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首页> 外文期刊>Biochemistry >Arginine Residues Are More Effective than Lysine Residues in Eliciting the Cellular Uptake of Onconase
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Arginine Residues Are More Effective than Lysine Residues in Eliciting the Cellular Uptake of Onconase

机译：精氨酸残基比赖氨酸残基更有效地提高细胞对Onconase的吸收

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摘要

Onconase is an amphibian member of the pancreatic ribonuclease family of enzymes that is in clinical trials for the treatment of cancer. Onconase, which has an abundance of lysine residues, is internalized by cancer cells through endocytosis in a mechanism similar to that of cell-penetrating peptides. Here, we compare the effect of lysine versus arginine residues on the biochemical attributes necessary for Onconase to elicit its cytotoxic activity. In the variant R-Onconase, 10 of the 12 lysine residues in Onconase are replaced with arginine, leaving only the two active-site lysines intact. Cytometric assays quantifying internalization showed a 3-fold increase in the internalization of R-Onconase compared with Onconase. R-Onconase also showed greater affinity for heparin and a 2-fold increase in ribonucleolytic activity. Nonetheless, arginine substitution endowed only a slight increase in toxicity toward human cancer cells. Analysis of denaturation induced with guanidine-HCl showed that R-Onconase has less conformational stability than does the wild-type enzyme; moreover, R-Onconase is more susceptible to proteolytic degradation. These data indicate that arginine residues are more effective than lysine in eliciting cellular internalization but can compromise other aspects of protein structure and function.
机译：Onconase是胰核糖核酸酶家族的两栖动物，目前正在临床试验中用于治疗癌症。具有丰富赖氨酸残基的Onconase通过内吞作用被癌细胞内化，其作用机理与细胞穿透肽相似。在这里，我们比较赖氨酸和精氨酸残基对Onconase引发其细胞毒性活性所必需的生化属性的影响。在变体R-Onconase中，Onconase中12个赖氨酸残基中的10个被精氨酸取代，仅保留了两个活性位点赖氨酸。定量内化作用的细胞分析表明，与Onconase相比，R-Onconase的内化作用增加了3倍。 R-Onconase还显示出对肝素的更大亲和力，核糖核酸分解活性提高了2倍。然而，精氨酸取代仅使对人类癌细胞的毒性略有增加。胍盐酸盐诱导的变性分析表明，R-Onconase的构象稳定性低于野生型酶。此外，R-Onconase更容易发生蛋白水解降解。这些数据表明精氨酸残基在引起细胞内在化方面比赖氨酸更有效，但是会损害蛋白质结构和功能的其他方面。

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