Novel pathway of 3-hydroxyanthranilic acid formation in limazepine biosynthesis reveals evolutionary relation between phenazines and pyrrolobenzodiazepines

Scientific Reports
Magdalena PavlikovaLucie Najmanova

Abstract

Natural pyrrolobenzodiazepines (PBDs) form a large and structurally diverse group of antitumour microbial metabolites produced through complex pathways, which are encoded within biosynthetic gene clusters. We sequenced the gene cluster of limazepines and proposed their biosynthetic pathway based on comparison with five available gene clusters for the biosynthesis of other PBDs. Furthermore, we tested two recombinant proteins from limazepine biosynthesis, Lim5 and Lim6, with the expected substrates in vitro. The reactions monitored by LC-MS revealed that limazepine biosynthesis involves a new way of 3-hydroxyanthranilic acid formation, which we refer to as the chorismate/DHHA pathway and which represents an alternative to the kynurenine pathway employed for the formation of the same precursor in the biosynthesis of other PBDs. The chorismate/DHHA pathway is presumably also involved in the biosynthesis of PBD tilivalline, several natural products unrelated to PBDs, and its part is shared also with phenazine biosynthesis. The similarities between limazepine and phenazine biosynthesis indicate tight evolutionary links between these groups of compounds.

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Citations

Feb 28, 2019·Proceedings of the National Academy of Sciences of the United States of America·Katrin UnterhauserEllen L Zechner
May 24, 2019·Journal of Natural Products·Xiachang WangJon S Thorson
Dec 24, 2019·Chemical Reviews·Jason B Hedges, Katherine S Ryan
Aug 28, 2021·International Journal of Environmental Research and Public Health·Kirstin I Arend, Julia E Bandow

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Datasets Mentioned

BETA
KT381463

Methods Mentioned

BETA
PCR
NMR

Software Mentioned

FgenesB
Velvet
Conserved
Glimmer
Khmer
BlastX
Bowtie

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