Cyclolization of D-Lysergic Acid Alkaloid Peptides
Cyclolization of D-Lysergic Acid Alkaloid Peptides
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DOI：
10.1016/j.chembiol.2013.11.008
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发表时间：
2014-01-16
影响因子：
--
通讯作者：
Keller, Ulrich
中科院分区：
文献类型：
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作者：
Havemann, Judith;Vogel, Dominik;Keller, Ulrich
麦角肽是一类具有重要药理意义的D-麦角酸型生物碱肽，其三肽链以氨基末端的α-羟基氨基酸和末端正构体为基础，以独特的双环形式排列。D-甘氨酰三肽是由麦角菌Clavicep Purpurea的非核糖体多肽合成酶LPS1和LPS2组装而成，释放为N-(D-甘氨酰基)-内酰胺类化合物。我们展示了由Fe2+/2-酮戊二酸依赖的双加氧酶(EASH)和LPS1/LPS2联合催化的麦角肽的全酶合成。对反应的分析表明，EASH在N-(D-甘氨酰基)-内酰胺的氨基残基的α-C处引入一个羟基，然后与末端的内酰胺羰基自发缩合。序列分析表明，EASH属于植酰辅酶A羟基酶的一个广泛而多样的家族。我们提供了EASH的高分辨晶体结构，它与人类植酰辅酶A羟基酶PhyH的晶体结构最相似。
The tripeptide chains of the ergopeptines, a class of pharmacologically important D-lysergic acid alkaloid peptides, are arranged in a unique bicyclic cyclol based on an amino-terminal alpha-hydroxyamino acid and a terminal orthostructure. D-lysergyl-tripeptides are assembled by the nonribosomal peptide synthetases LPS1 and LPS2 of the ergot fungus Claviceps purpurea and released as N-(D-lysergyl-aminoacyl)-lactams. We show total enzymatic synthesis of ergopeptines catalyzed by a Fe2+/2-ketoglutarate-dependent dioxygenase (EasH) in conjunction with LPS1/LPS2. Analysis of the reaction indicated that EasH introduces a hydroxyl group into N-(D-lysergyl-aminoacyl)-lactam at alpha-C of the aminoacyl residue followed by spontaneous condensation with the terminal lactam carbonyl group. Sequence analysis revealed that EasH belongs to the wide and diverse family of the phytanoyl coenzyme A hydroxylases. We provide a high-resolution crystal structure of EasH that is most similar to that of phytanoyl coenzyme A hydroxylase, PhyH, from human.