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Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli

  • 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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Document Type:Article
Author:Günter Schwarz, José Angel Santamaria-Araujo, Stefan Wolf, Heon-Jin Lee, Ibrahim M. Adham, Hermann-Josef Gröne, Herbert Schwegler, Jörn Oliver Sass, Tanja Otte, Petra Hänzelmann, Ralf R. Mendel, Wolfgang Engel, Jochen Reiss
Parent Title (English):Hum Mol Genet. (Human Molecular Genetics)
First Page:1249
Last Page:1255
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=15115759
Publisher:Oxford University Press
Publication year:2004
Departments, institutes and facilities:Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2018/08/18