant killer of cells. PLoS One 3 Article-No. e1846Google Scholar
  88. 88.
    Cheng Q, Antholine WE, Myers JM, Kalyanaraman B, Arner ES et al (2010) The selenium-independent inherent pro-oxidant NADPH oxidase activity of mammalian thioredoxin reductase and its selenium-dependent direct peroxidase activities. J Biol Chem 285:21708–21723PubMedCentralPubMedGoogle Scholar
  89. 89.
    Liu Z, Huang SL, Li MM, Huang ZS, Lee KS et al (2009) Inhibition of thioredoxin reductase by mansonone F analogues: Implications for anticancer activity. Chem Biol Interact 177:48–57PubMedGoogle Scholar
  90. 90.
    Javvadi P, Hertan L, Kosoff R, Datta T, Kolev J et al (2010) Thioredoxin reductase-1 mediates curcumin-induced radiosensitization of squamous carcinoma cells. Cancer Res 70:1941–1950PubMedCentralPubMedGoogle Scholar
  91. 91.
    Fang J, Lu J, Holmgren A (2005) Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. J Biol Chem 280:25284–25290PubMedGoogle Scholar
  92. 92.
    Wang L, Yang Z, Fu J, Yin H, Xiong K, Tan Q, Jin H, Li J, Wang T, Tang W, Yin J, Cai G, Liu M, Kehr S, Becker K, Zeng H (2011) Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent. Free Radic Biol Med 52:898–908PubMedGoogle Scholar
  93. 93.
    Watson WH, Heilman JM, Hughes LL, Spielberger JC (2008) Thioredoxin reductase-1 knock down does not result in thioredoxin-1 oxidation. Biochem Biophys Res Commun 368:832–836PubMedCentralPubMedGoogle Scholar
  94. 94.
    Mandal PK, Schneider M, Kolle P, Kuhlencordt P, Forster H et al (2010) Loss of thioredoxin reductase 1 renders tumors highly susceptible to pharmacologic glutathione deprivation. Cancer Res 70:9505–9514PubMedGoogle Scholar
  95. 95.
    Rollins MF, van der Heide DM, Weisend CM, Kundert JA, Comstock KM et al (2010) Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration. J Cell Sci 123:2402–2412PubMedCentralPubMedGoogle Scholar
  96. 96.
    Zeng HH, Wang LH (2010) Targeting thioredoxin reductase: anticancer agents and chemopreventive compounds. Med Chem 6:286–297PubMedGoogle Scholar
  97. 97.
    Kean WF, Kean IR (2008) Clinical pharmacology of gold. Inflammopharmacology 16:112–125PubMedGoogle Scholar
  98. 98.
    Pia Rigobello M, Messori L, Marcon G, Agostina Cinellu M, Bragadin M et al (2004) Gold complexes inhibit mitochondrial thioredoxin reductase: consequences on mitochondrial functions. J Inorg Biochem 98:1634–1641Google Scholar
  99. 99.
    Rackham O, Shearwood AM, Thyer R, McNamara E, Davies SM et al (2011) Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: implications for development of specific inhibitors. Free Radic Biol Med 50:689–699PubMedGoogle Scholar
  100. 100.
    Cox AG, Brown KK, Arner ES, Hampton MB (2008) The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation. Biochem Pharmacol 76:1097–1109PubMedGoogle Scholar
  101. 101.
    Marzano C, Gandin V, Folda A, Scutari G, Bindoli A et al (2007) Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells. Free Radic Biol Med 42:872–881PubMedGoogle Scholar
  102. 102.
    Liu JJ, Liu Q, Wei HL, Yi J, Zhao HS et al (2011) Inhibition of thioredoxin reductase by auranofin induces apoptosis in adriamycin-resistant human K562 chronic myeloid leukemia cells. Pharmazie 66:440–444PubMedGoogle Scholar
  103. 103.
    Hashemy SI, Ungerstedt JS, Zahedi Avval F, Holmgren A (2006) Motexafin gadolinium, a tumor-selective drug targeting thioredoxin reductase and ribonucleotide reductase. J Biol Chem 281:10691–10697PubMedGoogle Scholar
  104. 104.
    Francis D, Richards GM, Forouzannia A, Mehta MP, Khuntia D (2009) Motexafin gadolinium: a novel radiosensitizer for brain tumors. Expert Opin Pharmacother 10:2171–2180PubMedGoogle Scholar
  105. 105.
    Zahedi Avval F, Berndt C, Pramanik A, Holmgren A (2009) Mechanism of inhibition of ribonucleotide reductase with motexafin gadolinium (MGd). Biochem Biophys Res Commun 379:775–779PubMedGoogle Scholar
  106. 106.
    Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB et al (2008) Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14:4491–4499PubMedGoogle Scholar
  107. 107.
    Shi C, Yu L, Yang F, Yan J, Zeng H (2003) A novel organoselenium compound induces cell cycle arrest and apoptosis in prostate cancer cell lines. Biochem Biophys Res Commun 309:578–583PubMedGoogle Scholar
  108. 108.
    Zhao F, Yan J, Deng S, Lan L, He F et al (2006) A thioredoxin reductase inhibitor induces growth inhibition and apoptosis in five cultured human carcinoma cell lines. Cancer Lett 236:46–53PubMedGoogle Scholar
  109. 109.
    Peng ZF, Lan LX, Zhao F, Li J, Tan Q, Yin HW, Zeng HH (2008) A novel thioredoxin reductase inhibitor inhibits cell growth and induces apoptosis in HL-60 and K562 cells. J Zhejiang Univ Sci B 9:16–21PubMedCentralPubMedGoogle Scholar
  110. 110.
    Xing F, Li S, Ge X, Wang C, Zeng H et al (2008) The inhibitory effect of a novel organoselenium compound BBSKE on the tongue cancer Tca8113 in vitro and in vivo. Oral Oncol 44:963–969PubMedGoogle Scholar
  111. 111.
    Fu JN, Li J, Tan Q, Yin HW, Xiong K et al (2011) Thioredoxin reductase inhibitor ethaselen increases the drug sensitivity of the colon cancer cell line LoVo towards cisplatin via regulation of G1 phase and reversal of G2/M phase arrest. Invest New Drugs 29:627–636PubMedGoogle Scholar
  112. 112.
    Tan Q, Li J, Yin HW, Wang LH, Tang WC et al (2010) Augmented antitumor effects of combination therapy of cisplatin with ethaselen as a novel thioredoxin reductase inhibitor on human A549 cell in vivo. Invest New Drugs 28:205–215PubMedGoogle Scholar
  113. 113.
    Wang L, Fu JN, Wang JY, Jin CJ, Ren XY et al (2011) Selenium-containing thioredoxin reductase inhibitor ethaselen sensitizes non-small cell lung cancer to radiotherapy. Anticancer Drugs 22:732–740PubMedGoogle Scholar
  114. 114.
    Li R, Bianchet MA, Talalay P, Amzel LM (1995) The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. Proc Natl Acad Sci USA 92:8846–8850PubMedCentralPubMedGoogle Scholar
  115. 115.
    Ross D (2004) Quinone reductases multitasking in the metabolic world. Drug Metab Rev 36:639–654PubMedGoogle Scholar
  116. 116.
    Anwar A, Dehn D, Siegel D, Kepa JK, Tang LJ et al (2003) Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems. J Biol Chem 278:10368–10373PubMedGoogle Scholar
  117. 117.
    Asher G, Lotem J, Cohen B, Sachs L, Shaul Y (2001) Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci USA 98:1188–1193PubMedCentralPubMedGoogle Scholar
  118. 118.
    Colucci MA, Moody CJ, Couch GD (2008) Natural and synthetic quinones and their reduction by the quinone reductase enzyme NQO1: from synthetic organic chemistry to compounds with anticancer potential. Org Biomol Chem 6:637–656PubMedGoogle Scholar
  119. 119.
    Alcain FJ, Villalba JM (2007) NQO1-directed antitumour quinones. Expert Opin Ther Patents 17:649–665Google Scholar
  120. 120.
    Hoey BM, Butler J, Swallow AJ (1988) Reductive activation of mitomycin C. Biochemistry 27:2608–2614PubMedGoogle Scholar
  121. 121.
    Siegel D, Ross D (2000) Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic Biol Med 29:246–253PubMedGoogle Scholar
  122. 122.
    Siegel D, Franklin WA, Ross D (1998) Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors. Clin Cancer Res 4:2065–2070PubMedGoogle Scholar
  123. 123.
    Reinicke KE, Bey EA, Bentle MS, Pink JJ, Ingalls ST, Hoppel CL, Misico RI, Arzac GM, Burton G, Bornmann WG, Sutton D, Gao J, Boothman DA (2005) Development of β-lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels. Clin Cancer Res 11:3055–3064PubMedGoogle Scholar
  124. 124.
    Volpato M, Abou-Zeid N, Tanner RW, Glassbrook LT, Taylor J et al (2007) Chemical synthesis and biological evaluation of a NAD(P)H:quinone oxidoreductase-1 targeted tripartite quinone drug delivery system. Mol Cancer Ther 6:3122–3130PubMedGoogle Scholar
  125. 125.
    Kelsey KT, Ross D, Traver RD, Christiani DC, Zuo ZF et al (1997) Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy. Br J Cancer 76:852–854PubMedCentralPubMedGoogle Scholar
  126. 126.
    Fagerholm R, Hofstetter B, Tommiska J, Aaltonen K, Vrtel R et al (2008) NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet 40:844–853PubMedGoogle Scholar
  127. 127.
    Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PV et al (1992) NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res 52:797–802PubMedGoogle Scholar
  128. 128.
    Fleming RA, Drees J, Loggie BW, Russell GB, Geisinger KR et al (2002) Clinical significance of a NAD(P)H: quinone oxidoreductase 1 polymorphism in patients with disseminated peritoneal cancer receiving intraperitoneal hyperthermic chemotherapy with mitomycin C. Pharmacogenetics 12:31–37PubMedGoogle Scholar
  129. 129.
    Begleiter A, Hewitt D, Maksymiuk AW, Ross DA, Bird RP (2006) A NAD(P)H:quinone oxidoreductase 1 polymorphism is a risk factor for human colon cancer. Cancer Epidemiol Biomarkers Prev 15:2422–2426PubMedGoogle Scholar
  130. 130.
    Chao C, Zhang ZF, Berthiller J, Boffetta P, Hashibe M (2006) NAD(P)H:quinone oxidoreductase 1 (NQO1) Pro187Ser polymorphism and the risk of lung, bladder, and colorectal cancers: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15:979–987PubMedGoogle Scholar
  131. 131.
    Haydel SE (2010) Extensively drug-resistant tuberculosis: a sign of the times and an impetus for antimicrobial discovery. Pharmaceuticals 3:2268–2290PubMedCentralPubMedGoogle Scholar
  132. 132.
    Johnson R, Streicher EM, Louw GE, Warren RM, van Helden PD et al (2006) Drug resistance in Mycobacterium tuberculosis. Curr Issues Mol Biol 8:97–111PubMedGoogle Scholar
  133. 133.
    Dondorp AM, Nosten F, Yi P, Das D, Phyo AP et al (2009) Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361:455–467PubMedCentralPubMedGoogle Scholar
  134. 134.
    WHO (2010) Gobal tuberculosis controlGoogle Scholar
  135. 135.
    Myllykallio H, Lipowski G, Leduc D, Filee J, Forterre P et al (2002) An alternative flavin-dependent mechanism for thymidylate synthesis. Science 297:105–107PubMedGoogle Scholar
  136. 136.
    Koehn EM, Fleischmann T, Conrad JA, Palfey BA, Lesley SA et al (2009) An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene. Nature 458:919–923PubMedCentralPubMedGoogle Scholar
  137. 137.
    Myllykallio H, Leduc D, Filee J, Liebl U (2003) Life without dihydrofolate reductase FolA. Trends Microbiol 11:220–223PubMedGoogle Scholar
  138. 138.
    Chernyshev A, Fleischmann T, Kohen A (2007) Thymidyl biosynthesis enzymes as antibiotic targets. Appl Microbiol Biotechnol 74:282–289PubMedGoogle Scholar
  139. 139.
    Ulmer JE, Boum Y, Thouvenel CD, Myllykallio H, Sibley CH (2008) Functional analysis of the Mycobacterium tuberculosis FAD-dependent thymidylate synthase, ThyX, reveals new amino acid residues contributing to an extended ThyX motif. J Bacteriol 190:2056–2064PubMedCentralPubMedGoogle Scholar
  140. 140.
    Sampathkumar P, Turley S, Ulmer JE, Rhie HG, Sibley CH et al (2005) Structure of the Mycobacterium tuberculosis flavin dependent thymidylate synthase (MtbThyX) at 2.0 Å resolution. J Mol Biol 352:1091–1104PubMedGoogle Scholar
  141. 141.
    Fivian-Hughes A, Houghton J, Davis E (2011) Mycobacterium tuberculosis thymidylate synthase gene thyX is essential and potentially bifunctional, while thyA deletion confers resistance to para-aminosalicylic acid. Microbiology 158:308–318PubMedGoogle Scholar
  142. 142.
    Graziani S, Xia Y, Gurnon JR, Van Etten JL, Leduc D, Skouloubris S, Myllykallio H, Liebl U (2004) Functional analysis of FAD-dependent thymidylate synthase ThyX from Paramecium bursaria chlorella virus-1. J Biol Chem 279:54340–54347PubMedGoogle Scholar
  143. 143.
    Kogler M, Vanderhoydonck B, De Jonghe S, Rozenski J, Van Belle K et al (2011) Synthesis and evaluation of 5-substituted 2′-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. J Med Chem 54:4847–4862PubMedGoogle Scholar
  144. 144.
    Tian J, Bryk R, Shi S, Erdjument-Bromage H, Tempst P et al (2005) Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol Microbiol 57:859–868PubMedGoogle Scholar
  145. 145.
    Venugopal A, Bryk R, Shi S, Rhee K, Rath P et al (2011) Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe 9:21–31PubMedCentralPubMedGoogle Scholar
  146. 146.
    Bryk R, Arango N, Venugopal A, Warren JD, Park YH et al (2010) Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase. Biochemistry 49:1616–1627PubMedCentralPubMedGoogle Scholar
  147. 147.
    WHO (2010) World Malaria Report 2010Google Scholar
  148. 148.
    Becker K, Tilley L, Vennerstrom JL, Roberts D, Rogerson S et al (2004) Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. Int J Parasitol 34:163–189PubMedGoogle Scholar
  149. 149.
    Krauth-Siegel RL, Bauer H, Schirmer RH (2005) Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia. Angew Chem Int Ed 44:690–715Google Scholar
  150. 150.
    Böhme CC, Arscott LD, Becker K, Schirmer RH, Williams CH Jr (2000) Kinetic characterization of glutathione reductase from the malarial parasite Plasmodium falciparum. Comparison with the human enzyme. J Biol Chem 275:37317–37323PubMedGoogle Scholar
  151. 151.
    Buchholz K, Putrianti ED, Rahlfs S, Schirmer RH, Becker K, Matuschewski K (2010) Molecular genetics evidence for the in vivo roles of the two major NADPH-dependent disulfide reductases in the malaria parasite. J Biol Chem 285:37388–37395PubMedCentralPubMedGoogle Scholar
  152. 152.
    Pastrana-Mena R, Dinglasan RR, Franke-Fayard B, Vega-Rodriguez J, Fuentes-Caraballo M, Baerga-Ortiz A, Coppens I, Jacobs-Lorena M, Janse CJ, Serrano AE (2010) Glutathione reductase-null malaria parasites have normal blood stage growth but arrest during development in the mosquito. J Biol Chem 285:27045–27056PubMedCentralPubMedGoogle Scholar
  153. 153.
    Gilberger TW, Schirmer RH, Walter RD, Müller S (2000) Deletion of the parasite-specific insertions and mutation of the catalytic triad in glutathione reductase from chloroquine-sensitive Plasmodium falciparum 3D7. Mol Biochem Parasitol 107:169–179PubMedGoogle Scholar
  154. 154.
    Sarma GN, Savvides SN, Becker K, Schirmer M, Schirmer RH, Karplus PA (2003) Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and inhibitor development. J Mol Biol 328:893–907PubMedGoogle Scholar
  155. 155.
    Kanzok SM, Schirmer RH, Turbachova I, Iozef R, Becker K (2000) The thioredoxin system of the malaria parasite Plasmodium falciparum. Glutathione reduction revisited. J Biol Chem 275:40180–40186PubMedGoogle Scholar
  156. 156.
    Buchholz K, Schirmer RH, Eubel JK, Akoachere MB, Dandekar T et al (2008) Interactions of methylene blue with human disulfide reductases and their orthologues from Plasmodium falciparum. Antimicrob Agents Chemother 52:183–191PubMedCentralPubMedGoogle Scholar
  157. 157.
    Kasozi DM, Gromer S, Adler H, Zocher K, Rahlfs S et al (2011) The bacterial redox signaller pyocyanin as an antiplasmodial agent: comparisons with its thioanalog methylene blue. Redox Rep 16:154–165PubMedGoogle Scholar
  158. 158.
    Akoachere M, Buchholz K, Fischer E, Burhenne J, Haefeli WE et al (2005) In vitro assessment of methylene blue on chloroquine-sensitive and -resistant Plasmodium falciparum strains reveals synergistic action with artemisinins. Antimicrob Agents Chemother 49:4592–4597PubMedCentralPubMedGoogle Scholar
  159. 159.
    Meissner PE, Mandi G, Coulibaly B, Witte S, Tapsoba T et al (2006) Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine. Malar J 5:84PubMedCentralPubMedGoogle Scholar
  160. 160.
    Becker K, Schirmer RH (1995) 1,3-Bis(2-chloroethyl)-1-nitrosourea as thiol-carbamoylating agent in biological systems. Methods Enzymol 251:173–188PubMedGoogle Scholar
  161. 161.
    Karplus PA, Krauth-Siegel RL, Schirmer RH, Schulz GE (1988) Inhibition of human glutathione reductase by the nitrosourea drugs 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea. A crystallographic analysis. Eur J Biochem 171:193–198PubMedGoogle Scholar
  162. 162.
    Savvides SN, Scheiwein M, Bohme CC, Arteel GE, Karplus PA et al (2002) Crystal structure of the antioxidant enzyme glutathione reductase inactivated by peroxynitrite. J Biol Chem 277:2779–2784PubMedGoogle Scholar
  163. 163.
    Becker K, Christopherson RI, Cowden WB, Hunt NH, Schirmer RH (1990) Flavin analogs with antimalarial activity as glutathione reductase inhibitors. Biochem Pharmacol 39:59–65PubMedGoogle Scholar
  164. 164.
    Schonleben-Janas A, Kirsch P, Mittl PR, Schirmer RH, Krauth-Siegel RL (1996) Inhibition of human glutathione reductase by 10-arylisoalloxazines: crystalline, kinetic, and electrochemical studies. J Med Chem 39:1549–1554PubMedGoogle Scholar
  165. 165.
    Biot C, Bauer H, Schirmer RH, Davioud-Charvet E (2004) 5-substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials. J Med Chem 47:5972–5983PubMedGoogle Scholar
  166. 166.
    Müller T, Johann L, Jannack B, Brückner M, Lanfranchi DA, Bauer H, Sanchez C, Yardley V, Deregnaucourt C, Schrével J, Lanzer M, Schirmer RH, Davioud-Charvet E (2011) Glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones. A new strategy to combat malarial parasites. J Am Chem Soc 133:11557–11571PubMedGoogle Scholar
  167. 167.
    Morin C, Besset T, Moutet JC, Fayolle M, Bruckner M et al (2008) The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and glutathione reductases and of human erythrocyte glutathione reductase. Org Biomol Chem 6:2731–2742PubMedGoogle Scholar
  168. 168.
    Chandra R, Tripathi LM, Saxena JK, Puri SK (2011) Implication of intracellular glutathione and its related enzymes on resistance of malaria parasites to the antimalarial drug arteether. Parasitol Int 60:97–100PubMedGoogle Scholar
  169. 169.
    Davioud-Charvet E, Delarue S, Biot C, Schwobel B, Boehme CC et al (2001) A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline. J Med Chem 44:4268–4276PubMedGoogle Scholar
  170. 170.
    Chavain N, Davioud-Charvet E, Trivelli X, Mbeki L, Rottmann M et al (2009) Antimalarial activities of ferroquine conjugates with either glutathione reductase inhibitors or glutathione depletors via a hydrolyzable amide linker. Bioorg Med Chem 17:8048–8059PubMedGoogle Scholar
  171. 171.
    Ginsburg H, Famin O, Zhang J, Krugliak M (1998) Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. Biochem Pharmacol 56:1305–1313PubMedGoogle Scholar
  172. 172.
    Gallo V, Schwarzer E, Rahlfs S, Schirmer RH, van Zwieten R, et al (2009) Inherited glutathione reductase deficiency and Plasmodium falciparum malaria. A case study. PLoS One 4 Article-No. e7303Google Scholar
  173. 173.
    Nickel C, Rahlfs S, Deponte M, Koncarevic S, Becker K (2006) Thioredoxin networks in the malarial parasite Plasmodium falciparum. Antioxid Redox Signal 8:1227–1239PubMedGoogle Scholar
  174. 174.
    Müller S (2004) Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. Mol Microbiol 53:1291–1305PubMedGoogle Scholar
  175. 175.
    Krnajski Z, Gilberger TW, Walter RD, Cowman AF, Müller S (2002) Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages. J Biol Chem 277:25970–25975PubMedGoogle Scholar
  176. 176.
    Davioud-Charvet E, McLeish MJ, Veine DM, Giegel D, Arscott LD et al (2003) Mechanism-based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases. Implication for cytotoxicity. Biochemistry 42:13319–13330PubMedGoogle Scholar
  177. 177.
    Andricopulo AD, Akoachere MB, Krogh R, Nickel C, McLeish MJ et al (2006) Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents. Bioorg Med Chem Lett 16:2283–2292PubMedGoogle Scholar
  178. 178.
    Sturm N, Hu Y, Zimmermann H, Fritz-Wolf K, Wittlin S et al (2009) Compounds structurally related to ellagic acid show improved antiplasmodial activity. Antimicrob Agents Chemother 53:622–630PubMedCentralPubMedGoogle Scholar
  179. 179.
    Sannella AR, Casini A, Gabbiani C, Messori L, Bilia AR et al (2008) New uses for old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhibits potent antimalarial effects in vitro: Mechanistic and pharmacological implications. FEBS Lett 582:844–847PubMedGoogle Scholar
  180. 180.
    Reyes P, Rathod PK, Sanchez DJ, Mrema JE, Rieckmann KH et al (1982) Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum. Mol Biochem Parasitol 5:275–290PubMedGoogle Scholar
  181. 181.
    Subbayya IN, Ray SS, Balaram P, Balaram H (1997) Metabolic enzymes as potential drug targets in Plasmodium falciparum. Indian J Med Res 106:79–94PubMedGoogle Scholar
  182. 182.
    Baldwin J, Michnoff CH, Malmquist NA, White J, Roth MG et al (2005) High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J Biol Chem 280:21847–21853PubMedGoogle Scholar
  183. 183.
    Patel V, Booker M, Kramer M, Ross L, Celatka CA et al (2008) Identification and characterization of small molecule inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J Biol Chem 283:35078–35085PubMedCentralPubMedGoogle Scholar
  184. 184.
    Booker ML, Bastos CM, Kramer ML, Barker RH Jr, Skerlj R et al (2010) Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J Biol Chem 285:33054–33064PubMedCentralPubMedGoogle Scholar
  185. 185.
    Phillips MA, Gujjar R, Malmquist NA, White J, El Mazouni F et al (2008) Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum. J Med Chem 51:3649–3653PubMedCentralPubMedGoogle Scholar
  186. 186.
    Deng X, Gujjar R, El Mazouni F, Kaminsky W, Malmquist NA et al (2009) Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J Biol Chem 284:26999–27009PubMedCentralPubMedGoogle Scholar
  187. 187.
    Gujjar R, Marwaha A, El Mazouni F, White J, White KL et al (2009) Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J Med Chem 52:1864–1872PubMedCentralPubMedGoogle Scholar
  188. 188.
    Coteron JM, Marco M, Esquivias J, Deng X, White KL et al (2011) Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem 54:5540–5561PubMedCentralPubMedGoogle Scholar
  189. 189.
    Malvy D, Chappuis F (2011) Sleeping sickness. Clin Microbiol Infect 17:986–995PubMedGoogle Scholar
  190. 190.
    Burri C (2010) Chemotherapy against human African trypanosomiasis: is there a road to success? Parasitology 137:1987–1994PubMedGoogle Scholar
  191. 191.
    Astelbauer F, Walochnik J (2011) Antiprotozoal compounds: state of the art and new developments. Int J Antimicrob Agents 38:118–124PubMedGoogle Scholar
  192. 192.
    Müller S, Liebau E, Walter RD, Krauth-Siegel RL (2003) Thiol-based redox metabolism of protozoan parasites. Trends Parasitol 19:320–328PubMedGoogle Scholar
  193. 193.
    Krauth-Siegel RL, Comini MA (2008) Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim Biophys Acta 1780:1236–1248PubMedGoogle Scholar
  194. 194.
    Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH (2007) Target assessment for antiparasitic drug discovery. Trends Parasitol 23:589–595PubMedCentralPubMedGoogle Scholar
  195. 195.
    Olin-Sandoval V, Moreno-Sanchez R, Saavedra E (2010) Targeting trypanothione metabolism in trypanosomatid human parasites. Curr Drug Targets 11:1614–1630PubMedGoogle Scholar
  196. 196.
    Krauth-Siegel RL, Inhoff O (2003) Parasite-specific trypanothione reductase as a drug target molecule. Parasitol Res 90:S77–S85PubMedGoogle Scholar
  197. 197.
    Eberle C, Lauber BS, Fankhauser D, Kaiser M, Brun R et al (2011) Improved inhibitors of trypanothione reductase by combination of motifs: synthesis, inhibitory potency, binding mode, and antiprotozoal activities. ChemMedChem 6:292–301PubMedGoogle Scholar
  198. 198.
    Hunter WN (2007) Picking pockets to fuel antimicrobial drug discovery. Biochem Soc Trans 35:980–984PubMedGoogle Scholar
  199. 199.
    Chibale K, Haupt H, Kendrick H, Yardley V, Saravanamuthu A et al (2001) Antiprotozoal and cytotoxicity evaluation of sulfonamide and urea analogues of quinacrine. Bioorg Med Chem Lett 11:2655–2657PubMedGoogle Scholar
  200. 200.
    Hammond DJ, Croft SL, Hogg J, Gutteridge WE (1986) A strategy for the prevention of the transmission of Chagas’ disease during blood transfusion. Acta Trop 43:367–378PubMedGoogle Scholar
  201. 201.
    Benson TJ, McKie JH, Garforth J, Borges A, Fairlamb AH et al (1992) Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures. Biochem J 286:9–11PubMedCentralPubMedGoogle Scholar
  202. 202.
    Khan MO (2007) Trypanothione reductase: a viable chemotherapeutic target for antitrypanosomal and antileishmanial drug design. Drug Target Insights 2:129–146PubMedCentralPubMedGoogle Scholar
  203. 203.
    Li Z, Fennie MW, Ganem B, Hancock MT, Kobaslija M et al (2001) Polyamines with N-(3-phenylpropyl) substituents are effective competitive inhibitors of trypanothione reductase and trypanocidal agents. Bioorg Med Chem Lett 11:251–254PubMedGoogle Scholar
  204. 204.
    Ponasik JA, Strickland C, Faerman C, Savvides S, Karplus PA et al (1995) Kukoamine A and other hydrophobic acylpolyamines: potent and selective inhibitors of Crithidia fasciculata trypanothione reductase. Biochem J 311:371–375PubMedCentralPubMedGoogle Scholar
  205. 205.
    Bond CS, Zhang Y, Berriman M, Cunningham ML, Fairlamb AH et al (1999) Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors. Structure 7:81–89PubMedGoogle Scholar
  206. 206.
    Cota BB, Rosa LH, Fagundes EM, Martins-Filho OA, Correa-Oliveira R et al (2008) A potent trypanocidal component from the fungus Lentinus strigosus inhibits trypanothione reductase and modulates PBMC proliferation. Mem Inst Oswaldo Cruz 103:263–270PubMedGoogle Scholar
  207. 207.
    Schirmer RH, Müller JG, Krauth-Siegel RL (1995) Disulfide-reductase inhibitors as chemotherapeutic agents: the design of drugs for trypanosomiasis and malaria. Angew Chem Int Ed 34:141–154Google Scholar
  208. 208.
    Bonse S, Richards JM, Ross SA, Lowe G, Krauth-Siegel RL (2000) (2,2′:6′,2″-Terpyridine)platinum(II) complexes are irreversible inhibitors of Trypanosoma cruzi trypanothione reductase but not of human glutathione reductase. J Med Chem 43:4812–4821PubMedGoogle Scholar
  209. 209.
    Salmon-Chemin L, Buisine E, Yardley V, Kohler S, Debreu M-A, Landry V, Sergheraert C, Croft SL, Krauth-Siegel RL, Davioud-Charvet E (2001) 2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity. J Med Chem 44:548–565PubMedGoogle Scholar
  210. 210.
    Holloway GA, Charman WN, Fairlamb AH, Brun R, Kaiser M et al (2009) Trypanothione reductase high-throughput screening campaign identifies novel classes of inhibitors with antiparasitic activity. Antimicrob Agents Chemother 53:2824–2833PubMedCentralPubMedGoogle Scholar
  211. 211.
    Chan C, Yin H, Garforth J, McKie JH, Jaouhari R et al (1998) Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs. J Med Chem 41:148–156PubMedGoogle Scholar
  212. 212.
    Bonnet B, Soullez D, Davioud-Charvet E, Landry V, Horvath D et al (1997) New spermine and spermidine derivatives as potent inhibitors of Trypanosoma cruzi trypanothione reductase. Bioorg Med Chem 5:1249–1256PubMedGoogle Scholar
  213. 213.
    Khan MO, Austin SE, Chan C, Yin H, Marks D et al (2000) Use of an additional hydrophobic binding site, the Z site, in the rational drug design of a new class of stronger trypanothione reductase inhibitor, quaternary alkylammonium phenothiazines. J Med Chem 43:3148–3156PubMedGoogle Scholar
  214. 214.
    Lee B, Bauer H, Melchers J, Ruppert T, Rattray L et al (2005) Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: a divinyl ketone as key intermediate. J Med Chem 48:7400–7410PubMedGoogle Scholar
  215. 215.
    Schmidt A, Krauth-Siegel RL (2002) Enzymes of the trypanothione metabolism as targets for antitrypanosomal drug development. Curr Top Med Chem 2:1239–1259PubMedGoogle Scholar
  216. 216.
    Soeiro MN, de Castro SL (2009) Trypanosoma cruzi targets for new chemotherapeutic approaches. Expert Opin Ther Targets 13:105–121PubMedGoogle Scholar
  217. 217.
    Roldan A, Comini MA, Crispo M, Krauth-Siegel RL (2011) Lipoamide dehydrogenase is essential for both bloodstream and procyclic Trypanosoma brucei. Mol Microbiol 81:623–639PubMedGoogle Scholar
  218. 218.
    Sreider CM, Grinblat L, Stoppani AO (1992) Reduction of nitrofuran compounds by heart lipoamide dehydrogenase: role of flavin and the reactive disulfide groups. Biochem Int 28:323–334PubMedGoogle Scholar
  219. 219.
    Blumenstiel K, Schoneck R, Yardley V, Croft SL, Krauth-Siegel RL (1999) Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase. Biochem Pharmacol 58:1791–1799PubMedGoogle Scholar
  220. 220.
    Petrat F, Paluch S, Dogruoz E, Dorfler P, Kirsch M et al (2003) Reduction of Fe(III) ions complexed to physiological ligands by lipoyl dehydrogenase and other flavoenzymes in vitro: implications for an enzymatic reduction of Fe(III) ions of the labile iron pool. J Biol Chem 278:46403–46413PubMedGoogle Scholar
  221. 221.
    Ramos EI, Garza KM, Krauth-Siegel RL, Bader J, Martinez LE et al (2009) 2,3-diphenyl-1,4-naphthoquinone: a potential chemotherapeutic agent against Trypanosoma cruzi. J Parasitol 95:461–466PubMedCentralPubMedGoogle Scholar
  222. 222.
    Lohrer H, Krauth-Siegel RL (1990) Purification and characterization of lipoamide dehydrogenase from Trypanosoma cruzi. Eur J Biochem 194:863–869PubMedGoogle Scholar
  223. 223.
    Gutierrez-Correa J, Krauth-Siegel RL, Stoppani AO (2003) Phenothiazine radicals inactivate Trypanosoma cruzi dihydrolipoamide dehydrogenase: enzyme protection by radical scavengers. Free Radic Res 37:281–291PubMedGoogle Scholar
  224. 224.
    Gutierrez-Correa J (2006) Trypanosoma cruzi dihydrolipoamide dehydrogenase as target for phenothiazine cationic radicals. Effect of antioxidants. Curr Drug Targets 7:1155–1179PubMedGoogle Scholar
  225. 225.
    Logan FJ, Taylor MC, Wilkinson SR, Kaur H, Kelly JM (2007) The terminal step in vitamin C biosynthesis in Trypanosoma cruzi is mediated by a FMN-dependent galactonolactone oxidase. Biochem J 407:419–426PubMedCentralPubMedGoogle Scholar
  226. 226.
    Kulkarni SK, Dhir A (2009) Current investigational drugs for major depression. Expert Opin Investig Drugs 18:767–788PubMedGoogle Scholar
  227. 227.
    West ED, Dally PJ (1959) Effects of iproniazid in depressive syndromes. Br Med J 1:1491–1494PubMedCentralPubMedGoogle Scholar
  228. 228.
    Crane GE (1957) Iproniazid (marsilid) phosphate, a therapeutic agent for mental disorders and debilitating diseases. Psychiatr Res Rep Am Psychiatr Assoc 8:142–152PubMedGoogle Scholar
  229. 229.
    Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17:1285–1297PubMedGoogle Scholar
  230. 230.
    Knoll J, Magyar K (1972) Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 5:393–408PubMedGoogle Scholar
  231. 231.
    Bach AW, Lan NC, Johnson DL, Abell CW, Bembenek ME et al (1988) cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci USA 85:4934–4938PubMedCentralPubMedGoogle Scholar
  232. 232.
    Lan NC, Heinzmann C, Gal A, Klisak I, Orth U et al (1989) Human monoamine oxidase A and B genes map to Xp 11.23 and are deleted in a patient with Norrie disease. Genomics 4:552–559PubMedGoogle Scholar
  233. 233.
    Wong WK, Ou XM, Chen K, Shih JC (2002) Activation of human monoamine oxidase B gene expression by a protein kinase C MAPK signal transduction pathway involves c-Jun and Egr-1. J Biol Chem 277:22222–22230PubMedCentralPubMedGoogle Scholar
  234. 234.
    Wong WK, Chen K, Shih JC (2003) Decreased methylation and transcription repressor Sp3 up-regulated human monoamine oxidase (MAO) B expression during Caco-2 differentiation. J Biol Chem 278:36227–36235PubMedGoogle Scholar
  235. 235.
    Ou XM, Chen K, Shih JC (2004) Dual functions of transcription factors, transforming growth factor-beta-inducible early gene (TIEG)2 and Sp3, are mediated by CACCC element and Sp1 sites of human monoamine oxidase (MAO) B gene. J Biol Chem 279:21021–21028PubMedGoogle Scholar
  236. 236.
    Ou XM, Chen K, Shih JC (2006) Glucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1. J Biol Chem 281:21512–21525PubMedGoogle Scholar
  237. 237.
    Ou XM, Chen K, Shih JC (2006) Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. Proc Natl Acad Sci USA 103:10923–10928PubMedCentralPubMedGoogle Scholar
  238. 238.
    Westlund KN, Denney RM, Rose RM, Abell CW (1988) Localization of distinct monoamine oxidase A and monoamine oxidase B cell populations in human brainstem. Neuroscience 25:439–456PubMedGoogle Scholar
  239. 239.
    Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V et al (1994) Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 62:15–30PubMedGoogle Scholar
  240. 240.
    Jahng JW, Houpt TA, Joh TH, Son JH (1998) Differential expression of monoamine oxidase A, serotonin transporter, tyrosine hydroxylase and norepinephrine transporter mRNA by anorexia mutation and food deprivation. Brain Res Dev Brain Res 107:241–246PubMedGoogle Scholar
  241. 241.
    Westlund KN, Denney RM, Kochersperger LM, Rose RM, Abell CW (1985) Distinct monoamine oxidase A and B populations in primate brain. Science 230:181–183PubMedGoogle Scholar
  242. 242.
    Blier P, De Montigny C, Azzaro AJ (1986) Modification of serotonergic and noradrenergic neurotransmissions by repeated administration of monoamine oxidase inhibitors: electrophysiological studies in the rat central nervous system. J Pharmacol Exp Ther 237:987–994PubMedGoogle Scholar
  243. 243.
    Twist EC, Mitchell S, Brazell C, Stahl SM, Campbell IC (1990) 5HT2 receptor changes in rat cortex and platelets following chronic ritanserin and clorgyline administration. Biochem Pharmacol 39:161–166PubMedGoogle Scholar
  244. 244.
    Youdim MB, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7:295–309PubMedGoogle Scholar
  245. 245.
    Li M, Hubalek F, Newton-Vinson P, Edmondson DE (2002) High-level expression of human liver monoamine oxidase A in Pichia pastoris: comparison with the enzyme expressed in Saccharomyces cerevisiae. Protein Expr Purif 24:152–162PubMedGoogle Scholar
  246. 246.
    Newton-Vinson P, Hubalek F, Edmondson DE (2000) High-level expression of human liver monoamine oxidase B in Pichia pastoris. Protein Expr Purif 20:334–345PubMedGoogle Scholar
  247. 247.
    Binda C, Newton-Vinson P, Hubalek F, Edmondson DE, Mattevi A (2002) Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Biol 9:22–26PubMedGoogle Scholar
  248. 248.
    De Colibus L, Li M, Binda C, Lustig A, Edmondson DE et al (2005) Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B. Proc Natl Acad Sci USA 102:12684–12689PubMedCentralPubMedGoogle Scholar
  249. 249.
    Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E et al (2008) Structure of human monoamine oxidase A at 2.2-Å resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci USA 105:5739–5744PubMedCentralPubMedGoogle Scholar
  250. 250.
    Chen K, Wu HF, Shih JC (1996) Influence of C terminus on monoamine oxidase A and B catalytic activity. J Neurochem 66:797–803PubMedGoogle Scholar
  251. 251.
    Hubalek F, Binda C, Khalil A, Li M, Mattevi A et al (2005) Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors. J Biol Chem 280:15761–15766PubMedGoogle Scholar
  252. 252.
    Edmondson DE, Binda C, Wang J, Upadhyay AK, Mattevi A (2009) Molecular and mechanistic properties of the membrane-bound mitochondrial monoamine oxidases. Biochemistry 48:4220–4230PubMedCentralPubMedGoogle Scholar
  253. 253.
    Milczek EM, Binda C, Rovida S, Mattevi A, Edmondson DE (2011) The ‘gating’ residues Ile199 and Tyr326 in human monoamine oxidase B function in substrate and inhibitor recognition. FEBS J 278:4860–4869PubMedCentralPubMedGoogle Scholar
  254. 254.
    Binda C, Wang J, Li M, Hubalek F, Mattevi A et al (2008) Structural and mechanistic studies of arylalkylhydrazine inhibition of human monoamine oxidases A and B. Biochemistry 47:5616–5625PubMedGoogle Scholar
  255. 255.
    Milczek EM, Bonivento D, Binda C, Mattevi A, McDonald IA et al (2008) Structural and mechanistic studies of mofegiline inhibition of recombinant human monoamine oxidase B. J Med Chem 51:8019–8026PubMedCentralPubMedGoogle Scholar
  256. 256.
    Binda C, Li M, Hubalek F, Restelli N, Edmondson DE et al (2003) Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proc Natl Acad Sci USA 100:9750–9755PubMedCentralPubMedGoogle Scholar
  257. 257.
    Upadhyay AK, Wang J, Edmondson DE (2008) Comparison of the structural properties of the active site cavities of human and rat monoamine oxidase A and B in their soluble and membrane-bound forms. Biochemistry 47:526–536PubMedGoogle Scholar
  258. 258.
    Cases O, Seif I, Grimsby J, Gaspar P, Chen K et al (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766PubMedCentralPubMedGoogle Scholar
  259. 259.
    Grimsby J, Toth M, Chen K, Kumazawa T, Klaidman L et al (1997) Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Nat Genet 17:206–210PubMedGoogle Scholar
  260. 260.
    Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D et al (2006) Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63:1209–1216PubMedGoogle Scholar
  261. 261.
    Zeller EA, Barsky J (1952) In vivo inhibition of liver and brain monoamine oxidase by 1-isonicotinyl-2-isopropyl hydrazine. Proc Soc Exp Biol Med 81:459–461PubMedGoogle Scholar
  262. 262.
    Youdim MB, Weinstock M (2004) Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology 25:243–250PubMedGoogle Scholar
  263. 263.
    Da Prada M, Kettler R, Keller HH, Cesura AM, Richards JG et al (1990) From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors. J Neural Transm Suppl 29:279–292PubMedGoogle Scholar
  264. 264.
    Amsterdam JD, Shults J (2005) MAOI efficacy and safety in advanced stage treatment-resistant depression. A retrospective study. J Affect Disord 89:183–188PubMedGoogle Scholar
  265. 265.
    Vallejo J, Gasto C, Catalan R, Salamero M (1987) Double-blind study of imipramine versus phenelzine in melancholias and dysthymic disorders. Br J Psychiatry 151:639–642PubMedGoogle Scholar
  266. 266.
    Nierenberg AA, Alpert JE, Pava J, Rosenbaum JF, Fava M (1998) Course and treatment of atypical depression. J Clin Psychiatry 59(Suppl 18):5–9PubMedGoogle Scholar
  267. 267.
    Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909PubMedGoogle Scholar
  268. 268.
    Martin I, Dawson VL, Dawson TM (2011) Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet 12:301–325PubMedGoogle Scholar
  269. 269.
    Birkmayer W, Riederer P, Ambrozi L, Youdim MB (1977) Implications of combined treatment with ‘Madopar’ and L-deprenil in Parkinson’s disease. A long-term study. Lancet 1:439–443PubMedGoogle Scholar
  270. 270.
    Riederer P, Youdim MBH (1986) Monoamine-oxidase activity and monoamine metabolism in brains of Parkinsonian-patients treated with L-deprenyl. J Neurochem 46:1359–1365PubMedGoogle Scholar
  271. 271.
    Chiba K, Trevor A, Castagnoli N Jr (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120:574–578PubMedGoogle Scholar
  272. 272.
    Mallajosyula JK, Kaur D, Chinta SJ, Rajagopalan S, Rane A, et al (2008) MAO-B elevation in mouse brain astrocytes results in Parkinson’s pathology. PLoS One 3 Article-No. e1616Google Scholar
  273. 273.
    Parkinson study group (1996) Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol 39:37–45Google Scholar
  274. 274.
    Parkinson study group (2005) A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 62:241–248Google Scholar
  275. 275.
    Rascol O, Brooks DJ, Melamed E, Oertel W, Poewe W et al (2005) Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 365:947–954PubMedGoogle Scholar
  276. 276.
    Parkinson study group (1996) Effect of lazabemide on the progression of disability in early Parkinson’s disease. The Parkinson Study Group. Ann Neurol 40:99–107Google Scholar
  277. 277.
    Sieradzan K, Channon S, Ramponi C, Stern GM, Lees AJ et al (1995) The therapeutic potential of moclobemide, a reversible selective monoamine oxidase A inhibitor in Parkinson’s disease. J Clin Psychopharmacol 15:51S–59SPubMedGoogle Scholar
  278. 278.
    Haefely W, Burkard WP, Cesura AM, Kettler R, Lorez HP et al (1992) Biochemistry and Pharmacology of Moclobemide, a Prototype Rima. Psychopharmacology 106:S6–S14PubMedGoogle Scholar
  279. 279.
    Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87PubMedGoogle Scholar
  280. 280.
    Bortolato M, Chen K, Shih JC (2008) Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv Drug Deliv Rev 60:1527–1533PubMedCentralPubMedGoogle Scholar
  281. 281.
    Inaba-Hasegawa K, Akao Y, Maruyama W, Naoi M (2012) Type A monoamine oxidase is associated with induction of neuroprotective Bcl-2 by rasagiline, an inhibitor of type B monoamine oxidase. J Neural Transm 119:405–414PubMedGoogle Scholar
  282. 282.
    Boyer EW, Shannon M (2005) The serotonin syndrome. Reply. N Engl J Med 352:2455–2456Google Scholar
  283. 283.
    Petzer JP, Castagnoli N, Schwarzschild MA, Chen JF, van der Schyf CJ (2009) Dual-target-directed drugs that block monoamine oxidase B and adenosine A(2A) receptors for Parkinson’s disease. Neurotherapeutics 6:141–151PubMedGoogle Scholar
  284. 284.
    Youdim MB (2006) The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30. Curr Alzheimer Res 3:541–550PubMedGoogle Scholar
  285. 285.
    Mancuso C, Siciliano R, Barone E, Butterfield DA, Preziosi P (2011) Pharmacologists and Alzheimer disease therapy: to boldly go where no scientist has gone before. Expert Opin Investig Drugs 20:1243–1261PubMedGoogle Scholar
  286. 286.
    Jossan SS, Gillberg PG, Gottfries CG, Karlsson I, Oreland L (1991) Monoamine oxidase B in brains from patients with Alzheimer’s disease: a biochemical and autoradiographical study. Neuroscience 45:1–12PubMedGoogle Scholar
  287. 287.
    Birks J, Flicker L (2003) Selegiline for Alzheimer’s disease. Cochrane Database Syst Rev CD000442Google Scholar
  288. 288.
    Marin DB, Bierer LM, Lawlor BA, Ryan TM, Jacobson R et al (1995) L-deprenyl and physostigmine for the treatment of Alzheimer’s disease. Psychiatry Res 58:181–189PubMedGoogle Scholar
  289. 289.
    Saha S, Chant D, McGrath J (2007) A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry 64:1123–1131PubMedGoogle Scholar
  290. 290.
    van Os J, Kapur S (2009) Schizophrenia. Lancet 374:635–645PubMedGoogle Scholar
  291. 291.
    Kane JM (1996) Schizophrenia. N Engl J Med 334:34–41PubMedGoogle Scholar
  292. 292.
    Seto K, Dumontet J, Ensom MH (2011) Risperidone in schizophrenia: is there a role for therapeutic drug monitoring? Ther Drug Monit 33:275–283PubMedGoogle Scholar
  293. 293.
    Krebs HA (1935) Metabolism of amino-acids: Deamination of amino-acids. Biochem J 29:1620–1644PubMedCentralPubMedGoogle Scholar
  294. 294.
    Tishkov VI, Khoronenkova SV (2005) D-Amino acid oxidase: structure, catalytic mechanism, and practical application. Biochem-Moscow 70:40–54Google Scholar
  295. 295.
    Fukui K, Miyake Y (1992) Molecular cloning and chromosomal localization of a human gene encoding D-amino-acid oxidase. J Biol Chem 267:18631–18638PubMedGoogle Scholar
  296. 296.
    Momoi K, Fukui K, Watanabe F, Miyake Y (1988) Molecular cloning and sequence analysis of cDNA encoding human kidney D-amino acid oxidase. FEBS Lett 238:180–184PubMedGoogle Scholar
  297. 297.
    Molla G, Sacchi S, Bernasconi M, Pilone MS, Fukui K et al (2006) Characterization of human D-amino acid oxidase. FEBS Lett 580:2358–2364PubMedGoogle Scholar
  298. 298.
    Caldinelli L, Molla G, Sacchi S, Pilone MS, Pollegioni L (2009) Relevance of weak flavin binding in human D-amino acid oxidase. Protein Sci 18:801–810PubMedCentralPubMedGoogle Scholar
  299. 299.
    Nagata Y, Yamamoto K, Shimojo T, Konno R, Yasumura Y et al (1992) The presence of free D-alanine, D-proline and D-serine in mice. Biochim Biophys Acta 1115:208–211PubMedGoogle Scholar
  300. 300.
    Neims AH, Zieverink WD, Smilack JD (1966) Distribution of D-amino acid oxidase in bovine and human nervous tissues. J Neurochem 13:163–168PubMedGoogle Scholar
  301. 301.
    Inoue T, Hamase K, Morikawa A, Zaitsu K (2000) Determination of minute amounts of D-leucine in various brain regions of rat and mouse using column-switching high-performance liquid chromatography. J Chromatogr B 744:213–219Google Scholar
  302. 302.
    Wolosker H, Sheth KN, Takahashi M, Mothet JP, Brady RO Jr et al (1999) Purification of serine racemase: biosynthesis of the neuromodulator D-serine. Proc Natl Acad Sci USA 96:721–725PubMedCentralPubMedGoogle Scholar
  303. 303.
    Wolosker H, Blackshaw S, Snyder SH (1999) Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci USA 96:13409–13414PubMedCentralPubMedGoogle Scholar
  304. 304.
    Hamase K, Inoue T, Morikawa A, Konno R, Zaitsu K (2001) Determination of free D-proline and D-leucine in the brains of mutant mice lacking D-amino acid oxidase activity. Anal Biochem 298:253–258PubMedGoogle Scholar
  305. 305.
    Morikawa A, Hamase K, Inoue T, Konno R, Niwa A et al (2001) Determination of free D-aspartic acid, D-serine and D-alanine in the brain of mutant mice lacking D-amino acid oxidase activity. J Chromatogr B 757:119–125Google Scholar
  306. 306.
    Dunlop DS, Neidle A (1997) The origin and turnover of D-serine in brain. Biochem Biophys Res Commun 235:26–30PubMedGoogle Scholar
  307. 307.
    Bauer D, Hamacher K, Broer S, Pauleit D, Palm C et al (2005) Preferred stereoselective brain uptake of d-serine. A modulator of glutamatergic neurotransmission. Nucl Med Biol 32:793–797PubMedGoogle Scholar
  308. 308.
    Langen KJ, Hamacher K, Bauer D, Broer S, Pauleit D et al (2005) Preferred stereoselective transport of the D-isomer of cis-4-[18F]fluoro-proline at the blood-brain barrier. J Cereb Blood Flow Metab 25:607–616PubMedGoogle Scholar
  309. 309.
    Kawazoe T, Tsuge H, Pilone MS, Fukui K (2006) Crystal structure of human D-amino acid oxidase: context-dependent variability of the backbone conformation of the VAAGL hydrophobic stretch located at the si-face of the flavin ring. Protein Sci 15:2708–2717PubMedCentralPubMedGoogle Scholar
  310. 310.
    Verrall L, Walker M, Rawlings N, Benzel I, Kew JNC et al (2007) D-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. Eur J Neurosci 26:1657–1669PubMedCentralPubMedGoogle Scholar
  311. 311.
    Kitano R, Morimoto S (1975) Isolation of peroxisomes from the dog kidney cortex. Biochim Biophys Acta 411:113–120PubMedGoogle Scholar
  312. 312.
    Perotti ME, Gavazzi E, Trussardo L, Malgaretti N, Curti B (1987) Immunoelectron microscopic localization of D-amino acid oxidase in rat kidney and liver. Histochem J 19:157–169PubMedGoogle Scholar
  313. 313.
    Tarelli GT, Vanoni MA, Negri A, Curti B (1990) Characterization of a fully active N-terminal 37-kDa polypeptide obtained by limited tryptic cleavage of pig kidney D-amino acid oxidase. J Biol Chem 265:21242–21246PubMedGoogle Scholar
  314. 314.
    Sacchi S, Bernasconi M, Martineau M, Mothet JP, Ruzzene M et al (2008) pLG72 modulates intracellular D-serine levels through its interaction with D-amino acid oxidase: effect on schizophrenia susceptibility. J Biol Chem 283:22244–22256PubMedGoogle Scholar
  315. 315.
    Gaunt GL, de Duve C (1976) Subcellular distribution of D-amino acid oxidase and catalase in rat brain. J Neurochem 26:749–759PubMedGoogle Scholar
  316. 316.
    Robinson JM, Briggs RT, Karnovsky MJ (1978) Localization of D-amino acid oxidase on the cell surface of human polymorphonuclear leukocytes. J Cell Biol 77:59–71PubMedGoogle Scholar
  317. 317.
    Sakata K, Fukushima T, Minje L, Ogurusu T, Taira H et al (1999) Modulation by L- and D-isoforms of amino acids of the L-glutamate response of N-methyl-D-aspartate receptors. Biochemistry 38:10099–10106PubMedGoogle Scholar
  318. 318.
    Schell MJ, Molliver ME, Snyder SH (1995) D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci USA 92:3948–3952PubMedCentralPubMedGoogle Scholar
  319. 319.
    Schell MJ, Brady RO Jr, Molliver ME, Snyder SH (1997) D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J Neurosci 17:1604–1615PubMedGoogle Scholar
  320. 320.
    Almond SL, Fradley RL, Armstrong EJ, Heavens RB, Rutter AR et al (2006) Behavioral and biochemical characterization of a mutant mouse strain lacking D-amino acid oxidase activity and its implications for schizophrenia. Mol Cell Neurosci 32:324–334PubMedGoogle Scholar
  321. 321.
    Katsuki H, Nonaka M, Shirakawa H, Kume T, Akaike A (2004) Endogenous D-serine is involved in induction of neuronal death by N-methyl-D-aspartate and simulated ischemia in rat cerebrocortical slices. J Pharmacol Exp Ther 311:836–844PubMedGoogle Scholar
  322. 322.
    Wood PL, Emmett MR, Rao TS, Mick S, Cler J et al (1989) In vivo modulation of the N-methyl-D-aspartate receptor complex by D-serine: potentiation of ongoing neuronal activity as evidenced by increased cerebellar cyclic GMP. J Neurochem 53:979–981PubMedGoogle Scholar
  323. 323.
    Oliet SH, Mothet JP (2009) Regulation of N-methyl-D-aspartate receptors by astrocytic D-serine. Neuroscience 158:275–283PubMedGoogle Scholar
  324. 324.
    Junjaud G, Rouaud E, Turpin F, Mothet JP, Billard JM (2006) Age-related effects of the neuromodulator D-serine on neurotransmission and synaptic potentiation in the CA1 hippocampal area of the rat. J Neurochem 98:1159–1166PubMedGoogle Scholar
  325. 325.
    Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L et al (2006) Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125:775–784PubMedGoogle Scholar
  326. 326.
    Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiat 148:1301–1308PubMedGoogle Scholar
  327. 327.
    Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R et al (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiat 51:199–214PubMedGoogle Scholar
  328. 328.
    Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384PubMedGoogle Scholar
  329. 329.
    Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT (2006) Neurobiology of schizophrenia. Neuron 52:139–153PubMedGoogle Scholar
  330. 330.
    Morita Y, Ujike H, Tanaka Y, Otani K, Kishimoto M et al (2007) A genetic variant of the serine racemase gene is associated with schizophrenia. Biol Psychiatry 61:1200–1203PubMedGoogle Scholar
  331. 331.
    Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M et al (2002) Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 99:13675–13680PubMedCentralPubMedGoogle Scholar
  332. 332.
    Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H et al (2003) Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiat 60:572–576PubMedGoogle Scholar
  333. 333.
    Liu YL, Fann CSJ, Liu CM, Chang CC, Wu JY et al (2006) No association of G72 and D-amino acid oxidase genes with schizophrenia. Schizophr Res 87:15–20PubMedGoogle Scholar
  334. 334.
    Liu X, He G, Wang X, Chen Q, Qian X et al (2004) Association of DAAO with schizophrenia in the Chinese population. Neurosci Lett 369:228–233PubMedGoogle Scholar
  335. 335.
    Wood LS, Pickering EH, Dechairo BM (2007) Significant support for DAO as a schizophrenia susceptibility locus: examination of five genes putatively associated with schizophrenia. Biol Psychiatry 61:1195–1199PubMedGoogle Scholar
  336. 336.
    Shinkai T, De Luca V, Hwang R, Müller DJ, Lanktree M et al (2007) Association analyses of the DAOA/G30 and D-amino-acid oxidase genes in schizophrenia: Further evidence for a role in schizophrenia. Neuromol Med 9:169–177Google Scholar
  337. 337.
    Burnet PWJ, Eastwood SL, Bristow GC, Godlewska BR, Sikka P et al (2008) D-amino acid oxidase activity and expression are increased in schizophrenia. Mol Psychiatr 13:658–660Google Scholar
  338. 338.
    Madeira C, Freitas ME, Vargas-Lopes C, Wolosker H, Panizzutti R (2008) Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia. Schizophr Res 101:76–83PubMedGoogle Scholar
  339. 339.
    Labrie V, Wang W, Barger SW, Baker GB, Roder JC (2010) Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in mice. Genes Brain Behav 9:11–25PubMedCentralPubMedGoogle Scholar
  340. 340.
    Iwana S, Kawazoe T, Park HK, Tsuchiya K, Ono K et al (2008) Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase, product of a susceptibility gene for schizophrenia. J Enzym Inhib Med Chem 23:901–911Google Scholar
  341. 341.
    Abou El-Magd RM, Park HK, Kawazoe T, Iwana S, Ono K et al (2010) The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia. J Psychopharmacol 24:1055–1067PubMedGoogle Scholar
  342. 342.
    Adage T, Trillat AC, Quattropani A, Perrin D, Cavare L et al (2008) In vitro and in vivo pharmacological profile of AS057278, a selective D-amino acid oxidase inhibitor with potential anti-psychotic properties. Eur Neuropsychopharmacol 18:200–214PubMedGoogle Scholar
  343. 343.
    Smith SM, Uslaner JM, Yao LH, Mullins CM, Surles NO et al (2009) The behavioral and neurochemical effects of a novel D-amino acid oxidase inhibitor compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and D-serine. J Pharmacol Exp Ther 328:921–930PubMedGoogle Scholar
  344. 344.
    Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M et al (2009) Co-administration of a D-amino acid oxidase inhibitor potentiates the efficacy of D-serine in attenuating prepulse inhibition deficits after administration of dizocilpine. Biol Psychiatry 65:1103–1106PubMedGoogle Scholar
  345. 345.
    Horio M, Fujita Y, Ishima T, Iyo M, Ferraris D, Tsukamoto T et al (2009) Effects of D-amino acid oxidase inhibitor on the extracellular Dalanine levels and the efficacy of D-alanine on dizocilpineinduced prepulse inhibition deficits in mice. Open Clin Chem J 2:16–21Google Scholar
  346. 346.
    Ferraris D, Duvall B, Ko YS, Thomas AG, Rojas C et al (2008) Synthesis and biological evaluation of D-amino acid oxidase inhibitors. J Med Chem 51:3357–3359PubMedGoogle Scholar
  347. 347.
    Sagot Y, Toni N, Perrelet D, Lurot S, King B et al (2000) An orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease. Br J Pharmacol 131:721–728PubMedCentralPubMedGoogle Scholar
  348. 348.
    Waibel S, Reuter A, Malessa S, Blaugrund E, Ludolph AC (2004) Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. J Neurol 251:1080–1084PubMedGoogle Scholar
  349. 349.
    Feigin A, Kurlan R, McDermott MP, Beach J, Dimitsopulos T et al (1996) A controlled trial of deprenyl in children with Tourette’s syndrome and attention deficit hyperactivity disorder. Neurology 46:965–968PubMedGoogle Scholar
  350. 350.
    Rubinstein S, Malone MA, Roberts W, Logan WJ (2006) Placebo-controlled study examining effects of selegiline in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 16:404–415PubMedGoogle Scholar
  351. 351.
    Akhondzadeh S, Tavakolian R, Davari-Ashtiani R, Arabgol F, Amini H (2003) Selegiline in the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 27:841–845PubMedGoogle Scholar
  352. 352.
    Yanik M, Erel O, Kati M (2004) The relationship between potency of oxidative stress and severity of depression. Acta Neuropsychiatr 16:200–203Google Scholar
  353. 353.
    Berry CE, Hare JM (2004) Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol 555:589–606PubMedCentralPubMedGoogle Scholar
  354. 354.
    George J, Struthers AD (2008) The role of urate and xanthine oxidase inhibitors in cardiovascular disease. Cardiovasc Ther 26:59–64PubMedGoogle Scholar
  355. 355.
    Pacher P, Nivorozhkin A, Szabo C (2006) Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 58:87–114PubMedCentralPubMedGoogle Scholar
  356. 356.
    Kelkar A, Kuo A, Frishman WH (2011) Allopurinol as a cardiovascular drug. Cardiol Rev 19:265–271PubMedGoogle Scholar
  357. 357.
    Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189PubMedGoogle Scholar
  358. 358.
    Touyz RM, Briones AM, Sedeek M, Burger D, Montezano AC (2011) NOX isoforms and reactive oxygen species in vascular health. Mol Interv 11:27–35PubMedGoogle Scholar
  359. 359.
    Drummond GR, Selemidis S, Griendling KK, Sobey CG (2011) Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 10:453–471PubMedCentralPubMedGoogle Scholar
  360. 360.
    Aldieri E, Riganti C, Polimeni M, Gazzano E, Lussiana C et al (2008) Classical inhibitors of NOX NAD(P)H oxidases are not specific. Curr Drug Metab 9:686–696PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Esther Jortzik
    • 1
  • Lihui Wang
    • 1
  • Jipeng Ma
    • 1
  • Katja Becker
    • 1
    Email author
  1. 1.Interdisciplinary Research Center, Justus Liebig UniversityGiessenGermany

Personalised recommendations