Amino acid dependent formaldehyde metabolism in mammals.
Amino acid dependent formaldehyde metabolism in mammals.
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DOI：
10.1038/s42004-020-0324-z
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发表时间：
2020-06-16
影响因子：
5.9
通讯作者：
Vazquez, Alexei
中科院分区：
文献类型：
--
作者：
Pietzke, Matthias;Burgos-Barragan, Guillermo;Wit, Niek;Tait-Mulder, Jacqueline;Sumpton, David;Mackay, Gillian M.;Patel, Ketan J.;Vazquez, Alexei
醛脱氢酶3类，由人类中的ADH 5编码，催化甲醛的谷胱甘肽依赖性解毒。在这里，我们表明，ADH 5缺陷细胞使用替代途径从甲醛与游离氨基酸的反应开始转化甲醛。当哺乳动物细胞暴露于甲醛时，甲醛与氨基酸半胱氨酸和组氨酸的反应产物（timonacic和spinacine）的水平增加。这些反应自发地发生，并且timonacic的形成是可逆的。Adh 5 −/−小鼠血浆中的替莫那酸水平高于对照组，并且在给予甲醇后进一步增加。我们的结论是，哺乳动物具有半胱氨酸和组氨酸依赖的甲醛代谢途径，并认为替莫那酸是一个甲醛水库。已知甲醛与溶液中的亲核氨基酸反应，但其在体内的非酶反应性知之甚少。在这里，LC/MS和同位素标记研究表明，非酶促甲醛代谢可能发生在活的小鼠中，通过甲醛与氨基酸的直接反应性，包括可能的作用，甲醛和半胱氨酸的产物，作为一个水库。
Aldehyde dehydrogenase class 3, encoded by ADH5 in humans, catalyzes the glutathione dependent detoxification of formaldehyde. Here we show that ADH5 deficient cells turn over formaldehyde using alternative pathways starting from the reaction of formaldehyde with free amino acids. When mammalian cells are exposed to formaldehyde, the levels of the reaction products of formaldehyde with the amino acids cysteine and histidine - timonacic and spinacine - are increased. These reactions take place spontaneously and the formation of timonacic is reversible. The levels of timonacic are higher in the plasma of Adh5−/− mice relative to controls and they are further increased upon administration of methanol. We conclude that mammals possess pathways of cysteine and histidine dependent formaldehyde metabolism and that timonacic is a formaldehyde reservoir. Formaldehyde is known to react with nucleophilic amino acids in solution but its in vivo nonenzymatic reactivity is poorly understood. Here LC/MS and isotopic labeling studies suggest nonenzymatic formaldehyde metabolism may occur in living mice through the direct reactivity of formaldehyde with amino acids, including a possible role of timonacic, a product of formaldehyde and cysteine, as a reservoir.
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