Mutasynthesis of rapamycin analogues through the manipulation of a gene governing starter unit biosynthesis
Mutasynthesis of rapamycin analogues through the manipulation of a gene governing starter unit biosynthesis
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DOI：
10.1002/anie.200462784
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Sheridan, RM
中科院分区：
文献类型：
--
作者：
Gregory, MA;Petkovic, H;Sheridan, RM
雷帕霉素1（Rapamycin 1）、FK 506 2（FK 520 2）和FK 520 3（FK 520 3）是由聚酮化合物合成酶（PKS）/非核糖体肽合成酶（NRPS）混合系统合成的具有生物遗传学相关性的天然产物，具有较强的抗真菌和免疫抑制活性。化合物1-3具有共同的结构基序，其负责它们与FK 506结合蛋白（FKBP）的特异性结合。这种结合引发二元复合物随后与下游蛋白质靶标结合，所述下游蛋白质靶标是介导其生物学效应的mTOR（雷帕霉素的哺乳动物靶标）或钙调神经磷酸酶（FK 506、FK 520）。[1]mTOR抑制
Rapamycin 1, FK506 2, and FK520 3 are biogenetically related natural products which are synthesized by mixed polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) systems and which possess potent antifungal and immunosuppressive activities. Compounds 1–3 possess a common structural motif which is responsible for their specific binding to FK506-binding proteins (FKBPs). This binding triggers the subsequent binding of the binary complex to a downstream protein target, either mTOR (mammalian target of rapamycin) or calcineurin (FK506, FK520) which mediate their biological effects.[1] Inhibition of mTOR by