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Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli (2004)
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
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.
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