Substrate-assisted enzymatic formation of lysinoalanine in duramycin.
Substrate-assisted enzymatic formation of lysinoalanine in duramycin.
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DOI：
10.1038/s41589-018-0122-4
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发表时间：
2018-10
影响因子：
14.8
通讯作者：
van der Donk WA
中科院分区：
文献类型：
--
作者：
An L;Cogan DP;Navo CD;Jiménez-Osés G;Nair SK;van der Donk WA
耐久霉素是一种结合磷脂酰乙醇胺的重度后修饰肽。它已被研究作为抗生素，抑制病毒进入，治疗囊性纤维化，肿瘤和血管造影剂。Duramycin含有β-羟基化的Asp（Hya）和四个大环，包括一个必需的赖氨丙氨酸（Lal）交联。Lal形成的机制尚不清楚。我们在这里表明，Lal通过将Lys 19添加到脱氢丙氨酸中而被DurN立体特异性地安装。DurN的结构揭示了一个不寻常的二聚体与一个新的折叠。令人惊讶的是，在与DurN结合的耐久霉素的结构中，没有酶的残基靠近Lal交联。相反，底物的Hya 15与Lal相互作用，这表明它在催化过程中充当使Lys 19去质子化的碱。生化数据表明，DurN preorganizations的反应性构象的基板，这样的Hya 15的基板可以作为催化基地Lal形成。
Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, inhibitor of viral entry, therapeutic for cystic fibrosis, and tumor and vasculature imaging agent. Duramycin contains a β-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalanine (Lal) crosslink. The mechanism of Lal formation is not known. We here show that Lal is installed stereospecifically by DurN via addition of Lys19 to a dehydroalanine. The structure of DurN reveals an unusual dimer with a new fold. Surprisingly, in the structure of duramycin bound to DurN, no residues of the enzyme are near the Lal crosslink. Instead, Hya15 of the substrate makes interactions with Lal, suggesting it acts as a base to deprotonate Lys19 during catalysis. Biochemical data suggest that DurN preorganizes the reactive conformation of the substrate, such that the Hya15 of the substrate can serve as the catalytic base for Lal formation.
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DOI：
10.1107/s0907444909029436
发表时间：
2009-10-01
影响因子：
2.2
作者：
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