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Analyses of SGLT1 function and cooperative function of SGLT1 with disaccharidase

SGLT1功能及SGLT1与二糖酶协同作用的分析

基本信息

批准号：
12672160
负责人：
TAKASHI Mizuma
金额：
$ 2.24万
依托单位：
Tokyo University of Pharmacy and Life Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Functionai analysis of SGLT1-mediated transport of glucose conjugates was performed. Influence of aglycone moiety on SGLT1 function was evaluated in terms of binding (recognition) and translocation (transport). All of glucose conjugates studied in this project, except salicin, were classified to Class T (transportable compound). Turnover of SGLT1for transport did not depend on molecular size. Furthrmore, although the order of turnover rate of p-substituents of phenyl β-glucose was NH_2 > OH > NO_2, binding affinity (Km) were similar to each other. This indicated that the binding and translocation of SGLT1 were affected by substituents, but the influcences were different. Molecular modeling analysis showed that glucose conformation of glucosides were in 4^C_1 chair form, which is the same as previous results (p-nitrophyeny1 β-glucoside and acetaminophen β-glucoside). Therefore, the position of spare apace of SGLT1 affects SGLT1 function.Disaccharidase activities of disaccharide conjugate, maltase and LPH(lactase/phloridzin hydrolase) were found in Caco-2 cells. Furthermore, SGLT1 activity was detected in tri-iodothyronine-treated Caco-2 cells, although significant activity of SGLT1 was not detected i non-treated Caco-2 cells. This suggest that Caco-2 cells may be useful for the study of disaccharidase and SGLT1.

对SGLT 1介导的葡萄糖缀合物转运进行了功能分析。在结合（识别）和易位（转运）方面评价了糖苷配基部分对SGLT 1功能的影响。除水杨苷外，本项目研究的所有葡萄糖结合物均属于T类（可转运化合物）。SGLT 1转运周转率不依赖于分子大小。苯基β-葡萄糖的对位取代基转换速率顺序为NH_2 > OH > NO_2，但它们的结合亲和力（Km）相近。这表明SGLT 1的结合和转运受取代基的影响，但影响程度不同。分子模拟分析表明，葡萄糖的构象均为4^C_1椅式，与前人的结果（对硝基苯1 β-葡萄糖苷和对乙酰氨基酚β-葡萄糖苷）一致。在Caco-2细胞中发现了双糖缀合物、麦芽糖酶和LPH（乳糖酶/根皮苷水解酶）的二硫键脱氢酶活性。此外，在三碘甲状腺原氨酸处理的Caco-2细胞中检测到SGLT 1活性，但在未处理的Caco-2细胞中未检测到显著的SGLT 1活性。这表明Caco-2细胞可用于研究dissodidase和SGLT 1。