Journal Article

Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from <i>Escherichia coli</i>

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 and Jochen Reiss

in Human Molecular Genetics

Volume 13, issue 12, pages 1249-1255
Published in print June 2004 | ISSN: 0964-6906
Published online April 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh136
Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli

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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.

Journal Article.  5166 words.  Illustrated.

Subjects: Genetics and Genomics

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