title: Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli.
abstract: Substitution therapies for orphan genetic diseases, including enzyme replacement methods, are frequently hampered by the limited availability of the required therapeutic substance. We describe the isolation of a pterin intermediate from bacteria that was successfully used for the therapy of a hitherto incurable and lethal disease. Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder characterized by the loss of the molybdenum-dependent enzymes sulphite oxidase, xanthine oxidoreductase and aldehyde oxidase due to mutations in Moco biosynthesis genes. An intermediate of this pathway-'precursor Z'-is more stable than the cofactor itself and has an identical structure in all phyla. Thus, it was overproduced in the bacterium Escherichia coli, purified and used to inject precursor Z-deficient knockout mice that display a phenotype which resembles that of the human deficiency state. Precursor Z-substituted mice reach adulthood and fertility. Biochemical analyses further suggest that the described treatment can lead to the alleviation of most symptoms associated with human Moco deficiency.
authors.affiliation: Institut für Pflanzenbiologie der Technischen Universität Braunschweig, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schwarz
authors.forename: José Angel
authors.initials: JA
authors.lastname: Santamaria-Araujo
authors.forename: Stefan
authors.initials: S
authors.lastname: Wolf
authors.forename: Heon-Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Adham
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Herbert
authors.initials: H
authors.lastname: Schwegler
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
authors.forename: Tanja
authors.initials: T
authors.lastname: Otte
authors.forename: Petra
authors.initials: P
authors.lastname: Hänzelmann
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Mendel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Engel
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiss
mesh_terms: D000818:Animals; D003067:Coenzymes / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003677:Deficiency Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000302:isolation & purification / Q000627:therapeutic use*; D008667:Metalloproteins / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D000090006:Molybdenum Cofactors; D011498:Protein Precursors / Q000008:administration & dosage / Q000235:genetics / Q000302:isolation & purification / Q000627:therapeutic use*; D011621:Pteridines / Q000378:metabolism
chemical_list: D003067:Coenzymes; D029968:Escherichia coli Proteins; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D011498:Protein Precursors; D011621:Pteridines; C022261:molybdopterin