IDENTIFICATION OF RAS FARNESYLTRANSFERASE INHIBITORS BY MICROBIAL SCREENING
IDENTIFICATION OF RAS FARNESYLTRANSFERASE INHIBITORS BY MICROBIAL SCREENING
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DOI：
10.1073/pnas.90.6.2281
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发表时间：
1993-03-15
影响因子：
11.1
通讯作者：
TAMANOI, F
中科院分区：
文献类型：
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作者：
HARA, M;AKASAKA, K;TAMANOI, F
使用GPA 1基因中具有条件缺陷的酵母菌株进行微生物筛选以寻找蛋白法尼基转移酶（PFT）的抑制剂。发现一株链霉菌产生活性化合物，命名为UCF 1-A、UCF 1-B和UCF 1-C。这些化合物的结构测定表明，UCF 1-C与已知抗生素manumycin相同，而UCF 1-A和UCF 1-B在结构上与manumycin相关。所有三种UCF 1化合物均抑制gpa 1破坏的致死性，其中UCF 1-C表现出最强的活性。UCF 1抑制酵母菌以及大鼠脑PFT。用5 μ M UCF 1-C观察到酵母PFT活性的50%抑制。抑制的动力学分析表明，UCF 1-C作为PFT相对于法呢基焦磷酸的竞争性抑制剂，表现出1.2 μ M的K（i），而相同的化合物似乎作为PFT相对于法呢基受体Ras蛋白的非竞争性抑制剂。UCF 1-C显示出显著的抑制Ki-ras转化的纤维肉瘤生长的活性，提高了其用作抗肿瘤药物的可能性。
A microbial screen using a yeast strain with conditional deficiency in the GPA1 gene was carried out to search for inhibitors of protein farnesyltransferase (PFT). A strain of Streptomyces was found to produce active compounds named UCF1-A, UCF1-B, and UCF1-C. Structural determination of these compounds revealed that UCF1-C is identical to the known antibiotic, manumycin, whereas UCF1-A and UCF1-B are structurally related to manumycin. All three UCF1 compounds suppress the lethality of gpa1 disruption, with UCF1-C exhibiting the strongest activity. UCF1 inhibits yeast as well as rat brain PFT. Fifty percent inhibition of yeast PFT activity is observed with 5 muM UCF1-C. Kinetic analyses of the inhibition suggest that UCF1-C acts as a competitive inhibitor of PFT with respect to farnesyl pyrophosphate, exhibiting a K(i) of 1.2 muM, whereas the same compound appears to act as a noncompetitive inhibitor of PFT with respect to the farnesyl acceptor, the Ras protein. UCF1-C shows significant activity to inhibit the growth of Ki-ras-transformed fibrosarcoma, raising the possibility of its use as an antitumor drug.