POSTTRANSLATIONAL MODIFICATIONS IN MICROCIN B17 DEFINE AN ADDITIONAL CLASS OF DNA GYRASE INHIBITOR
POSTTRANSLATIONAL MODIFICATIONS IN MICROCIN B17 DEFINE AN ADDITIONAL CLASS OF DNA GYRASE INHIBITOR
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DOI：
10.1073/pnas.91.10.4519
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发表时间：
1994-05-10
影响因子：
11.1
通讯作者：
KOLTER, R
中科院分区：
文献类型：
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作者：
YORGEY, P;LEE, J;KOLTER, R
抑制 DNA 旋转酶活性的药物几乎完全分为两个结构类别：喹诺酮类和香豆素类。第三类 DNA 旋转酶抑制剂是核糖体合成肽抗生素 microcin B17 (MccB17)。 MccB17 含有 43 个氨基酸残基，但其中 14 个经过翻译后修饰。在这里，我们描述了这些修饰的结构表征。我们提出四个半胱氨酸和四个丝氨酸侧链与前面残基的羰基进行缩合，然后进行α/β脱氢，分别产生四个噻唑和四个恶唑环。参与催化这些修饰的三种蛋白质 (McbBCD) 将构成唯一已确定的噻唑/恶唑生物合成酶。这些结果为 DNA 旋转酶抑制剂的设计开辟了可能性，并增加了具有蛋白质工程潜力的翻译后修饰库。大肠杆菌 sbmA 突变体缺乏参与 McB17 摄取的内膜蛋白 (SbmA)，被发现对博莱霉素具有抗性。博莱霉素在结构上与 McB17 无关，只是它含有两个噻唑环。这表明噻唑环是 SbmA 识别的 MccB17 结构的一部分。这一观察结果以及 SbmA 同系物广泛保守并可发挥发育作用的发现 [Glazebrook, J.、Ichige, A. 和 Walker, G. C. (1993) Genes Dev.。 [7, 1485-1497]表明，含噻唑和恶唑的化合物可以作为不同环境中多种细菌的信号分子，包括病原体与植物和动物宿主的相互作用。
Drugs that inhibit the activity of DNA gyrase fall almost exclusively into two structural classes, the quinolones and the coumarins. A third class of DNA gyrase inhibitor is defined by the ribosomally synthesized peptide antibiotic micro cin B17 (MccB17). MccB17 contains 43 amino acid residues, but 14 of these are posttranslationally modified. Here we describe the characterization of the structure of these modifications. We propose that four cysteine and four serine side chains undergo condensation with the carbonyl group of the preceding residue, followed by alpha/beta dehydrogenation to yield four thiazole and four oxazole rings, respectively. The three proteins implicated in catalyzing these modifications (McbBCD) would constitute the only thiazole/oxazole biosynthetic enzymes identified. These results open up possibilities for the design of DNA gyrase inhibitors and add to the repertoire of posttranslational modifications with potential for protein engineering. Escherichia coli sbmA mutants, which lack the inner membrane protein (SbmA) involved in MccB17 uptake, were found to be resistant to bleomycin. Bleomycin is structurally unrelated to MccB17 except for the fact that it contains two thiazole rings. This suggests that thiazole rings are part of the MccB17 structure recognized by SbmA. This observation and the finding that SbmA homologs are widely conserved and can play developmental roles [Glazebrook, J., Ichige, A. and Walker, G. C. (1993) Genes Dev. 7, 1485-1497] suggest that thiazole- and oxazole-containing compounds may serve as signaling molecules for a wide variety of bacteria in diverse environments, including pathogen interactions with plant and animal hosts.