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The biosynthesis of the molybdenum cofactors

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Abstract

The biosynthesis of the molybdenum cofactors (Moco) is an ancient, ubiquitous, and highly conserved pathway leading to the biochemical activation of molybdenum. Moco is the essential component of a group of redox enzymes, which are diverse in terms of their phylogenetic distribution and their architectures, both at the overall level and in their catalytic geometry. A wide variety of transformations are catalyzed by these enzymes at carbon, sulfur and nitrogen atoms, which include the transfer of an oxo group or two electrons to or from the substrate. More than 50 molybdoenzymes were identified to date. In all molybdoenzymes except nitrogenase, molybdenum is coordinated to a dithiolene group on the 6-alkyl side chain of a pterin called molybdopterin (MPT). The biosynthesis of Moco can be divided into three general steps, with a fourth one present only in bacteria and archaea: (1) formation of the cyclic pyranopterin monophosphate, (2) formation of MPT, (3) insertion of molybdenum into molybdopterin to form Moco, and (4) additional modification of Moco in bacteria with the attachment of a nucleotide to the phosphate group of MPT, forming the dinucleotide variant of Moco. This review will focus on the biosynthesis of Moco in bacteria, humans and plants.

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References

  1. Rajagopalan KV, Johnson JL (1992) The pterin molybdenum cofactors. J Biol Chem 267:10199–10202

    CAS  PubMed  Google Scholar 

  2. Leimkühler S, Wuebbens MM, Rajagopalan KV (2011) The history of the discovery of the molybdenum cofactor and novel aspects of its biosynthesis in bacteria. Coord Chem Rev 255:1129–1144

    PubMed Central  PubMed  Google Scholar 

  3. Leimkühler S (2014) The biosynthesis of the molybdenum cofactor in Escherichia coli and its connection to FeS cluster assembly and the thiolation of tRNA. Adv Biol 2014. doi:10.1155/2014/808569

  4. Mendel RR (2013) The molybdenum cofactor. J Biol Chem 288:13165–13172

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Mendel RR, Schwarz G (2011) Molybdenum cofactor biosynthesis in plants and humans. Coord Chem Rev 255:1145–1158

    CAS  Google Scholar 

  6. Hille R (1996) The mononuclear molybdenum enzymes. Chem Rev 96:2757–2816

    CAS  PubMed  Google Scholar 

  7. Hille R, Hall J, Basu P (2014) The mononuclear molybdenum enzymes. Chem Rev 114(7):3963–4038. doi:10.1021/cr400443z

  8. Rajagopalan KV (1996) Biosynthesis of the molybdenum cofactor. In: Neidhardt FC (ed) Escherichia coli and Salmonella. Cellular and Molecular Biology. ASM Press, Washington, DC, pp 674–679

    Google Scholar 

  9. Wuebbens MM, Rajagopalan KV (1993) Structural characterization of a molybdopterin precursor. J Biol Chem 268:13493–13498

    CAS  PubMed  Google Scholar 

  10. Pitterle DM, Johnson JL, Rajagopalan KV (1993) In vitro synthesis of molybdopterin from precursor Z using purified converting factor. Role of protein-bound sulfur in formation of the dithiolene. J Biol Chem 268:13506–13509

    CAS  PubMed  Google Scholar 

  11. Joshi MS, Johnson JL, Rajagopalan KV (1996) Molybdenum cofactor biosynthesis in Escherichia coli mod and mog mutants. J Bacteriol 178:4310–4312

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Neumann M, Seduk F, Iobbi-Nivol C, Leimkühler S (2011) Molybdopterin dinucleotide biosynthesis in Escherichia coli: identification of amino acid residues of molybdopterin dinucleotide transferases that determine specificity for binding of guanine or cytosine nucleotides. J Biol Chem 286:1400–1408

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Reschke S, Sigfridsson KG, Kaufmann P, Leidel N, Horn S, Gast K, Schulzke C, Haumann M, Leimkühler S (2013) Identification of a bis-molybdopterin intermediate in molybdenum cofactor biosynthesis in Escherichia coli. J Biol Chem 288:29736–29745

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Shanmugam KT, Stewart V, Gunsalus RP, Boxer DH, Cole JA, Chippaux M, DeMoss JA, Giordano G, Lin ECC, Rajagopalan KV (1992) Proposed nomenclature for the genes involved in molybdenum metabolism in Escherichia coli and Salmonella typhimurium. Mol Microbiol 6:3452–3454

    CAS  PubMed  Google Scholar 

  15. Mendel RR, Kruse T (2012) Cell biology of molybdenum in plants and humans. Biochim Biophys Acta 1823:1568–1579

    CAS  PubMed  Google Scholar 

  16. Reiss J, Cohen N, Dorche C, Mandel H, Mendel RR, Stallmeyer B, Zabot MT, Dierks T (1998) Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency. Nat Genet 20:51–53

    CAS  PubMed  Google Scholar 

  17. Reiss J (2000) Genetics of molybdenum cofactor deficiency. Hum Genet 106:157–163

    CAS  PubMed  Google Scholar 

  18. Hille R, Nishino T, Bittner F (2011) Molybdenum enzymes in higher organisms. Coord Chem Rev 255:1179–1205

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Duran M, Beemer FA, van der Heiden C, Korteland J, de Bree PK, Brink M, Wadman SK, Lombeck I (1978) Combined deficiency of xanthine oxidase and sulphite oxidase: a defect of molybdenum metabolism or transport? J Inher Metab Dis 1:175–178

    CAS  PubMed  Google Scholar 

  20. Duran M, de Bree PK, de Klerk JBC, Dorland L, Berger R (1996) Molybdenum cofactor deficiency: clinical presentation and laboratory diagnosis. Int Pediatr 11:334–338

    Google Scholar 

  21. Santamaria-Araujo JA, Fischer B, Otte T, Nimtz M, Mendel RR, Wray V, Schwarz G (2004) The tetrahydropyranopterin structure of the sulfur- and metal-free molybdenum cofactor precursor. J Biol Chem 279:15994–15999

    CAS  PubMed  Google Scholar 

  22. Hover BM, Loksztejn A, Ribeiro AA, Yokoyama K (2013) Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis. J Am Chem Soc 135:7019–7032

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Mehta AP, Abdelwahed SH, Begley TP (2013) Molybdopterin biosynthesis: trapping an unusual purine ribose adduct in the MoaA-catalyzed reaction. J Am Chem Soc 135:10883–10885

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Wuebbens MM, Rajagopalan KV (1995) Investigation of the early steps of molybdopterin biosynthesis in Escherichia coli through the use of in vivo labeling studies. J Biol Chem 270:1082–1087

    CAS  PubMed  Google Scholar 

  25. Sofia HJ, Chen G, Hetzler BG, Reyes-Spindola JF, Miller NE (2001) Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional characterization using new analysis and information visualization methods. Nucleic Acids Res 29:1097–1106

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Hänzelmann P, Hernandez HL, Menzel C, Garcia-Serres R, Huynh BH, Johnson MK, Mendel RR, Schindelin H (2004) Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in human molybdenum cofactor biosynthesis. J Biol Chem 279:34721–34732

    PubMed  Google Scholar 

  27. Hänzelmann P, Schindelin H (2004) Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans. Proc Natl Acad Sci USA 101:12870–12875

    PubMed Central  PubMed  Google Scholar 

  28. Hänzelmann P, Schindelin H (2006) Binding of 5′-GTP to the C-terminal FeS cluster of the radical S-adenosylmethionine enzyme MoaA provides insights into its mechanism. Proc Natl Acad Sci USA 103:6829–6834

    PubMed Central  PubMed  Google Scholar 

  29. Wuebbens MM, Liu MT, Rajagopalan K, Schindelin H (2000) Insights into molybdenum cofactor deficiency provided by the crystal structure of the molybdenum cofactor biosynthesis protein MoaC. Struct Fold Des 8:709–718

    CAS  Google Scholar 

  30. Kanaujia SP, Jeyakanthan J, Nakagawa N, Balasubramaniam S, Shinkai A, Kuramitsu S, Yokoyama S, Sekar K (2010) Structures of apo and GTP-bound molybdenum cofactor biosynthesis protein MoaC from Thermus thermophilus HB8. Acta Crystallogr D Biol Crystallogr 66:821–833

    CAS  PubMed  Google Scholar 

  31. Reiss J, Christensen E, Kurlemann G, Zabot M-T, Dorche C (1998) Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A. Hum Genet 103:639–644

    CAS  PubMed  Google Scholar 

  32. Gross-Hard S, Reiss J (2002) The bicistronic MOCS1 gene has alternative start codons on two mutually exclusive exons. Mol Genet Metab 76:340–343

    Google Scholar 

  33. Gray TA, Nicholls RD (2000) Diverse splicing mechanisms fuse the evolutionarily conserved bicistronic MOCS1A and MOCS1B open reading frames. RNA 6:928–936

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Hänzelmann P, Schwarz G, Mendel RR (2002) Functionality of alternative splice forms of the first enzymes involved in human molybdenum cofactor biosynthesis. J Biol Chem 277:18303–18312

    PubMed  Google Scholar 

  35. Teschner J, Lachmann N, Schulze J, Geisler M, Selbach K, Santamaria-Araujo J, Balk J, Mendel RR, Bittner F (2010) A novel role for Arabidopsis mitochondrial ABC transporter ATM3 in molybdenum cofactor biosynthesis. Plant Cell 22:468–480

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Pitterle DM, Johnson JL, Rajagopalan KV (1990) Molybdopterin formation by converting factor of E. coli chlA1. FASEB J 4:A1957

    Google Scholar 

  37. Pitterle DM, Rajagopalan KV (1989) Two proteins encoded at the chlA locus constitute the converting factor of Escherichia coli chlA1. J Bacteriol 171:3373–3378

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Pitterle DM, Rajagopalan KV (1991) Purification and characterization of the converting factor from E. coli chlA1. FASEB J 5:A468

    Google Scholar 

  39. Pitterle DM, Rajagopalan KV (1993) The biosynthesis of molybdopterin in Escherichia coli. Purification and characterization of the converting factor. J Biol Chem 268:13499–13505

    CAS  PubMed  Google Scholar 

  40. Daniels JN, Wuebbens MM, Rajagopalan KV, Schindelin H (2008) Crystal structure of a molybdopterin synthase-precursor Z complex: insight into its sulfur transfer mechanism and its role in molybdenum cofactor deficiency. Biochemistry 47(2):615–626

  41. Rudolph MJ, Wuebbens MM, Rajagopalan KV, Schindelin H (2001) Crystal structure of molybdopterin synthase and its evolutionary relationship to ubiquitin activation. Nat Struct Biol 8:42–46

    CAS  PubMed  Google Scholar 

  42. Gutzke G, Fischer B, Mendel RR, Schwarz G (2001) Thiocarboxylation of molybdopterin synthase provides evidence for the mechanism of dithiolene formation in metal-binding pterins. J Biol Chem 276:36268–36274

    CAS  PubMed  Google Scholar 

  43. Leimkühler S, Freuer A, Araujo JA, Rajagopalan KV, Mendel RR (2003) Mechanistic studies of human molybdopterin synthase reaction and characterization of mutants identified in group B patients of molybdenum cofactor deficiency. J Biol Chem 278:26127–26134

    PubMed  Google Scholar 

  44. Wuebbens MM, Rajagopalan KV (2003) Mechanistic and mutational studies of Escherichia coli molybdopterin synthase clarify the final step of molybdopterin biosynthesis. J Biol Chem 278:14523–14532

    CAS  PubMed  Google Scholar 

  45. Leimkühler S, Wuebbens MM, Rajagopalan KV (2001) Characterization of Escherichia coli MoeB and its involvement in the activation of molybdopterin synthase for the biosynthesis of the molybdenum cofactor. J Biol Chem 276:34695–34701

    PubMed  Google Scholar 

  46. Schindelin H (2005) Evolutionary origin of the activation step during ubiquitin-dependent protein degradation. In: Mayer RJ, Ciechanover A, Rechsteiner M (eds) Protein degradation: ubiquitin and the chemistry of life. WILEY-VCH, Weinheim, pp 21–43

    Google Scholar 

  47. Lake MW, Wuebbens MM, Rajagopalan KV, Schindelin H (2001) Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB–MoaD complex. Nature 414:325–329

    CAS  PubMed  Google Scholar 

  48. Schmitz J, Wuebbens MM, Rajagopalan KV, Leimkühler S (2007) Role of the C-terminal Gly-Gly motif of Escherichia coli MoaD, a molybdenum cofactor biosynthesis protein with a ubiquitin fold. Biochemistry 46:909–916

    CAS  PubMed  Google Scholar 

  49. Tong Y, Wuebbens MM, Rajagopalan KV, Fitzgerald MC (2005) Thermodynamic analysis of subunit interactions in Escherichia coli molybdopterin synthase. Biochemistry 44:2595–2601

    CAS  PubMed  Google Scholar 

  50. Leimkühler S, Rajagopalan KV (2001) An Escherichia coli NifS-like sulfurtransferase is required for the transfer of cysteine sulfur in the in vitro synthesis of molybdopterin from precursor Z. J Biol Chem 276:22024–22031

    PubMed  Google Scholar 

  51. Zhang W, Urban A, Mihara H, Leimkühler S, Kurihara T, Esaki N (2010) IscS functions as a primary sulfur-donating enzyme by interacting specifically with MoeB and MoaD in the biosynthesis of molybdopterin in Escherichia coli. J Biol Chem 285:2302–2308

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Dahl JU, Radon C, Bühning M, Nimtz M, Leichert LI, Denis Y, Jourlin-Castelli C, Iobbi-Nivol C, Mejean V, Leimkühler S (2013) The sulfur carrier protein TusA has a pleiotropic role in Escherichia coli that also affects molybdenum cofactor biosynthesis. J Biol Chem 288:5426–5442

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Dahl JU, Urban A, Bolte A, Sriyabhaya P, Donahue JL, Nimtz M, Larson TJ, Leimkühler S (2011) The identification of a novel protein involved in molybdenum cofactor biosynthesis in Escherichia coli. J Biol Chem 286:35801–35812

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Iobbi-Nivol C, Leimkühler S (2013) Molybdenum enzymes, their maturation and molybdenum cofactor biosynthesis in Escherichia coli. Biochim Biophys Acta 1827:1086–1101

    CAS  PubMed  Google Scholar 

  55. Stallmeyer B, Drugeon G, Reiss J, Haenni AL, Mendel RR (1999) Human molybdopterin synthase gene: identification of a bicistronic transcript with overlapping reading frames. Am J Hum Genet 64:698–705

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Hahnewald R, Leimkühler S, Vilaseca A, Acquaviva-Bourdain C, Lenz U, Reiss J (2006) A novel MOCS2 mutation reveals coordinated expression of the small and large subunit of molybdopterin synthase. Mol Genet Metab 89(3):210–213

  57. Matthies A, Rajagopalan KV, Mendel RR, Leimkühler S (2004) Evidence for the physiological role of a rhodanese-like protein for the biosynthesis of the molybdenum cofactor in humans. Proc Natl Acad Sci USA 101:5946–5951

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Bordo D, Bork P (2002) The rhodanese/Cdc25 phosphatase superfamily. EMBO Rep 3:741–746

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Matthies A, Nimtz M, Leimkühler S (2005) Molybdenum cofactor biosynthesis in humans: identification of a persulfide group in the rhodanese-like domain of MOCS3 by mass spectrometry. Biochemistry 44:7912–7920

    CAS  PubMed  Google Scholar 

  60. Krepinsky K, Leimkühler S (2007) Site-directed mutagenesis of the active-site loop of the rhodanese-like domain of the human molybdopterin synthase sulfurase MOCS3: major differences in substrate specificity between eukaryotic and bacterial homologues. FEBS J 274:2778–2787

    CAS  PubMed  Google Scholar 

  61. Marelja Z, Stöcklein W, Nimtz M, Leimkühler S (2008) A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis. J Biol Chem 283:25178–25185

    CAS  PubMed  Google Scholar 

  62. Liu MT, Wuebbens MM, Rajagopalan KV, Schindelin H (2000) Crystal structure of the gephyrin-related molybdenum cofactor biosynthesis protein MogA from Escherichia coli. J Biol Chem 275:1814–1822

    CAS  PubMed  Google Scholar 

  63. Xiang S, Nichols J, Rajagopalan KV, Schindelin H (2001) The crystal structure of Escherichia coli MoeA and its relationship to the multifunctional protein gephyrin. Structure 9:299–310

    CAS  PubMed  Google Scholar 

  64. Schrag JD, Huang W, Sivaraman J, Smith C, Plamondon J, Larocque R, Matte A, Cygler M (2001) The crystal structure of Escherichia coli MoeA, a protein from the molybdopterin synthesis pathway. J Mol Biol 310:419–431

    CAS  PubMed  Google Scholar 

  65. Nichols J, Rajagopalan KV (2002) Escherichia coli MoeA and MogA. Function in metal incorporation step of molybdenum cofactor biosynthesis. J Biol Chem 277:24995–25000

    CAS  PubMed  Google Scholar 

  66. Nichols JD, Rajagopalan KV (2005) In vitro molybdenum ligation to molybdopterin using purified components. J Biol Chem 280:7817–7822

    CAS  PubMed  Google Scholar 

  67. Stallmeyer B, Nerlich A, Schiemann J, Brinkmann H, Mendel RR (1995) Molybdenum cofactor biosynthesis: the A. thaliana cDNA cnx1 encodes a multifunctional two-domain protein homologous to a mammalian neuroprotein, the insect protein Cinnamon and three E. coli proteins. Plant J 8:751–762

    CAS  PubMed  Google Scholar 

  68. Stallmeyer B, Schwarz G, Schulze J, Nerlich A, Reiss J, Kirsch J, Mendel RR (1999) The neurotransmitter receptor-anchoring protein gephyrin reconstitutes molybdenum cofactor biosynthesis in bacteria, plants, and mammalian cells. Proc Natl Acad Sci USA 96:1333–1338

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Kuper J, Llamas A, Hecht HJ, Mendel RR, Schwarz G (2004) Structure of the molybdopterin-bound Cnx1G domain links molybdenum and copper metabolism. Nature 430:803–806

    CAS  PubMed  Google Scholar 

  70. Llamas A, Mendel RR, Schwarz G (2004) Synthesis of adenylated molybdopterin: an essential step for molybdenum insertion. J Biol Chem 279:55241–55246

    CAS  PubMed  Google Scholar 

  71. Llamas A, Otte T, Multhaup G, Mendel RR, Schwarz G (2006) The mechanism of nucleotide-assisted molybdenum insertion into molybdopterin. A novel route toward metal cofactor assembly. J Biol Chem 281:18343–18350

    CAS  PubMed  Google Scholar 

  72. Belaidi AA, Schwarz G (2013) Metal insertion into the molybdenum cofactor: product-substrate channelling demonstrates the functional origin of domain fusion in gephyrin. Biochem J 450:149–157

    CAS  PubMed  Google Scholar 

  73. Morrison MS, Cobine PA, Hegg EL (2007) Probing the role of copper in the biosynthesis of the molybdenum cofactor in Escherichia coli and Rhodobacter sphaeroides. J Biol Inorg Chem 12:1129–1139

    CAS  PubMed  Google Scholar 

  74. Leimkühler S, Rajagopalan KV (2001) In vitro incorporation of nascent molybdenum cofactor into human sulfite oxidase. J Biol Chem 276:1837–1844

    PubMed  Google Scholar 

  75. Schwarz G (2005) Molybdenum cofactor biosynthesis and deficiency. Cell Mol Life Sci 62:2792–2810

    CAS  PubMed  Google Scholar 

  76. Herweg J, Schwarz G (2012) Splice-specific glycine receptor binding, folding, and phosphorylation of the scaffolding protein gephyrin. J Biol Chem 287:12645–12656

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Temple CA, Rajagopalan KV (2000) Mechanism of assembly of the Bis(Molybdopterin guanine dinucleotide)molybdenum cofactor in Rhodobacter sphaeroides dimethyl sulfoxide reductase. J Biol Chem 275:40202–40210

    CAS  PubMed  Google Scholar 

  78. Palmer T, Santini C-L, Iobbi-Nivol C, Eaves DJ, Boxer DH, Giordano G (1996) Involvement of the narJ and mob gene products in the biosynthesis of the molybdoenzyme nitrate reductase in Escherichia coli. Mol Microbiol 20:875–884

    CAS  PubMed  Google Scholar 

  79. Lake MW, Temple CA, Rajagopalan KV, Schindelin H (2000) The crystal structure of the Escherichia coli MobA protein provides insight into molybdopterin guanine dinucleotide biosynthesis. J Biol Chem 275:40211–40217

    CAS  PubMed  Google Scholar 

  80. Stevenson CE, Sargent F, Buchanan G, Palmer T, Lawson DM (2000) Crystal structure of the molybdenum cofactor biosynthesis protein MobA from Escherichia coli at near-atomic resolution. Struct Fold Des 8:1115–1125

    CAS  Google Scholar 

  81. Thome R, Gust A, Toci R, Mendel R, Bittner F, Magalon A, Walburger A (2012) A sulfurtransferase is essential for activity of formate dehydrogenases in Escherichia coli. J Biol Chem 287:4671–4678

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Raaijmakers HC, Romao MJ (2006) Formate-reduced E. coli formate dehydrogenase H: the reinterpretation of the crystal structure suggests a new reaction mechanism. J Biol Inorg Chem 11:849–854

    CAS  PubMed  Google Scholar 

  83. Coelho C, Gonzalez PJ, Moura JG, Moura I, Trincao J, Joao Romao M (2011) The crystal structure of Cupriavidus necator nitrate reductase in oxidized and partially reduced states. J Mol Biol 408:932–948

    CAS  PubMed  Google Scholar 

  84. Neumann M, Mittelstädt G, Seduk F, Iobbi-Nivol C, Leimkühler S (2009) MocA is a specific cytidylyltransferase involved in molybdopterin cytosine dinucleotide biosynthesis in Escherichia coli. J Biol Chem 284:21891–21898

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Neumann M, Leimkühler S (2011) The role of system-specific molecular chaperones in the maturation of molybdoenzymes in bacteria. Biochem Res Int 2011:850924

    PubMed Central  PubMed  Google Scholar 

  86. Neumann M, Stöcklein W, Walburger A, Magalon A, Leimkühler S (2007) Identification of a Rhodobacter capsulatus l-cysteine desulfurase that sulfurates the molybdenum cofactor when bound to XdhC and before its insertion into xanthine dehydrogenase. Biochemistry 46:9586–9595

    CAS  PubMed  Google Scholar 

  87. Neumann M, Stöcklein W, Leimkühler S (2007) Transfer of the molybdenum cofactor synthesized by Rhodobacter capsulatus MoeA to XdhC and MobA. J Biol Chem 282:28493–28500

    CAS  PubMed  Google Scholar 

  88. Bittner F, Oreb M, Mendel RR (2001) ABA3 is a molybdenum cofactor sulfurase required for activation of aldehyde oxidase and xanthine dehydrogenase in Arabidopsis thaliana. J Biol Chem 276:40381–40384

    CAS  PubMed  Google Scholar 

  89. Heidenreich T, Wollers S, Mendel RR, Bittner F (2005) Characterization of the NifS-like domain of ABA3 from Arabidopsis thaliana provides insight into the mechanism of molybdenum cofactor sulfuration. J Biol Chem 280:4213–4218

    CAS  PubMed  Google Scholar 

  90. Wollers S, Heidenreich T, Zarepour M, Zachmann D, Kraft C, Zhao Y, Mendel RR, Bittner F (2008) Binding of sulfurated molybdenum cofactor to the C-terminal domain of ABA3 from Arabidopsis thaliana provides insight into the mechanism of molybdenum cofactor sulfuration. J Biol Chem 283:9642–9650

    CAS  PubMed  Google Scholar 

  91. Lehrke M, Rump S, Heidenreich T, Wissing J, Mendel RR, Bittner F (2012) Identification of persulfide-binding and disulfide-forming cysteine residues in the NifS-like domain of the molybdenum cofactor sulfurase ABA3 by cysteine-scanning mutagenesis. Biochem J 441:823–832

    CAS  PubMed  Google Scholar 

  92. Kisker C, Schindelin H, Rees DC (1997) Molybdenum-cofactor-containing enzymes: structure and mechanism. Ann Rev Biochem 66:233–267

    CAS  PubMed  Google Scholar 

  93. Genest O, Mejean V, Iobbi-Nivol C (2009) Multiple roles of TorD-like chaperones in the biogenesis of molybdoenzymes. FEMS Microbiol Lett 297:1–9

    CAS  PubMed  Google Scholar 

  94. Böhmer N, Hartmann T, Leimkühler S (2014) The chaperone FdsC for Rhodobacter capsulatus formate dehydrogenase binds the bis-molybdopterin guanine dinucleotide cofactor. FEBS Lett 588:531–537

    PubMed  Google Scholar 

  95. Witte CP, Igeno MI, Mendel R, Schwarz G, Fernandez E (1998) The Chlamydomonas reinhardtii MoCo carrier protein is multimeric and stabilizes molybdopterin cofactor in a molybdate charged form. FEBS Lett 431:205–209

    CAS  PubMed  Google Scholar 

  96. Fischer K, Llamas A, Tejada-Jimenez M, Schrader N, Kuper J, Ataya FS, Galvan A, Mendel RR, Fernandez E, Schwarz G (2006) Function and structure of the molybdenum cofactor carrier protein from Chlamydomonas reinhardtii. J Biol Chem 281:30186–30194

    CAS  PubMed  Google Scholar 

  97. Kruse T, Gehl C, Geisler M, Lehrke M, Ringel P, Hallier S, Hansch R, Mendel RR (2010) Identification and biochemical characterization of molybdenum cofactor-binding proteins from Arabidopsis thaliana. J Biol Chem 285:6623–6635

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Jack RL, Buchanan G, Dubini A, Hatzixanthis K, Palmer T, Sargent F (2004) Coordinating assembly and export of complex bacterial proteins. EMBO J 23:3962–3972

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Berks BC (1996) A common export pathway for proteins binding complex redox cofactors? Mol Microbiol 22:393–404

    CAS  PubMed  Google Scholar 

  100. Berks BC, Palmer T, Sargent F (2005) Protein targeting by the bacterial twin-arginine translocation (Tat) pathway. Curr Opin Microbiol 8:174–181

    CAS  PubMed  Google Scholar 

  101. Harrison R (2004) Physiological roles of xanthine oxidoreductase. Drug Metab Rev 36:363–375

    CAS  PubMed  Google Scholar 

  102. Garattini E, Mendel R, Romao MJ, Wright R, Terao M (2003) Mammalian molybdo-flavoenzymes, an expanding family of proteins: structure, genetics, regulation, function and pathophysiology. Biochem J 372:15–32

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Kisker C, Schindelin H, Pacheco A, Wehbi WA, Garrett RM, Rajagopalan KV, Enemark JH, Rees DC (1997) Molecular basis of sulfite oxidase deficiency from the structure of sulfite oxidase. Cell 91:973–983

    CAS  PubMed  Google Scholar 

  104. Klein JM, Schwarz G (2012) Cofactor-dependent maturation of mammalian sulfite oxidase links two mitochondrial import pathways. J Cell Sci 125:4876–4885

    CAS  PubMed  Google Scholar 

  105. Plitzko B, Ott G, Reichmann D, Henderson CJ, Wolf CR, Mendel R, Bittner F, Clement B, Havemeyer A (2013) The involvement of mitochondrial amidoxime reducing components 1 and 2 and mitochondrial cytochrome b5 in N-reductive metabolism in human cells. J Biol Chem 288:20228–20237

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Klein JM, Busch JD, Potting C, Baker MJ, Langer T, Schwarz G (2012) The mitochondrial amidoxime-reducing component (mARC1) is a novel signal-anchored protein of the outer mitochondrial membrane. J Biol Chem 287:42795–42803

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Veldman A, Santamaria-Araujo JA, Sollazzo S, Pitt J, Gianello R, Yaplito-Lee J, Wong F, Ramsden CA, Reiss J, Cook I, Fairweather J, Schwarz G (2010) Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics 125:e1249–e1254

    PubMed  Google Scholar 

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Acknowledgments

The authors thank all current and former members of their research groups in addition to collaboration partners who were involved in this work over the past years and decades. The work was mainly supported by continuous grants of the Deutsche Forschungsgemeinschaft to S.L. and to R.R.M.

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Correspondence to Silke Leimkühler.

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Responsible Editors: José Moura and Paul Bernhardt.

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Mendel, R.R., Leimkühler, S. The biosynthesis of the molybdenum cofactors. J Biol Inorg Chem 20, 337–347 (2015). https://doi.org/10.1007/s00775-014-1173-y

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  • DOI: https://doi.org/10.1007/s00775-014-1173-y

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