Vahlensieck H F, Pridzun L, Reichenbach H, Hinnen A
Ciba-Geigy AG, Biotechnology Department K-681.109, Basel, Switzerland.
Curr Genet. 1994 Feb;25(2):95-100. doi: 10.1007/BF00309532.
Soraphen A, a polyketide isolated from the myxobacterium Sorangium cellulosum, is a potent inhibitor of fungal growth. We have used a genetic approach to localize the target of this drug, employing Saccharomyces cerevisiae as a model organism. we have isolated soraphen A-resistant mutants and found that all of them map at the same genetic locus and exhibit a broad range of semidominant phenotypes. Data from genetic crosses of soraphen A-resistant clones with an acc1 mutant revealed that ACC1, coding for acetyl-CoA carboxylase (E.C. 6.4.1.2), is tightly linked to soraphen A resistance. Partially-purified enzyme extracts containing acetyl-CoA carboxylase were prepared and assayed for their soraphen A sensitivity. Our experiments showed that the catalytic activity of the wild-type enzyme is inhibited in vitro by soraphen A while the mutant enzyme remains catalytically active. Taken together these data strongly suggest that the ACC1 gene product is the primary target for soraphen A in vivo.
索拉芬A是一种从粘细菌纤维堆囊菌中分离出的聚酮化合物，是一种有效的真菌生长抑制剂。我们采用遗传学方法，以酿酒酵母作为模式生物来定位这种药物的作用靶点。我们分离出了对索拉芬A具有抗性的突变体，发现它们都定位在同一个基因座上，并表现出广泛的半显性表型。对索拉芬A抗性克隆与acc1突变体进行遗传杂交的数据表明，编码乙酰辅酶A羧化酶（E.C. 6.4.1.2）的ACC1与索拉芬A抗性紧密连锁。制备了含有乙酰辅酶A羧化酶的部分纯化酶提取物，并检测了它们对索拉芬A的敏感性。我们的实验表明，野生型酶的催化活性在体外被索拉芬A抑制，而突变型酶仍保持催化活性。综合这些数据强烈表明，ACC1基因产物是索拉芬A在体内的主要作用靶点。
