亲环蛋白的亚型特异性抑制
Isoform-specific inhibition of cyclophilins.
作者信息
Daum Sebastian, Schumann Michael, Mathea Sebastian, Aumüller Tobias, Balsley Molly A, Constant Stephanie L, de Lacroix Boris Féaux, Kruska Fabian, Braun Manfred, Schiene-Fischer Cordelia
机构信息
Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, 06120 Halle/Saale, Germany.
出版信息
Biochemistry. 2009 Jul 7;48(26):6268-77. doi: 10.1021/bi9007287.
Cyclophilins belong to the enzyme class of peptidyl prolyl cis-trans isomerases which catalyze the cis-trans isomerization of prolyl bonds in peptides and proteins in different folding states. Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4(+) T cells by the inhibitor provided biological proof of discrimination in vivo.
亲环蛋白属于肽基脯氨酰顺反异构酶类，可催化处于不同折叠状态的肽和蛋白质中脯氨酰键的顺反异构化。亲环蛋白已被证明参与多种细胞功能，如细胞生长、增殖和运动。在20种人类亲环蛋白同工酶中，亲环蛋白家族中含量最丰富的两个成员，即亲环蛋白A（CypA）和亲环蛋白B（CypB），在几种炎症性疾病、癌症发展和丙型肝炎病毒（HCV）复制中表现出特定的细胞功能。现已证明，一种基于芳基1-茚满酮的小分子抑制剂在体外可区分CypA和CypB。该抑制剂与CypA的结合已通过基于荧光各向异性和等温滴定量热法的环孢菌素竞争试验进行了表征。该抑制剂对小鼠CD4(+) T细胞的CypA介导而非CypB介导的趋化作用的抑制为体内区分提供了生物学证据。
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