N-联糖基化可防止糖肽和糖蛋白脱酰胺,ACS Chemical Biology

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N-联糖基化可防止糖肽和糖蛋白脱酰胺
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-12-03 , DOI: 10.1021/acschembio.0c00734
Hailiang Joshua Zhu ₁ , Ding Liu ₁ , Vy P Tran ₂ , Zhigang Wu ₁ , Kuan Jiang ₁ , He Zhu ₁ , Jiabin Zhang ₁ , Christopher Gibbons ₁ , Bingzhong Xue ₂ , Hang Shi ₂ , Peng George Wang ₁

Affiliation

脱酰胺已被认为是蛋白质降解的常见自发途径，也是制药行业普遍关注的问题。脱酰胺作用在某些情况下导致蛋白质/多肽药物功效和保质期降低。更重要的是，生理蛋白的脱酰胺作用与几种人类疾病有关，被认为是疾病的“计时器”。N-联糖基化具有多种重要的生物学功能，有趣的是，它直接发生在脱酰胺位-天冬酰胺上。已经认识到N-糖基化可以防止脱酰胺作用，但是仍然缺乏实验支持以清楚地理解N-糖基化在脱酰胺作用上的作用。我们的结果表明，自然发生的N-联糖基化可以防止脱酰胺作用。使用糖肽和相应的非糖基化肽比较它们的脱酰胺率。对于相应的糖基化肽，所有非糖基化肽的半衰期都不同，为1至20天。所有结果表明，引入N-联糖基化显着减少了脱酰胺反应。与非糖基化蛋白RNase A相比，糖蛋白RNase B也显示出显着延长的脱酰胺半衰期。最后，治疗性肽INGAP-P上的N联糖基化也增加了INGAP-P的脱酰胺半衰期。作为其治疗功效。所有结果表明，引入N-联糖基化显着减少了脱酰胺反应。与非糖基化蛋白RNase A相比，糖蛋白RNase B也显示出显着延长的脱酰胺半衰期。最后，治疗性肽INGAP-P上的N联糖基化也增加了INGAP-P的脱酰胺半衰期。作为其治疗功效。所有结果表明，引入N-联糖基化显着减少了脱酰胺反应。与非糖基化蛋白RNase A相比，糖蛋白RNase B也显示出显着延长的脱酰胺半衰期。最后，治疗性肽INGAP-P上的N联糖基化也增加了INGAP-P的脱酰胺半衰期。作为其治疗功效。

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N-Linked Glycosylation Prevents Deamidation of Glycopeptide and Glycoprotein

Deamidation has been recognized as a common spontaneous pathway of protein degradation and a prevalent concern in the pharmaceutical industry; deamidation caused the reduction of protein/peptide drug efficacy and shelf life in several cases. More importantly, deamidation of physiological proteins is related to several human diseases and considered a “timer” for the diseases. N-linked glycosylation has a variety of significant biological functions, and it interestingly occurs right on the deamidation site—asparagine. It has been perceived that N-glycosylation could prevent deamidation, but experimental support is still lacking for clearly understanding the role of N-glycosylation on deamidation. Our results presented that deamidation is prevented by naturally occurring N-linked glycosylation. Glycopeptides and corresponding nonglycosylated peptides were used to compare their deamidation rates. All the nonglycosylated peptides have different half-lives ranging from one to 20 days, for the corresponding glycosylated peptides; all the results showed that the deamidation reaction was significantly reduced by the introduction of N-linked glycosylation. A glycoprotein, RNase B, also showed a significantly elongated deamidation half-life compared to nonglycosylated protein RNase A. At last, N-linked glycosylation on INGAP-P, a therapeutic peptide, increased the deamidation half-life of INGAP-P as well as its therapeutic potency.

更新日期：2020-12-18

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