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Study of the functional share of lysosomal cathepsins by the development of specific inhibitors.

机译:通过开发特异性抑制剂来研究溶酶体组织蛋白酶的功能份额。

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To analyze the functional share of individual cathepsins, we developed powerful and specific inhibitors for individual cathepsins using computer graphics of substrate binding pockets based on X-ray crystallography. These new inhibitors were named CLIK group. Epoxy succinate peptide derivatives, CLIK-066, 088, 112, 121, 148, 181, 185 and 187, are typical specific inhibitors for cathepsin L. Aldehyde derivatives CLIK-060 and CLIK-164 showed specific inhibition against cathepsin S and cathepsin K, respectively. We found that pyridoxal phosphate (PLP), a coenzyme form of vitamin B6, inhibits all cathepsins and also new artificially synthesized pyridoxal derivatives, CLIK-071 and -072, in which the phosphate esters of PLP were replaced by propionic acid, exhibited strong inhibition for cathepsins. Furthermore, CLIK-071 was easy to incorporate into cells and showed powerful inhibition for intracellular cathepsins. Using these selective inhibitors, the allotment of individual cathepsin functions in cells has been studied as follows. Cathepsin L and/or K participate in bone resorption based on bone type-1 collagen degradation and the L-type protease inhibitors suppressed the bone resorption. Cathepsins B and S participate in antigen presentations based on antigen processing and invariant chain degradation, respectively. Also cathepsin L participates in cell apoptosis mediated by caspase III activation.
机译:为了分析单个组织蛋白酶的功能份额,我们使用了基于X射线晶体学的底物结合口袋的计算机图形学,为单个组织蛋白酶开发了功能强大且特异性的抑制剂。这些新的抑制剂被命名为CLIK组。环氧琥珀酸酯肽衍生物CLIK-066、088、112、121、121、148、181、185和187是组织蛋白酶L的典型特异性抑制剂。醛衍生物CLIK-060和CLIK-164显示出对组织蛋白酶S和组织蛋白酶K的特异性抑制,分别。我们发现吡pyr醛磷酸盐(PLP)是维生素B6的一种辅酶形式,可抑制所有组织蛋白酶,而且新的人工合成吡ido醛衍生物CLIK-071和-072(其中PLP的磷酸酯被丙酸替代)表现出强烈的抑制作用。用于组织蛋白酶。此外,CLIK-071易于掺入细胞并显示出对细胞内组织蛋白酶的强大抑制作用。使用这些选择性抑制剂,已对细胞中各个组织蛋白酶功能的分配进行了如下研究。组织蛋白酶L和/或K基于骨1型胶原降解参与骨吸收,并且L型蛋白酶抑制剂抑制骨吸收。组织蛋白酶B和S分别基于抗原加工和不变链降解参与抗原呈递。组织蛋白酶L也参与由胱天蛋白酶III活化介导的细胞凋亡。

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