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Nature Medicine

November 14, 2011

Treatments that raise nitric oxide levels could be useful for treating a congenital metabolic disease, argininosuccinic aciduria (ASA), reports a study published online this week in Nature Medicine.

The enzyme that is defective in individuals with ASA, argininosuccinate lyase (ASL), generates the amino acid arginine, which is then used to make both nitric oxide, which regulates vascular function, and urea, which is used to dispose of waste nitrogen in the liver. Surprisingly, administration of the product of the defective enzyme, arginine, is not fully effective in treating individuals with ASA.

Based on studies in both a newly-generated mouse model of ASA and individuals with ASA, Brendan Lee and his colleagues found that the answer to this paradox is that ASL has an additional and unexpected role in making nitric oxide: it acts as a structural component of a multiprotein complex that converts arginine to nitric oxide. Because of ASL’s structural role, cells lacking the enzyme can’t make nitric oxide even if they are given arginine. To begin to translate these mechanistic studies into a therapy for ASA, the researchers showed that treatment of the ASA mouse model with an agent that raises nitric oxide levels, sodium nitrite, had beneficial effects on growth and survival.

DOI:10.1038/nm.2544 | Original article

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