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Biosynthesis of the Central Piperidine Nitrogen Heterocycle in Series a Thiopeptides
Author(s) -
Liu Jingyu,
Lin Zhi,
Chen Hua,
Guo Heng,
Tao Jiang,
Liu Wen
Publication year - 2019
Publication title -
chinese journal of chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.28
H-Index - 41
eISSN - 1614-7065
pISSN - 1001-604X
DOI - 10.1002/cjoc.201800497
Subject(s) - piperidine , chemistry , stereochemistry , biosynthesis , ring (chemistry) , substrate (aquarium) , combinatorial chemistry , enzyme , biochemistry , organic chemistry , oceanography , geology
Summary of main observation and conclusion Thiopeptides, arising from complex posttranslational modifications of a genetically encoded precursor peptide, are of great interest due to their structural complexity and important biological activities. All of these antibiotics share a macrocyclic peptidyl core that contains a central, six‐membered nitrogen heterocycle and are classified into five series a — e based on the oxidation state of the central nitrogenous ring. Here, we report that the biosynthesis of the central piperidine heterocycle of series a thiopeptides relies on the activity of homologues of an F 420 H 2 ‐dependent reductase TppX 4 by exploiting and characterizing the piperidine‐containing thiopeptin biosynthetic gene (tpp ) cluster in Streptomyces tateyamensis . In vitro reconstruction of TppX 4 activity demonstrated that the piperidine heterocycle of thiopeptins was transformed from a dehydropiperidine heterocycle, and TppX 4 tolerated the changes in the C‐termini and macrocyclic peptidyl core of substrate and also tolerated dehyropiperidine‐containing monocyclic or bicyclic thiopeptides. The identification of TppX 4 and its substrate tolerance enriches the biosynthetic toolbox for development of additional thiopeptide analogs for clinical drug screening.