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Enzymatic Tailoring in Luzopeptin Biosynthesis Involves Cytochrome P450‐Mediated Carbon–Nitrogen Bond Desaturation for Hydrazone Formation
Author(s) -
Shi Xinjie,
Huang Liming,
Song Kaihui,
Zhao Guiyun,
Liu Yu,
Lv Longxian,
Du YiLing
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202105312
Subject(s) - chemistry , enzyme , biosynthesis , pharmacophore , cytochrome p450 , acyltransferase , biochemistry , stereochemistry
Luzopeptins and related decadepsipeptides are bisintercalator nonribosomal peptides featuring rare acyl‐substituted tetrahydropyridazine‐3‐carboxylic acid (Thp) subunits that are critical to their biological activities. Herein, we reconstitute the biosynthetic tailoring pathway in luzopeptin A biosynthesis through in vivo genetic and in vitro biochemical approaches. Significantly, we revealed a multitasking cytochrome P450 enzyme that catalyzes four consecutive oxidations including the highly unusual carbon–nitrogen bond desaturation, forming the hydrazone‐bearing 4‐OH‐Thp residues. Moreover, we identified a membrane‐bound acyltransferase that likely mediates the subsequent O ‐acetylation extracellularly, as a potential self‐protective strategy for the producer strain. Further genome mining of novel decadepsipeptides and an associated P450 enzyme have provided mechanistic insights into the P450‐mediated carbon–nitrogen bond desaturation. Our results not only reveal the molecular basis of pharmacophore formation in bisintercalator decadepsipeptides, but also expand the catalytic versatility of P450 family enzymes.