Tropschug M, Barthelmess I B, Neupert W
Institut für Physiologische Chemie, Universität München, FRG.
Nature. 1989;342(6252):953-5. doi: 10.1038/342953a0.
Cyclosporin A, a cyclic fungal undecapeptide produced by Tolypocladium inflatum, is a potent immunosuppressive drug originally isolated as an antifungal antibiotic. Cyclosporin A (CsA) is widely used in humans to prevent rejection of transplanted organs such as kidney, heart, bone marrow and liver. The biochemical basis of CsA action is not known: its primary cellular target has been suggested to be calmodulin, the prolactin receptor or cyclophilin, a CsA-binding protein originally isolated from the cytosol of bovine thymocytes. Cyclophilin has been shown to be a highly conserved protein present in all eukaryotic cells tested and to be identical to peptidyl-prolyl cis-trans isomerase, a novel type of enzyme that accelerates the slow refolding phase of certain proteins in vitro. We demonstrate that in the lower eukaryotes N. crassa and S. cerevisiae, cyclo philin mediates the cytotoxic CsA effect. In CsA-resistant mutants of both organisms, the cyclophilin protein is either lost completely or, if present, has lost its ability to bind CsA.
环孢素A是由Inflatum头孢霉产生的一种环状真菌十一肽，是一种强效免疫抑制药物，最初作为抗真菌抗生素分离出来。环孢素A（CsA）在人类中广泛用于预防移植器官（如肾脏、心脏、骨髓和肝脏）的排斥反应。CsA作用的生化基础尚不清楚：其主要细胞靶点被认为是钙调蛋白、催乳素受体或亲环蛋白，亲环蛋白是一种最初从牛胸腺细胞胞质溶胶中分离出来的CsA结合蛋白。亲环蛋白已被证明是一种在所有测试的真核细胞中都存在的高度保守的蛋白质，并且与肽基脯氨酰顺反异构酶相同，肽基脯氨酰顺反异构酶是一种新型酶，在体外可加速某些蛋白质的缓慢重折叠阶段。我们证明，在低等真核生物粗糙脉孢菌和酿酒酵母中，亲环蛋白介导了CsA的细胞毒性作用。在这两种生物的CsA抗性突变体中，亲环蛋白要么完全缺失，要么即使存在，也失去了结合CsA的能力。
