The structural basis for substrate versatility of chloramphenicol acetyltransferase CATI
The structural basis for substrate versatility of chloramphenicol acetyltransferase CATI
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DOI：
10.1002/pro.2036
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发表时间：
2012-04-01
期刊：
影响因子：
8
通讯作者：
Tsodikov, Oleg V.
中科院分区：
文献类型：
--
作者：
Biswas, Tapan;Houghton, Jacob L.;Tsodikov, Oleg V.
需要新的抗生素来克服不断进化的细菌耐药性的挑战。这引发了人们对曾经流行的抗生素（如氯霉素（CAM））的机制研究的新兴趣。氯霉素乙酰转移酶（CAT）是共价修饰CAM的酶，使其对靶标核糖体无活性，从而引起对CAM的抗性。在三种主要类型的CAT（CATI-III）中，CAM特异性CATIII已被广泛研究。对另一种临床上重要的类型CATI的了解要少得多。除了使CAM失活之外，与CATIII不同，CATI赋予对结构上不同的抗生素夫西地酸的抗性。CATI更广泛的底物特异性的起源尚未完全阐明。为了了解CATI的底物结合特征，测定了其未结合（apo）和CAM结合形式的晶体结构。对这些和先前确定的CATI-FA和CATIII-CAM结构的分析揭示了负责CATI与其底物结合的相互作用，并澄清了CATI与CATIIII相比更广泛的底物偏好。
Novel antibiotics are needed to overcome the challenge of continually evolving bacterial resistance. This has led to a renewed interest in mechanistic studies of once popular antibiotics like chloramphenicol (CAM). Chloramphenicol acetyltransferases (CATs) are enzymes that covalently modify CAM, rendering it inactive against its target, the ribosome, and thereby causing resistance to CAM. Of the three major types of CAT (CATI-III), the CAM-specific CATIII has been studied extensively. Much less is known about another clinically important type, CATI. In addition to inactivating CAM and unlike CATIII, CATI confers resistance to a structurally distinct antibiotic, fusidic acid. The origin of the broader substrate specificity of CATI has not been fully elucidated. To understand the substrate binding features of CATI, its crystal structures in the unbound (apo) and CAM-bound forms were determined. The analysis of these and previously determined CATI-FA and CATIII-CAM structures revealed interactions responsible for CATI binding to its substrates and clarified the broader substrate preference of CATI compared to that of CATIII.