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首页> 外文期刊>Comparative and functional genomics >Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice
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Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice

机译：同型半胱氨酸代谢基因的突变增加小鼠角蛋白N-同型半胱氨酸化和损伤。

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Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism increase Hcy-thiolactone, which causes protein damage by forming isopetide bonds with lysine residues, generating N-Hcy-protein. In the present work, we studied the prevalence and genetic determinants of keratin damage caused by homocysteinylation. We found that in mammals and birds, 35 to 98% of Hcy was bound to hair keratin via amide or isopeptide bond (Hcy-keratin), while 2 to 65% was S-Hcy-keratin. A major fraction of hair Hcy-keratin (56% to 93%), significantly higher in birds than in mammals, was sodium dodecyl sulfate-insoluble. Genetic hyperhomocysteinemia significantly increased N-Hcy-keratin levels in the mouse pelage. N-Hcy-keratin was elevated 3.5-, 6.3-, and 11.7-fold in hair from Mthfr−/−, Cse−/−, or Cbs−/− mice, respectively. The accumulation of N-Hcy in hair keratin led to a progressive reduction of N-Hcy-keratin solubility in sodium dodecyl sulfate, from 0.39 ± 0.04 in wild-type mice to 0.19 ± 0.03, 0.14 ± 0.01, and 0.07 ± 0.03 in Mthfr−/−, Cse−/−, or Cbs−/−animals, respectively. N-Hcy-keratin accelerated aggregation of unmodified keratin in Cbs−/− mouse hair. Keratin methionine, copper, and iron levels in mouse hair were not affected by hyperhomocysteinemia. These findings provide evidence that pelage keratin is N-homocysteinylated in vivo in mammals and birds, and that this process causes keratin damage, manifested by a reduced solubility.
机译：同型半胱氨酸（Hcy）代谢的遗传或营养缺陷会增加Hcy-硫代内酯，这会通过与赖氨酸残基形成异戊二烯键而导致蛋白质损坏，从而生成N-Hcy-蛋白质。在目前的工作中，我们研究了由同型半胱氨酸化引起的角蛋白损害的发生率和遗传决定因素。我们发现，在哺乳动物和鸟类中，Hcy的35％至98％通过酰胺或异肽键（Hcy-keratin）与毛发角蛋白结合，而S-Hcy-角蛋白则占2％至65％。十二烷基硫酸钠不溶性是头发中Hcy-角蛋白的主要部分（56％至93％），在鸟类中明显高于哺乳动物。遗传性高同型半胱氨酸血症显着增加了小鼠体内的N-Hcy-角蛋白水平。从Mthfr-/-，Cse-/-或Cbs-/-小鼠的头发中，N-Hcy-角蛋白分别升高了3.5-，6.3-和11.7倍。 N-Hcy在毛发角蛋白中的积累导致N-Hcy-角蛋白在十二烷基硫酸钠中的溶解度逐渐降低，从野生型小鼠的0.39±0.04降至Mthfr的0.19±0.03、0.14±0.01和0.07±0.03 -/-，Cse-/-或Cbs-/-动物。 N-Hcy-角蛋白可加速Cbs-/-小鼠毛发中未修饰角蛋白的聚集。高同型半胱氨酸血症不影响小鼠头发中的角蛋白蛋氨酸，铜和铁水平。这些发现提供了证据，在哺乳动物和鸟类体内，分离的角蛋白在体内是N-同型半胱氨酸化的，并且该过程引起角蛋白损害，表现为溶解度降低。

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