Advertisement

Molybdenum Cofactor Disorders

  • Günter SchwarzEmail author
  • Alex Veldman
Chapter

Abstract

Molybdenum (Mo) cofactor deficiency (MoCD) is characterized by neonatal seizures, high-pitch crying, convulsions, and abnormal EEG and MRI findings accompanied by rapidly progressing neurodegeneration. In the absence of treatment, patients usually die within the first years of life and show no neurodevelopmental improvement. The molecular cause of the disease is mainly due to the loss of sulfite oxidase activity, one out of four molybdenum cofactor-dependent enzymes. Sulfite oxidase catalyzes the terminal step in the oxidative degradation of cysteine; a loss of activity results in the accumulation of toxic sulfite, which in turn triggers the alteration of secondary-related metabolites such as S-sulfocysteine, thiosulfate, taurine, hypotaurine, and cystine. Xanthine oxidoreductase catalyzes the catabolism of purines from hypoxanthine to xanthine and further to uric acid, which is reduced in patients while xanthine and to a lesser extent hypoxanthine accumulate. The molybdenum cofactor (Moco) is synthesized by a three-step biosynthetic pathway, which involves gene products of the MOCS1, MOCS2, MOCS3, and GEPH loci. Depending on the mutation, type A, B, and C deficiencies are known. While MoCD types A and B are clinically indistinguishable, MoCD type C has a more severe neurological presentation due to the loss of synaptic inhibition, which is dependent on GEPHYRIN function. Dietary restriction (low cysteine and methionine) has been reported in some case, however, disease improvement was marginal. A first causative therapy has been established for MoCD type A patients and is based on the treatment with cyclic pyranopterin monophosphate, the first intermediate in the molybdenum cofactor pathway. Given the high neurotoxicity of sulfite and its related compounds, early diagnosis has been shown to be the key determinant in the treatment outcome. Patients that were treated shortly after birth and have not been exposed to extensive anticonvulsive therapy showed best clinical and neurodevelopmental outcome.

Keywords

Sulfite Oxidase Molybdenum Cofactor Xanthine Oxidoreductase Spastic Quadriplegia Global Cerebral Edema 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Arenas M, Fairbanks LD, Vijayakumar K, Carr L, Escuredo E, Marinaki AM (2009) An unusual genetic variant in the MOCS1 gene leads to complete missplicing of an alternatively spliced exon in a patient with molybdenum cofactor deficiency. J Inherit Metab Dis 32:560–569PubMedCrossRefGoogle Scholar
  2. Arslanoglu S, Yalaz M, Goksen D, Coker M, Tutuncuoglu S, Akisu M, Darcan S, Kultursay N, Ciris M, Demirtas E (2001) Molybdenum cofactor deficiency associated with Dandy-Walker complex. Brain Dev 23:815–818PubMedCrossRefGoogle Scholar
  3. Bagley PJ, Stipanuk MH (1994) The activities of rat hepatic cysteine dioxygenase and cysteinesulfinate decarboxylase are regulated in a reciprocal manner in response to dietary casein level. J Nutr 124:2410–2421PubMedGoogle Scholar
  4. Bamforth FJ, Johnson JL, Davidson AGF, Wong LTK, Lockitsch G, Applegrath DA (1990) Biochemical investigation of a child with molybdenum deficiency. Clin Biochem 23:537–542PubMedCrossRefGoogle Scholar
  5. Baranano DE, Ferris CD, Snyder SH (2001) Atypical neural messengers. Trends Neurosci 24:99–106PubMedCrossRefGoogle Scholar
  6. Barbot C, Martins E, Vilarinho L, Dorche C, Cardoso ML (1995) A mild form of infantile isolated sulphite oxidase deficiency. Neuropediatrics 26:322–324PubMedCrossRefGoogle Scholar
  7. Bayram E, Topcu Y, Karakaya P, Yis U, Cakmakci H, Ichida K, Kurul SH (2013) Molybdenum cofactor deficiency: review of 12 cases (MoCD and review). Eur J Paediatr Neurol 17:1–6PubMedCrossRefGoogle Scholar
  8. Belaidi AA, Schwarz G (2013) Molybdenum cofactor deficiency: metabolic link between taurine and S-sulfocysteine. Adv Exp Med Biol 776:13–19PubMedCrossRefGoogle Scholar
  9. Belaidi AA, Arjune S, Santamaria-Araujo JA, Sass JO, Schwarz G (2012) Molybdenum cofactor deficiency: a new HPLC method for fast quantification of s-sulfocysteine in urine and serum. JIMD Rep 5:35–43PubMedCentralPubMedCrossRefGoogle Scholar
  10. Boles RG, Ment LR, Meyn MS, Horwich AL, Kratz LE, Rinaldo P (1993) Short-term response to dietary therapy in molybdenum cofactor deficiency. Ann Neurol 34:742–744PubMedCrossRefGoogle Scholar
  11. Chowdhury MM, Dosche C, Lohmannsroben HG, Leimkuhler S (2012) Dual role of the molybdenum cofactor biosynthesis protein MOCS3 in tRNA thiolation and molybdenum cofactor biosynthesis in humans. J Biol Chem 287:17297–17307PubMedCentralPubMedCrossRefGoogle Scholar
  12. Chung TK, Funk MA, Baker DH (1990) L-2-oxothiazolidine-4-carboxylate as a cysteine precursor: efficacy for growth and hepatic glutathione synthesis in chicks and rats. J Nutr 120:158–165PubMedGoogle Scholar
  13. Del Rizzo M, Burlina AP, Sass JO, Beermann F, Zanco C, Cazzorla C, Bordugo A, Giordano L, Manara R, Burlina AB (2013) Metabolic stroke in a late-onset form of isolated sulfite oxidase deficiency. Mol Genet Metab 108:263–266PubMedCrossRefGoogle Scholar
  14. Dunlop J, Fear A, Griffiths R (1991) Glutamate uptake into synaptic vesicles – inhibition by sulphur amino acids. Neuroreport 2:377–379PubMedCrossRefGoogle Scholar
  15. Duran M, Beemer FA, van de 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 Inherit Metab Dis 1:175–178PubMedCrossRefGoogle Scholar
  16. El Idrissi A, Trenkner E (1999) Growth factors and taurine protect against excitotoxicity by stabilizing calcium homeostasis and energy metabolism. J Neurosci 19:9459–9468PubMedGoogle Scholar
  17. Feng G, Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H, Sanes JR (1998) Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity [see comments]. Science 282:1321–1324PubMedCrossRefGoogle Scholar
  18. Footitt EJ, Heales SJ, Mills PB, Allen GF, Oppenheim M, Clayton PT (2011) Pyridoxal 5′-phosphate in cerebrospinal fluid; factors affecting concentration. J Inherit Metab Dis 34:529–538PubMedCrossRefGoogle Scholar
  19. Fritschy JM, Harvey RJ, Schwarz G (2008) Gephyrin: where do we stand, where do we go? Trends Neurosci 31:257–264PubMedCrossRefGoogle Scholar
  20. Gorman A, Griffiths R (1994) Sulphur-containing excitatory amino acid-stimulated inositol phosphate formation in primary cultures of cerebellar granule cells is mediated predominantly by N-methyl-D-aspartate receptors. Neuroscience 59:299–308PubMedCrossRefGoogle Scholar
  21. Graf WD, Oleinik OE, Jack RM, Weiss AH, Johnson JL (1998) A homocysteinemia in molybdenum cofactor deficiency. Neurology 51:860–862PubMedCrossRefGoogle Scholar
  22. Gray TA, Nicholls RD (2000) Diverse splicing mechanisms fuse the evolutionarily conserved bicistronic MOCS1A and MOCS1B open reading frames. RNA 6:928–936PubMedCentralPubMedCrossRefGoogle Scholar
  23. 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 U S A 101:12870–12875PubMedCentralPubMedCrossRefGoogle Scholar
  24. 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 277:18303–18312PubMedCrossRefGoogle Scholar
  25. Havemeyer A, Bittner F, Wollers S, Mendel R, Kunze T, Clement B (2006) Identification of the missing component in the mitochondrial benzamidoxime prodrug-converting system as a novel molybdenum enzyme. J Biol Chem 281:34796–34802PubMedCrossRefGoogle Scholar
  26. Hildebrandt TM, Grieshaber MK (2008) Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J 275:3352–3361PubMedCrossRefGoogle Scholar
  27. Hille R (1996) The mononuclear molybdenum enzymes. Chem Rev 96:2757–2816PubMedCrossRefGoogle Scholar
  28. Hitzert MM, Bos AF, Bergman KA, Veldman A, Schwarz G, Santamaria-Araujo JA, Heiner-Fokkema R, Sival DA, Lunsing RJ, Arjune S et al (2012) Favorable outcome in a newborn with molybdenum cofactor type A deficiency treated with cPMP. Pediatrics 130:e1005–e1010PubMedCrossRefGoogle Scholar
  29. Ichida K, Matsumura T, Sakuma R, Hosoya T, Nishino T (2001) Mutation of human molybdenum cofactor sulfurase gene is responsible for classical xanthinuria type II. Biochem Biophys Res Commun 282:1194–1200PubMedCrossRefGoogle Scholar
  30. Jahoor F, Jackson A, Gazzard B, Philips G, Sharpstone D, Frazer ME, Heird W (1999) Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. Am J Physiol 276:E205–E211PubMedGoogle Scholar
  31. Johnson JL, Duran M (2001) Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. In: Scriver C, Beaudet A, Sly W, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 3163–3177Google Scholar
  32. Johnson JL, Hainline BE, Rajagopalan KV, Arison BH (1984) The pterin component of the molybdenum cofactor. Structural characterization of two fluorescent derivatives. J Biol Chem 259:5414–5422PubMedGoogle Scholar
  33. Johnson JL, Coyne KE, Rajagopalan KV, Van Hove JL, Mackay M, Pitt J, Boneh A (2001) Molybdopterin synthase mutations in a mild case of molybdenum cofactor deficiency. Am J Med Genet 104:169–173PubMedCrossRefGoogle Scholar
  34. Kabil O, Banerjee R (2010) Redox biochemistry of hydrogen sulfide. J Biol Chem 285:21903–21907PubMedCentralPubMedCrossRefGoogle Scholar
  35. Kamoun P (2004) Endogenous production of hydrogen sulfide in mammals. Amino Acids 26:243–254PubMedCrossRefGoogle Scholar
  36. Kuper J, Llamas A, Hecht HJ, Mendel RR, Schwarz G (2004) Structure of molybdopterin-bound Cnx1G domain links molybdenum and copper metabolism. Nature 430:803–806PubMedCrossRefGoogle Scholar
  37. Lee H-J, Adham IM, Schwarz G, Kneussel M, Sass J-O, Engel W, Reiss J (2002) Molybdenum cofactor-deficient mice resemble the phenotype of human patients. Hum Mol Genet 11:3309–3317PubMedCrossRefGoogle Scholar
  38. 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 281:18343–18350PubMedCrossRefGoogle Scholar
  39. Maric HM, Mukherjee J, Tretter V, Moss SJ, Schindelin H (2011) Gephyrin-mediated gamma-aminobutyric acid type a and glycine receptor clustering relies on a common binding site. J Biol Chem 286:42105–42114PubMedCentralPubMedCrossRefGoogle Scholar
  40. Matthies A, Rajagopalan KV, Mendel RR, Leimkuhler 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 U S A 101:5946–5951PubMedCentralPubMedCrossRefGoogle Scholar
  41. Mehta AP, Hanes JW, Abdelwahed SH, Hilmey DG, Hanzelmann P, Begley TP (2013) Catalysis of a new ribose carbon-insertion reaction by the molybdenum cofactor biosyn-thetic enzyme MoaA. Biochemistry 52(7):1134–1136PubMedCentralPubMedCrossRefGoogle Scholar
  42. Mills PB, Footitt EJ, Ceyhan S, Waters PJ, Jakobs C, Clayton PT, Struys EA (2012) Urinary AASA excretion is elevated in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency. J Inherit Metab Dis 35:1031–1036PubMedCrossRefGoogle Scholar
  43. Nam B, Kim H, Choi Y, Lee H, Hong ES, Park JK, Lee KM, Kim Y (2004) Neurologic sequela of hydrogen sulfide poisoning. Ind Health 42:83–87PubMedCrossRefGoogle Scholar
  44. Olney JW, Misra CH, de Gubareff T (1975) Cysteine-S-sulfate: brain damaging metabolite in sulfite oxidase deficiency. J Neuropathol Exp Neurol 34:167–177PubMedCrossRefGoogle Scholar
  45. Rees MI, Harvey K, Ward H, White JH, Evans LI, Duguid IC, Hsu CC, Coleman SL, Miller J, Baer K et al (2003) Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor and mutation analysis in hyperekplexia. J Biol Chem 278:24688–24696PubMedCrossRefGoogle Scholar
  46. Reiss J, Hahnewald R (2011) Molybdenum cofactor deficiency: mutations in GPHN, MOCS1, and MOCS2. Hum Mutat 32:10–18PubMedCrossRefGoogle Scholar
  47. Reiss J, Christensen E, Kurlemann G, Zabot M-T, Dorche C (1998a) Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A. Hum Genet 103:639–644PubMedCrossRefGoogle Scholar
  48. Reiss J, Cohen N, Dorche C, Mandel H, Mendel RR, Stallmeyer B, Zabot MT, Dierks T (1998b) Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency. Nat Genet 20:51–53PubMedCrossRefGoogle Scholar
  49. Reiss J, Christensen E, Dorche C (1999a) Molybdenum cofactor deficiency: first prenatal genetic analysis. Prenat Diagn 19:386–388PubMedCrossRefGoogle Scholar
  50. Reiss J, Dorche C, Stallmeyer B, Mendel RR, Cohen N, Zabot MT (1999b) Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. Am J Hum Genet 64:706–711PubMedCentralPubMedCrossRefGoogle Scholar
  51. Reiss J, Gross-Hardt S, Christensen E, Schmidt P, Mendel RR, Schwarz G (2001) A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency. Am J Hum Genet 68:208–213PubMedCentralPubMedCrossRefGoogle Scholar
  52. Reiss J, Bonin M, Schwegler H, Sass JO, Garattini E, Wagner S, Lee HJ, Engel W, Riess O, Schwarz G (2005) The pathogenesis of molybdenum cofactor deficiency, its delay by maternal clearance, and its expression pattern in microarray analysis. Mol Genet Metab 85:12–20PubMedCrossRefGoogle Scholar
  53. Reiss J, Lenz U, Aquaviva-Bourdain C, Joriot-Chekaf S, Mention-Mulliez K, Holder-Espinasse M (2011) A GPHN point mutation leading to molybdenum cofactor deficiency. Clin Genet 80:598–599PubMedCrossRefGoogle Scholar
  54. Reynolds AP, Harkness RA (1991) Urinary thiosulphate/creatinine concentration ratio in hospitalized children. J Inherit Metab Dis 14:938–939PubMedCrossRefGoogle Scholar
  55. Rupar CA, Gillett J, Gordon BA, Ramsay DA, Johnson JL, Garrett RM, Rajagopalan KV, Jung JH, Bacheyie GS, Sellers AR (1996) Isolated sulfite oxidase deficiency. Neuropediatrics 27:299–304PubMedCrossRefGoogle Scholar
  56. Santamaria-Araujo JA, Fischer B, Otte T, Nimtz M, Mendel RR, Wray V, Schwarz G (2004) The tetrahydropyranopterin structure of the sulfur-free and metal-free molybdenum cofactor precursor. J Biol Chem 279:15994–15999PubMedCrossRefGoogle Scholar
  57. Sass JO, Kishikawa M, Puttinger R, Reiss J, Erwa W, Shimizu A, Sperl W (2003) Hypohomocysteinaemia and highly increased proportion of S-sulfonated plasma transthyretin in molybdenum cofactor deficiency. J Inherit Metab Dis 26:80–82PubMedCrossRefGoogle Scholar
  58. Schrader N, Kim EY, Winking J, Paulukat J, Schindelin H, Schwarz G (2004) Biochemical characterization of the high affinity binding between the glycine receptor and gephyrin. J Biol Chem 279:18733–18741PubMedCrossRefGoogle Scholar
  59. Schwarz G, Santamaria-Araujo JA, Wolf S, Lee HJ, Adham IM, Grone HJ, Schwegler H, Sass JO, Otte T, Hanzelmann P et al (2004) Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli. Hum Mol Genet 13:1249–1255PubMedCrossRefGoogle Scholar
  60. Schwarz G, Mendel RR, Ribbe MW (2009) Molybdenum cofactors, enzymes and pathways. Nature 460:839–847PubMedCrossRefGoogle Scholar
  61. 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 64:698–705PubMedCentralPubMedCrossRefGoogle Scholar
  62. Tan WH, Eichler FS, Hoda S, Lee MS, Baris H, Hanley CA, Grant PE, Krishnamoorthy KS, Shih VE (2005) Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature. Pediatrics 116:757–766PubMedCrossRefGoogle Scholar
  63. Tiranti V, Viscomi C, Hildebrandt T, Di Meo I, Mineri R, Tiveron C, Levitt MD, Prelle A, Fagiolari G, Rimoldi M et al (2009) Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med 15:200–205PubMedCrossRefGoogle Scholar
  64. Touati G, Rusthoven E, Depondt E, Dorche C, Duran M, Heron B, Rabier D, Russo M, Saudubray JM (2000) Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. Evidence for clinical and biological improvement. J Inherit Metab Dis 23:45–53PubMedCrossRefGoogle Scholar
  65. Townsend DM, Tew KD, Tapiero H (2003) The importance of glutathione in human disease. Biomed Pharmacother 57:145–155PubMedCrossRefGoogle Scholar
  66. Ueki I, Roman HB, Valli A, Fieselmann K, Lam J, Peters R, Hirschberger LL, Stipanuk MH (2011) Knockout of the cysteine dioxygenase gene results in severe impairment in taurine synthesis and increased catabolism of cysteine to hydrogen sulfide. Am J Physiol Endocrinol Metab 301(4):E668–E684PubMedCentralPubMedCrossRefGoogle Scholar
  67. van Gennip AH, Stroomer A, Plandsoen WG, Abeling NG (1991) The effect of molybdenum cofactor deficiency on the purine pattern of cerebrospinal fluid. J Inherit Metab Dis 14:364–366PubMedCrossRefGoogle Scholar
  68. Veldman A, Santamaria-Araujo JA, Sollazzo S, Pitt J, Gianello R, Yaplito-Lee J, Wong F, Ramsden CA, Reiss J, Cook I et al (2010) Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics 125:e1249–e1254PubMedCrossRefGoogle Scholar
  69. Vijayakumar K, Gunny R, Grunewald S, Carr L, Chong KW, DeVile C, Robinson R, McSweeney N, Prabhakar P (2011) Clinical neuroimaging features and outcome in molybdenum cofactor deficiency. Pediatr Neurol 45:246–252PubMedCrossRefGoogle Scholar
  70. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND (2004) Glutathione metabolism and its implications for health. J Nutr 134:489–492PubMedGoogle Scholar
  71. Wuebbens MM, Rajagopalan KV (1993) Structural characterization of a molybdopterin precursor. J Biol Chem 268:13493–13498PubMedGoogle Scholar
  72. Wuebbens MM, Rajagopalan KV (2003) Mechanistic and mutational studies of Escherichia coli molybdopterin synthase clarify the final step of molybdopterin biosynthesis. J Biol Chem 278:14523–14532PubMedCrossRefGoogle Scholar
  73. Zhang X, Vincent AS, Halliwell B, Wong KP (2004) A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. J Biol Chem 279:43035–43045PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of ChemistryInstitute of Biochemistry, University of CologneKölnGermany
  2. 2.Colbourne Pharmaceuticals GmbHNiederkasselGermany

Personalised recommendations