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Human Molecular Genetics Advance Access published online on April 28, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh136
© 2004 by Oxford University Press
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Article

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

Günter Schwarz 1, José Angel Santamaria-Araujo 1, Stefan Wolf 2, Heon-Jin Lee 2, Ibrahim M. Adham 2, Hermann-Josef Gröne 3, Herbert Schwegler 4, Jörn Oliver Sass 5, Tanja Otte 1, Petra Hänzelmann 1, Ralf R. Mendel 1, Wolfgang Engel 2, Jochen Reiss 6*

1 Institut für Pflanzenbiologie der Technischen Universität Braunschweig, Germany
2 Institut für Humangenetik der Universitätskliniken Göttingen, Germany
3 Abteilung Zelluläre und Molekulare Pathologie, Deutsches Krebsforschungszentrum Heidelberg, Germany
4 Institut für Anatomie, Universität Magdeburg, Germany
5 Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Freiburg, Germany
6 Institut für Humangenetik der Universität Göttingen, Heinrich-Düker-Weg 12, D-37073 Göttingen, Germany

* To whom correspondence should be addressed. E-mail: jreiss{at}gwdg.de.


  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.


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