靶向发现和生物合成法尼基转移酶抑制剂肽酰基精氨酸脱亚氨酶 E。
Targeted Rediscovery and Biosynthesis of the Farnesyl-Transferase Inhibitor Pepticinnamin E.
机构信息
Department of Chemistry, University of North Carolina at Chapel Hill, CB#3290, Chapel Hill, NC, 27514, USA.
出版信息
Chembiochem. 2019 Jun 3;20(11):1387-1393. doi: 10.1002/cbic.201900025. Epub 2019 May 2.
Abstract
The natural product pepticinnamin E potently inhibits protein farnesyl transferases and has potential applications in treating cancer and malaria. Pepticinnamin E contains a rare N-terminal cinnamoyl moiety as well as several nonproteinogenic amino acids, including the unusual 2-chloro-3-hydroxy-4-methoxy-N-methyl-L-phenylalanine. The biosynthesis of pepticinnamin E has remained uncharacterized because its original producing strain is no longer available. Here we identified a gene cluster (pcm) for this natural product in a new producer, Actinobacteria bacterium OK006, by means of a targeted rediscovery strategy. We demonstrated that the pcm cluster is responsible for the biosynthesis of pepticinnamin E, a nonribosomal peptide/polyketide hybrid. We also characterized a key O-methyltransferase that modifies 3,4-dihydroxy-l-phenylalanine. Our work has identified the gene cluster for pepticinnamins for the first time and sets the stage for elucidating the unique chemistry required for biosynthesis.
摘要
天然产物肽酰肉桂胺 E 能强力抑制蛋白质法呢基转移酶，有望用于治疗癌症和疟疾。肽酰肉桂胺 E 含有一个罕见的 N 端肉桂酰部分以及几种非天然氨基酸，包括不寻常的 2-氯-3-羟基-4-甲氧基-N-甲基-L-苯丙氨酸。由于其原始生产菌株已不复存在，因此肽酰肉桂胺 E 的生物合成仍未得到阐明。在这里，我们通过靶向再发现策略，在一种新的生产菌放线菌 OK006 中鉴定了该天然产物的基因簇（pcm）。我们证明 pcm 簇负责肽酰肉桂胺 E 的生物合成，肽酰肉桂胺 E 是一种非核糖体肽/聚酮杂合化合物。我们还鉴定了一个关键的 O-甲基转移酶，该酶修饰 3,4-二羟基-L-苯丙氨酸。我们的工作首次鉴定了肽酰肉桂胺的基因簇，为阐明生物合成所需的独特化学性质奠定了基础。
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