Antimycins (>40 members) were discovered nearly 65 years ago but the discovery of the gene cluster encoding antimycin biosynthesis in 2011 has facilitated rapid progress in understanding the unusual biosynthetic pathway. Antimycin A is widely used as a piscicide in the catfish farming industry and also has potent killing activity against insects, nematodes and fungi. The mode of action of antimycins is to inhibit cytochrome c reductase in the electron transport chain and halt respiration. However, more recently, antimycin A has attracted attention as a potent and selective inhibitor of the mitochondrial anti-apoptotic proteins Bcl-2 and Bcl-xL. Remarkably, this inhibition is independent of the main mode of action of antimycins such that an artificial derivative named 2-methoxyantimycin A inhibits Bcl-xL but does not inhibit respiration. The Bcl-2/Bcl-xL family of proteins are over-produced in cancer cells that are resistant to apoptosis-inducing chemotherapy agents, so antimycins have great potential as anticancer drugs used in combination with existing chemotherapeutics. Here we review what is known about antimycins, the regulation of the ant gene cluster and the unusual biosynthetic pathway.
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机译:抗霉素(> 40个成员)是在近65年前发现的,但2011年编码抗霉素生物合成的基因簇的发现促进了对异常生物合成途径的快速了解。抗霉素A在the鱼养殖业中广泛用作杀虫剂,对昆虫,线虫和真菌也具有有效的杀灭活性。抗霉素的作用方式是抑制电子传输链中的细胞色素c还原酶并停止呼吸。然而,最近,抗霉素A作为线粒体抗凋亡蛋白Bcl-2和Bcl-x L sub>的有效和选择性抑制剂已引起关注。值得注意的是,这种抑制作用与抗霉素的主要作用方式无关,因此,名为2-甲氧基抗霉素A的人工衍生物抑制Bcl-x L sub>,但不抑制呼吸作用。 Bcl-2 / Bcl-x L sub>蛋白家族在对凋亡诱导化疗药物具有耐药性的癌细胞中过度生产,因此抗霉素作为与现有化学疗法联合使用的抗癌药物具有巨大潜力。在这里,我们回顾一下有关抗霉素,蚂蚁基因簇的调控和异常的生物合成途径的知识。
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