ArnT：负责对多粘菌素类抗生素产生抗性的氨基阿拉伯糖转移酶的结构和机制,Biophysical Journal

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ArnT：负责对多粘菌素类抗生素产生抗性的氨基阿拉伯糖转移酶的结构和机制
Biophysical Journal ( IF 3.2 ) Pub Date : 2016-02-01 , DOI: 10.1016/j.bpj.2015.11.274
Vasileios I. Petrou , Carmen M. Herrera , Kathryn M. Schultz , Oliver B. Clarke , Jeremie Vendome , David Tomasek , Surajit Banerjee , Kanagalaghatta R. Rajashankar , Brian Kloss , Edda Kloppmann , Burkhard Rost , Candice S. Klug , M. Stephen Trent , Lawrence Shapiro , Filippo Mancia

多粘菌素是一种阳离子肽类抗生素，曾因毒性问题而被废弃，但已在临床上复兴并广泛用于治疗多重耐药（MDR）感染。对多粘菌素类抗生素的耐药性越来越受到关注，因此，它会严重损害我们对抗 MDR 感染的能力。 ArnT（4-氨基-4-脱氧-L-阿拉伯糖转移酶）是一种完整的脂质-脂质修饰脂质 A 的糖基转移酶，脂质 A 是细菌脂多糖 (LPS) 的脂质成分。ArnT 位于革兰氏阴性菌的内膜中，催化修饰的阿拉伯糖部分从十一碳烯磷酸酯转移到脂质 A。添加阿拉伯糖部分会导致细菌外膜的电荷修饰，限制其与阳离子肽的相互作用, 并使细菌对多粘菌素类抗生素和天然抗菌肽产生抗性。在这里，我们分别报道了革兰氏阴性细菌 ArnT 的晶体结构，单独和与脂质载体磷酸十一碳烯酯复合，分辨率分别为 2.8 和 3.2A。ArnT 由一个具有 13 个跨膜螺旋的跨膜结构域和一个周质可溶性结构域组成。整体折叠让人联想到来自细菌和古细菌的蛋白质糖基转移酶，但 ArnT 具有与其作为脂质糖基转移酶的功能相关的独特特征。地点。

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ArnT: Structure and Mechanism of the Aminoarabinose Transferase Responsible for Resistance to Polymyxin-Class Antibiotics

Polymyxins are cationic peptide antibiotics, once discarded due to toxicity concerns, that have been revived in the clinic and are widely used to treat multi-drug resistant (MDR) infections. Resistance to polymyxin-class antibiotics is a growing concern, as a result, one that can critically impair our ability to combat MDR infections.ArnT (4-amino-4-deoxy-L-arabinose transferase) is an integral lipid-to-lipid glycosyltransferase that modifies lipid A, the lipid component of bacterial lipopolysaccharide (LPS). ArnT is located in the inner membrane of Gram-negative bacteria and catalyzes the transfer of a modified arabinose moiety from undecaprenyl phosphate to lipid A. The addition of the arabinose moiety causes a charge modification of the bacterial outer membrane, limiting its interactions with cationic peptides, and enabling bacteria to develop resistance to polymyxin-class antibiotics and natural antimicrobial peptides.Here we report crystal structures of ArnT from a gram-negative bacterium, alone and in complex with the lipid carrier undecaprenyl phosphate, at 2.8 and 3.2A resolution, respectively. ArnT consists of a transmembrane domain with thirteen transmembrane helices and a periplasmic soluble domain. The overall fold is reminiscent of protein glycosyltransferases from bacteria and archaea, but ArnT possesses unique features that are related to its function as a lipid glycosyltransferase.Notably, we identify cavities for both lipidic substrates, accessible to the membrane environment, that converge at the active site. We observe a significant coil-to-helix structural transition upon binding of undecaprenyl phosphate that stabilizes the carrier lipid near the active site and expands the lipid A cavity, likely enabling subsequent binding of lipid A. Finally, we utilize a polymyxin resistance assay to investigate the role of particular residues in light of the structures, and propose a model for catalysis by ArnT family enzymes.

更新日期：2016-02-01

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