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Biosynthesis of cittilins, unusual ribosomally synthesized and post-translationally modified peptides from Myxococcus xanthus
bioRxiv - Biochemistry Pub Date : 2020-05-27 , DOI: 10.1101/2020.05.25.114512
Joachim J. Hug , Jan Dastbaz , Sebastian Adam , Ole Revermann , Jesko Koehnke , Daniel Krug , Rolf Müller

Cittilins are secondary metabolites from myxobacteria comprised of three L-tyrosines and one L-isoleucine forming a bicyclic tetrapeptide scaffold with biaryl and aryl-oxygen-aryl ether bonds. Here we reveal that cittilins belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products, for which only the crocagins have been reported from myxobacteria. A 27 amino acid precursor peptide harbors a C-terminal four amino acid core peptide, which is enzymatically modified and finally exported to yield cittilins. The small biosynthetic gene cluster responsible for cittilin biosynthesis also encodes a cytochrome P450 enzyme and a methyltransferase, whereas a gene encoding a prolyl endopeptidase for the cleavage of the precursor peptide is located outside of the cittilin biosynthetic gene cluster. We confirm the roles of the biosynthetic genes responsible for the formation of cittilins using targeted gene inactivation and heterologous expression in Streptomyces. We also report first steps towards the biochemical characterization of the proposed biosynthetic pathway in vitro. An investigation of the cellular uptake properties of cittilin A connected it to a potential biological function as an inhibitor of the prokaryotic carbon storage regulator A (CsrA).

中文翻译:

黄腐霉菌中特异的核糖体合成和翻译后修饰的肽类黄花素的生物合成

黄体素是来自粘杆菌的次级代谢产物,其由三个L-酪氨酸和一个L-异亮氨酸组成,形成具有双芳基和芳基-氧-芳基醚键的双环四肽支架。在这里,我们揭示了cittilins属于天然产物的核糖体合成和翻译后修饰的肽(RiPP)家族,对于其从黏菌属中仅报告了克鲁卡汀。一个27个氨基酸的前体肽带有一个C端的四个氨基酸核心肽,该肽经过酶修饰,最后输出以产生黄体素。负责黄体素生物合成的小型生物合成基因簇还编码细胞色素P450酶和甲基转移酶,而编码用于前体肽裂解的脯氨酰内肽酶的基因位于黄体素生物合成基因簇的外部。我们证实了使用链霉菌中的靶向基因失活和异源表达,负责形成柠檬绿素的生物合成基因的作用。我们还报告了对拟议的生物合成途径在体外生化特性的第一步。对黄霉素A的细胞摄取特性的研究将其与潜在的生物学功能联系起来,作为原核碳储存调节剂A(CsrA)的抑制剂。
更新日期:2020-05-27
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