Research press release


Nature Medicine

Take NO for an answer



新しく作成されたASAのマウスモデルを使った実験とASA患者での研究に基づいてB Leeたちは、この矛盾の原因は、ASLが一酸化窒素の生成に別の意外な役割を担っているからであることを発見した。ASLは、アルギニンを一酸化窒素に変換する多タンパク質複合体の構造成分としても働くのである。この構造上の役割のゆえに、ASLをもたない細胞は、アルギニンがあっても一酸化窒素をつくれない。この機構研究の結果をASAの治療に活かそうと、LeeたちはASAのマウスモデルに一酸化窒素レベルを上昇させる作用がある亜硝酸ナトリウムを投与し、これが成長や生存に有益な作用を示すことを明らかにした。

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


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