title: Molybdenum cofactor biosynthesis in humans. Identification of two complementation groups of cofactor-deficient patients and preliminary characterization of a diffusible molybdopterin precursor.
abstract: Molybdenum cofactor deficiency is a devastating disease with affected patients displaying the symptoms of a combined deficiency of sulfite oxidase and xanthine dehydrogenase. Because of the extreme lability of the isolated, functional molybdenum cofactor, direct cofactor replacement therapy is not feasible, and a search for stable biosynthetic intermediates was undertaken. From studies of cocultured fibroblasts from affected individuals, two complementation groups were identified. Coculture of group A and group B cells, without heterokaryon formation, led to the appearance of active sulfite oxidase. Use of conditioned media indicated that a relatively stable, diffusible precursor produced by group B cells could be used to repair sulfite oxidase in group A recipient cells. Although the extremely low levels of precursor produced by group B cells preclude its direct characterization, studies with a heterologous, in vitro reconstitution system suggest that the precursor that accumulates in group B cells is the same as a molybdopterin precursor identified in the Neurospora crassa molybdopterin mutant nit-1, and that a converting enzyme is present in group A cells which catalyzes an activation reaction analogous to that of a converting enzyme identified in the Escherichia coli molybdopterin mutant ChlA1.
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: J L
authors.initials: JL
authors.lastname: Johnson
authors.forename: M M
authors.initials: MM
authors.lastname: Wuebbens
authors.forename: R
authors.initials: R
authors.lastname: Mandell
authors.forename: V E
authors.initials: VE
authors.lastname: Shih
mesh_terms: D002478:Cells, Cultured; D003067:Coenzymes; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008667:Metalloproteins / Q000096:biosynthesis / Q000172:deficiency* / Q000652:urine; D008970:Molecular Weight; D008982:Molybdenum; D000090006:Molybdenum Cofactors; D009154:Mutation; D009492:Neurospora crassa / Q000235:genetics / Q000378:metabolism; D050901:Nitrate Reductase; D009565:Nitrate Reductases / Q000378:metabolism; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000172:deficiency / Q000378:metabolism; D011498:Protein Precursors / Q000096:biosynthesis / Q000652:urine; D011621:Pteridines / Q000096:biosynthesis / Q000172:deficiency* / Q000652:urine
chemical_list: D003067:Coenzymes; D008667:Metalloproteins; D008982:Molybdenum; D000090006:Molybdenum Cofactors; D050901:Nitrate Reductase; D009565:Nitrate Reductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; D011498:Protein Precursors; D011621:Pteridines; C022261:molybdopterin