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MOCS2  -  molybdenum cofactor synthesis 2

Homo sapiens

Synonyms: MCBPE, MOCO1, MOCODB, MPTS
 
 
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Disease relevance of MOCS2

  • MOCS2A and MOCS2B were purified after heterologous expression in E. coli, and the separately purified subunits readily assemble into a functional MPT synthase tetramer [1].
 

High impact information on MOCS2

  • In a defined in vitro system for the generation of MPT from precursor Z, the sulfurated form of MOCS3-RLD was able to provide the sulfur for the thiocarboxylation of MOCS2A, the small MPT synthase subunit in humans [2].
  • Most patients harbor MOCS1 mutations, which prohibit formation of a precursor, or carry MOCS2 mutations, which abrogate precursor conversion to molybdopterin [3].
  • Moco contains a tricyclic pyranopterin, termed molybdopterin (MPT), that bears the cis-dithiolene group responsible for molybdenum ligation [4].
  • Gephyrin is essential for both the postsynaptic localization of inhibitory neurotransmitter receptors in the central nervous system and the biosynthesis of the molybdenum cofactor (Moco) in different peripheral organs [5].
  • MOCS2 encodes the small and large subunits of molybdopterin synthase via a single transcript with two overlapping reading frames [6].
 

Chemical compound and disease context of MOCS2

  • The Escherichia coli MoeA and MogA proteins are involved in the final step of Moco biosynthesis: the incorporation of molybdenum into molybdopterin (MPT), the organic pyranopterin moiety of Moco [7].
 

Biological context of MOCS2

 

Anatomical context of MOCS2

  • MogA is related to the protein gephyrin, which, in addition to its role in Moco biosynthesis, is also responsible for anchoring glycinergic receptors to the cytoskeleton at inhibitory synapses [12].
 

Associations of MOCS2 with chemical compounds

  • Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase [13].
  • In both cases, the A proteins share a highly conserved ubiquitin-like double glycine motif, which is functionally important at least for the small subunit of molybdopterin (MPT) synthase (MOCS2A) [14].
  • The conversion of MPT into Moco by molybdate chelation apparently occurs concomitantly with the insertion of MPT into sulfite oxidase [15].
  • After the inclusion of sodium molybdate in the reconstitution mixture, active sulfite oxidase was obtained, revealing that in vitro MPT synthase and aposulfite oxidase are sufficient for the insertion of MPT into sulfite oxidase and the conversion of MPT into Moco in the presence of high concentrations of molybdate [15].
  • The biochemical hallmark of this disorder is the inactivity of the Moco-dependent sulfite oxidase, which results in elevated sulfite and diminished sulfate levels throughout the organism [16].
 

Enzymatic interactions of MOCS2

  • Recent studies have shown that the MOCS3 rhodanese-like domain (MOCS3-RLD) catalyzes the transfer of sulfur from thiosulfate to cyanide and is also able to provide the sulfur for the thiocarboxylation of MOCS2A in a defined in vitro system for the generation of MPT from precursor Z [17].
 

Other interactions of MOCS2

  • Disease-causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH [8].
 

Analytical, diagnostic and therapeutic context of MOCS2

  • We have recently described a murine model for Moco-deficiency, which reflects all enzyme and metabolite changes observed in the patients, and an efficient therapy using a biosynthetic precursor of Moco has been established in this animal model [16].
  • We observed undisturbed production of both transcripts, while Western blot analysis demonstrated that MOCS2B, the large subunit, is unstable in the absence of MOCS2A [18].
  • The Nucleus multichannel implantable hearing prosthesis (Nucleus Ltd., Sydney, Australia) has been modified by computer programming (MOCO, Inc., Scituate, Mass.) into a 22-channel neural stimulator for use in functional electrical stimulation (FES) [19].
  • Responses of groups receiving SRP followed by one dose per pocket of the minocycline microspheres (SRP + MPTS) were compared to SRP alone, MPTS alone or no treatment [20].

References

  1. Mechanistic studies of human molybdopterin synthase reaction and characterization of mutants identified in group B patients of molybdenum cofactor deficiency. Leimkuhler, S., Freuer, A., Araujo, J.A., Rajagopalan, K.V., Mendel, R.R. J. Biol. Chem. (2003) [Pubmed]
  2. Evidence for the physiological role of a rhodanese-like protein for the biosynthesis of the molybdenum cofactor in humans. Matthies, A., Rajagopalan, K.V., Mendel, R.R., Leimkühler, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency. Reiss, J., Gross-Hardt, S., Christensen, E., Schmidt, P., Mendel, R.R., Schwarz, G. Am. J. Hum. Genet. (2001) [Pubmed]
  4. Crystal structure of molybdopterin synthase and its evolutionary relationship to ubiquitin activation. Rudolph, M.J., Wuebbens, M.M., Rajagopalan, K.V., Schindelin, H. Nat. Struct. Biol. (2001) [Pubmed]
  5. Diversity and phylogeny of gephyrin: tissue-specific splice variants, gene structure, and sequence similarities to molybdenum cofactor-synthesizing and cytoskeleton-associated proteins. Ramming, M., Kins, S., Werner, N., Hermann, A., Betz, H., Kirsch, J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. Reiss, J., Dorche, C., Stallmeyer, B., Mendel, R.R., Cohen, N., Zabot, M.T. Am. J. Hum. Genet. (1999) [Pubmed]
  7. The crystal structure of Escherichia coli MoeA and its relationship to the multifunctional protein gephyrin. Xiang, S., Nichols, J., Rajagopalan, K.V., Schindelin, H. Structure (Camb.) (2001) [Pubmed]
  8. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Reiss, J., Johnson, J.L. Hum. Mutat. (2003) [Pubmed]
  9. The two subunits of human molybdopterin synthase: evidence for a bicistronic messenger RNA with overlapping reading frames. Sloan, J., Kinghorn, J.R., Unkles, S.E. Nucleic Acids Res. (1999) [Pubmed]
  10. The human gephyrin (GPHN) gene: structure, chromosome localization and expression in non-neuronal cells. David-Watine, B. Gene (2001) [Pubmed]
  11. The 1.2 A structure of the human sulfite oxidase cytochrome b(5) domain. Rudolph, M.J., Johnson, J.L., Rajagopalan, K.V., Kisker, C. Acta Crystallogr. D Biol. Crystallogr. (2003) [Pubmed]
  12. Crystal structure of the gephyrin-related molybdenum cofactor biosynthesis protein MogA from Escherichia coli. Liu, M.T., Wuebbens, M.M., Rajagopalan, K.V., Schindelin, H. J. Biol. Chem. (2000) [Pubmed]
  13. Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase. Leimkühler, S., Charcosset, M., Latour, P., Dorche, C., Kleppe, S., Scaglia, F., Szymczak, I., Schupp, P., Hahnewald, R., Reiss, J. Hum. Genet. (2005) [Pubmed]
  14. Functionality of alternative splice forms of the first enzymes involved in human molybdenum cofactor biosynthesis. Hänzelmann, P., Schwarz, G., Mendel, R.R. J. Biol. Chem. (2002) [Pubmed]
  15. In vitro incorporation of nascent molybdenum cofactor into human sulfite oxidase. Leimkühler, S., Rajagopalan, K.V. J. Biol. Chem. (2001) [Pubmed]
  16. The pathogenesis of molybdenum cofactor deficiency, its delay by maternal clearance, and its expression pattern in microarray analysis. Reiss, J., Bonin, M., Schwegler, H., Sass, J.O., Garattini, E., Wagner, S., Lee, H.J., Engel, W., Riess, O., Schwarz, G. Mol. Genet. Metab. (2005) [Pubmed]
  17. Molybdenum cofactor biosynthesis in humans: identification of a persulfide group in the rhodanese-like domain of MOCS3 by mass spectrometry. Matthies, A., Nimtz, M., Leimkühler, S. Biochemistry (2005) [Pubmed]
  18. A novel MOCS2 mutation reveals coordinated expression of the small and large subunit of molybdopterin synthase. Hahnewald, R., Leimk??hler, S., Vilaseca, A., Acquaviva-Bourdain, C., Lenz, U., Reiss, J. Mol. Genet. Metab. (2006) [Pubmed]
  19. Computer-controlled 22-channel stimulator for limb movement. Davis, R., Eckhouse, R., Patrick, J.F., Delehanty, A. Acta neurochirurgica. Supplementum. (1987) [Pubmed]
  20. Enhancing the value of scaling and root-planing: Arestin clinical trial results. Van Dyke, T.E., Offenbacher, S., Braswell, L., Lessem, J. Journal of the International Academy of Periodontology. (2002) [Pubmed]
 
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