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- Title
Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli.
- Authors
Schwarz, Günter; Santamaria-Araujo, José Angel; Wolf, Stefan; Lee, Heon-Jin; Adham, Ibrahim M.; Gröne, Hermann-Josef; Schwegler, Herbert; Sass, Jörn Oliver; Otte, Tanja; Hänzelmann, Petra; Mendel, Ralf R.; Engel, Wolfgang; Reiss, Jochen
- 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.
- Publication
Human Molecular Genetics, 2004, Vol 13, Issue 12, p1249
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddh136