@article{SchwarzSantamariaAraujoWolfetal.2004, author = {G{\"u}nter Schwarz and Jos{\´e} Angel Santamaria-Araujo and Stefan Wolf and Heon-Jin Lee and Ibrahim M. Adham and Hermann-Josef Gr{\"o}ne and Herbert Schwegler and J{\"o}rn Oliver Sass and Tanja Otte and Petra H{\"a}nzelmann and Ralf R. Mendel and Wolfgang Engel and Jochen Reiss}, title = {Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli}, series = {Hum Mol Genet. (Human Molecular Genetics)}, volume = {13}, number = {12}, publisher = {Oxford University Press}, issn = {0964-6906}, doi = {10.1093/hmg/ddh136}, pages = {1249 -- 1255}, year = {2004}, 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.}, language = {en} }