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

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.

Molybdenum cofactor biosynthesis and deficiency

“…Among all intermediates of the Moco synthetic pathway, cPMP has the highest stability at neutral pH values (t 1/2 = 1 h) due to its unique pyranopterin nature and the absence of the very reactive dithiolate sulfurs and Mo. Therefore, a method was established to produce and purify relatively large amounts of cPMP in E. coli in order to use cPMP for a substitution therapy of Moco defi ciency [152]. Repeated injections of cPMP into MOCS1-defi cient mice resulted in a dose-dependent extension of life span [152].…”

Sulfite-oxidizing enzymes

“…The inborn error is characterized by dislocation of ocular lenses, mental retardation, and in severe cases, attenuated growth of the brain [9]. These severe neurological symptoms result from either point mutations in the SO protein itself (so-called isolated SO deficiency, in which only SO activity is affected), or the inability to properly produce the pyranopterindithiolate cofactor, which results in deficiencies in all Mo-containing enzymes (so-called Mo cofactor deficiency) [10][11][12]. The development of methods to clone and express human SO has revealed several different clinical point mutations that result in isolated SO deficiency [13][14][15][16].…”

Molybdenum Cofactor Deficiency: Metabolic Link Between Taurine and S-Sulfocysteine

“…Using a knockout animal model for MoCD (Lee et al 2002 ) a substitution therapy with cyclic pyranopterin monophosphate has been established (Schwarz et al 2004 ) and recently a fi rst successful treatment for an MoCD (type A) patient has been reported (Veldman et al 2010 ) . Before treatment was initiated, a manifested rapid increase of urinary sul fi te, thiosulfate, and SSC values was recorded.…”