文章基本信息

标题：Influence of N-Terminal Peptide and Oligosaccharide on the Clearance of t-PA
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作者：Shoichi AOKI ; Norihide SHIMIZU ; Jun-ichi KOYAMA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2000
卷号：23
期号：4
页码：477-481
DOI：10.1248/bpb.23.477
出版社：The Pharmaceutical Society of Japan
摘要：We have studied the influence of Gly-Ala-Arg peptide at the N-terminus and the oligosaccharide at Asn184 on the clearance of tissue plasminogen activator (t-PA). In order to intensify the influence of these structural features, Gln117 t-PA, which is a mutant tissue plasminogen activator (mt-PA) expressed in mouse C127 cells, was used for the investigation. It is altered to remove a high mannose type oligosaccharide by the mutation of an amino acid from Asn117 to Gln. We isolated 4 variants of Gln117 t-PA by cation-exchange chromatography, which are abbreviated as S-I, S-II, L-I and L-II. These variants originated from the heterogeneity of the peptide chains (S-chain, 527 amino acids, L-chain, 530 amino acids) and oligosaccharide (Type I, 2 oligosaccharides, Type II, 1 oligosaccharide). Pharmacolinetics of these variants were investigated after single intravenous administration to male rats at a dose of 250 μg/kg. Significant difference in pharmacokinetic parameters were observed among these variants, but there was no considerable difference in fibrin clot lysis time (FCLT) activity. Gly-Ala-Arg peptide at the N-terminus increased the CL_t, whereas the oligosaccharide at Asn184 decreased the CL_t. Moreover, the effects of the N-terminal peptide and the oligosaccharide on the CL_t were independent of each other. Our study with Gln117 t-PA revealed the role of the N-terminal peptide found in the L-chain produced during the processing of t-PA precursor.
关键词：tissue plasminogen activator;Gln117 t-PA;variant;L-chain;S-chain