Shortened insulin analogues: marked changes in biological activity resulting from replacement of TyrB26 and N-methylation of peptide bonds in the C-terminus of the B-chain.
Shortened insulin analogues: marked changes in biological activity resulting from replacement of TyrB26 and N-methylation of peptide bonds in the C-terminus of the B-chain.
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缩短的胰岛素类似物：由于 TyrB26 的替换和 B 链 C 末端肽键的 N-甲基化而导致生物活性显着变化。
DOI：
10.1021/bi036001w
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发表时间：
2004
期刊：
影响因子：
2.9
通讯作者：
Š. Zórad
中科院分区：
文献类型：
--
作者：
L. Žáková;T. Barth;J. Jiráček;J. Barthová;Š. Zórad
研究了三个高度保守的胰岛素残基PheB24、PheB25和TyrB26的作用，以更好地了解胰岛素及其受体之间结构-功能关系的微妙之处。通过胰蛋白酶催化去-八肽(B23-B30)-胰岛素与合成肽的偶联，合成了10个b链β链修饰的缩短胰岛素类似物。胰岛素类似物在B26位置有单个氨基酸取代和/或在不同位置的肽键有单个n -甲基化，都在b链的c端缩短了4个氨基酸。随后进行了两种类型的体外实验，即与大鼠脂肪质膜受体的结合和刺激葡萄糖转运到分离的大鼠脂肪细胞。从我们的研究结果可以得出以下结论：(1)苯基丙氨酸取代酪氨酸对缩短的类似物的结合亲和力和刺激葡萄糖转运没有显著影响，而组氨酸取代TyrB26对效价有高度积极的影响；[NMeHisB26]-des-tetrapeptide (B27-B30)-insulin-B26-amide和[NMeHisB26]-des-tetrapeptide (B27-B30)-insulin-B26-amide的结合亲和力分别为人胰岛素的529%和5250%；（ii）在体外研究中，无论B26位置是否存在氨基酸，B24-B25肽键的n -甲基化都会对类似物的效力产生破坏性影响；（iii） B23-B24肽键的n-甲基化显著降低了各自类似物[NMePheB24]-des-tetrapeptide (B27-B30)-insulin-B26-amide的结合亲和力和葡萄糖转运。
The role of three highly conserved insulin residues PheB24, PheB25, and TyrB26 was studied to better understand the subtleties of the structure-function relationship between insulin and its receptor. Ten shortened insulin analogues with modifications in the beta-strand of the B-chain were synthesized by trypsin-catalyzed coupling of des-octapeptide (B23-B30)-insulin with synthetic peptides. Insulin analogues with a single amino acid substitution in the position B26 and/or single N-methylation of the peptide bond at various positions were all shortened in the C-terminus of the B-chain by four amino acids. The effect of modifications was followed by two types of in vitro assays, i.e., by the binding to the receptor of rat adipose plasma membranes and by the stimulation of the glucose transport into the isolated rat adipocytes. From our results, we can deduce several conclusions: (i) the replacement of tyrosine in the position B26 by phenylalanine has no significant effect on the binding affinity and the stimulation of the glucose transport of shortened analogues, whereas the replacement of TyrB26 by histidine affects the potency highly positively; [HisB26]-des-tetrapeptide (B27-B30)-insulin-B26-amide and [NMeHisB26]-des-tetrapeptide (B27-B30)-insulin-B26-amide show binding affinity 529 and 5250%, respectively, of that of human insulin; (ii) N-methylation of the B24-B25 peptide bond exhibits a disruptive effect on the potency of analogues in both in vitro studies regardless the presence of amino acid in the position B26; (iii) N-methylation of the B23-B24 peptide bond markedly reduces the binding affinity and the glucose transport of respective analogue [NMePheB24]-des-tetrapeptide (B27-B30)-insulin-B26-amide.
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DOI：
10.1016/s0021-9258(18)52312-7
发表时间：
1991-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
R. Mirmira;S. Nakagawa;H. Tager
通讯作者：
R. Mirmira;S. Nakagawa;H. Tager
DOI：
10.1016/s0021-9258(17)38396-5
发表时间：
1986-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
S. Nakagawa;H. Tager
通讯作者：
S. Nakagawa;H. Tager
影响因子：
2.9
作者：
M. Weiss;S. Nakagawa;W. Jia;Bin Xu;Q. Hua;Y. Chu;Run-ying Wang;P. Katsoyannis
通讯作者：
M. Weiss;S. Nakagawa;W. Jia;Bin Xu;Q. Hua;Y. Chu;Run-ying Wang;P. Katsoyannis
DOI：
10.1073/pnas.80.24.7390
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
SHOELSON, S;FICKOVA, M;TAGER, H
通讯作者：
TAGER, H
高效胰岛素：des-(B26-B30)-[AspB10,TyrB25-NH2]胰岛素（人）。
DOI：
10.1073/pnas.86.2.458
发表时间：
1989
影响因子：
11.1
作者：
Schwartz,GP;Burke,GT;Katsoyannis,PG
通讯作者：
Katsoyannis,PG