Amalgamation of nucleosides and amino acids in antibiotic biosynthesis: discovery of an L-threonine:uridine-5'-aldehyde transaldolase.
Amalgamation of nucleosides and amino acids in antibiotic biosynthesis: discovery of an L-threonine:uridine-5'-aldehyde transaldolase.
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DOI：
10.1021/ja308185q
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发表时间：
2012-11-14
影响因子：
15
通讯作者：
Van Lanen, Steven G.
中科院分区：
文献类型：
--
作者：
Barnard-Britson, Sandra;Chi, Xiuling;Nonaka, Koichi;Spork, Anatol P.;Tibrewal, Nidhi;Goswami, Anwesha;Pahari, Pallab;Ducho, Christian;Rohr, Jurgen;Van Lanen, Steven G.
A-90289、卡普雷霉素和Muraymycin重复的脂肽基核苷类抗生素在结构上突出显示为含有非蛋白原性β-羟基-α-氨基酸（称为5′-C-甘氨酰尿苷（GlyU））的核苷核心。生物合成基因簇的生物信息学分析揭示了一个共享的开放阅读框架，编码一种与丝氨酸羟甲基转移酶具有序列相似性的蛋白质，从而提出这种共享的酶催化与甘氨酸和尿苷-5 ′-醛的醛醇型缩合以提供GlyU。以A-90289生物合成中的LipK为模型，我们将GlyU生物合成过程中负责C-C键形成事件的酶功能性地指定和表征为l-苏氨酸：尿苷-5 ′-醛转醛酶。生化分析表明，这种转化依赖于吡哆醛-5 ′-磷酸，该酶与替代氨基酸如甘氨酸或丝氨酸作为羟醛供体没有活性，乙醛是副产物。酶产物的结构表征与苏型非对映异构体（5′S，6′S）-GlyU的立体化学归属一致。因此，这种酶协调C-C键断裂和形成，伴随着两个立体中心的安装，以产生具有核苷侧链的新的l-α-氨基酸。
The lipopeptidyl nucleoside antibiotics reperesented by A-90289, caprazamycin, and muraymycin, are structurally highlighted by a nucleoside core that contains a nonproteinogenic β-hydroxy-α-amino acid named 5′-C-glycyluridine (GlyU). Bioinformatic analysis of the biosynthetic gene clusters revealed a shared open reading frame encoding a protein with sequence similarity to serine hydroxymethyltransferases, resulting in the proposal that this shared enzyme catalyzes an aldol-type condensation with glycine and uridine-5′-aldehyde to furnish GlyU. Using LipK involved in A-90289 biosynthesis as a model, we now functionally assign and characterize the enzyme responsible for the C-C bond-forming event during GlyU biosynthesis as an l-threonine:uridine-5′-aldehyde transaldolase. Biochemical analysis revealed this transformation is dependent upon pyridoxal-5′-phosphate, the enzyme has no activity with alternative amino acids such as glycine or serine as aldol donors, and acetaldehyde is a co-product. Structural characterization of the enzyme product is consistent with stereochemical assignment as the threo diastereomer (5′S,6′S)-GlyU. Thus this enzyme orchestrates C-C bond breaking and formation with concomitant installation of two stereocenters to make a new l-α-amino acid with a nucleoside side chain.
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