molybdenum-cofactor and Deficiency-Diseases

Molybdenum cofactor (MoCo) deficiency leads to a combined deficiency of the molybdoenzymes sulphite oxidase, xanthine dehydrogenase and aldehyde oxidase. Effective therapy is not available for this rare disease, which results in neonatal seizures and other neurological symptoms identical to those of sulphite oxidase deficiency. It is an autosomal recessive trait and leads to early childhood death. Biosynthesis of MoCo can be divided into the formation of a precursor and its subsequent conversion to the organic moiety of MoCo by molybdopterin synthase. These two steps are the molecular basis of the two observed complementation groups A and B and of two types of MoCo deficiency with an identical phenotype. MOCS1 is defective in the majority of patients (group A) and was shown to encode two enzymes functioning in the formation of a precursor. The corresponding transcript is bicistronic with two consecutive open reading frames (ORFs). MOCS2 encodes the small and large subunits of molybdopterin synthase via a single transcript with two overlapping reading frames. This gene carries lesions in the B complementation group less frequently observed in patients. Both genes, MOCS1 and MOCS2, share the unusual bicistronic architecture, have identical and very low expression profiles and extremely conserved C-terminal ends in their 5'-ORF. These observations point to a novel form of microcompartmentalization and render the MOCS genes ideal candidates for a somatic gene therapy approach.

Topics: Carbon-Carbon Lyases; Carrier Proteins; Coenzymes; Deficiency Diseases; Genetic Complementation Test; Genetic Therapy; Humans; Membrane Proteins; Metalloproteins; Molecular Sequence Data; Molybdenum; Molybdenum Cofactors; Nuclear Proteins; Pteridines; Sulfurtransferases

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.

Topics: Animals; Coenzymes; Deficiency Diseases; Enzyme Activation; Escherichia coli Proteins; Metalloproteins; Mice; Mice, Knockout; Models, Animal; Molybdenum Cofactors; Protein Precursors; Pteridines