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.
Schwarz
Günter
G
Institut für Pflanzenbiologie der Technischen Universität Braunschweig, Germany.
Santamaria-Araujo
José Angel
JA
Wolf
Stefan
S
Lee
Heon-Jin
HJ
Adham
Ibrahim M
IM
Gröne
Hermann-Josef
HJ
Schwegler
Herbert
H
Sass
Jörn Oliver
JO
Otte
Tanja
T
Hänzelmann
Petra
P
Mendel
Ralf R
RR
Engel
Wolfgang
W
Reiss
Jochen
J
D000818:Animals; D003067:Coenzymes / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003677:Deficiency Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000302:isolation & purification / Q000627:therapeutic use*; D008667:Metalloproteins / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D000090006:Molybdenum Cofactors; D011498:Protein Precursors / Q000008:administration & dosage / Q000235:genetics / Q000302:isolation & purification / Q000627:therapeutic use*; D011621:Pteridines / Q000378:metabolism
D003067:Coenzymes; D029968:Escherichia coli Proteins; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D011498:Protein Precursors; D011621:Pteridines; C022261:molybdopterin