J Nat Prod. 2026 Jun 12. doi: 10.1021/acs.jnatprod.6c00490. Online ahead of print.

ABSTRACT

The tryptophan-to-kynurenine pathway gives rise to neuroactive metabolites associated with neurological, immunological, and metabolic processes, leading to increased interest in the biocatalysis and total synthesis of kynurenine-based drug candidates. Kynurenine scaffolds have been identified in a range of natural product compound classes, including pigments and antibiotics. Herein, we describe the biosynthetic gene cluster responsible for the bioproduction of the 6-chlorokynurenic acid-derived lodopyridone A, a mixed polyketide/nonribosomal peptide synthetase assembly line product isolated from the Saccharomonospora piscinae CNQ490 marine actinobacterium. We characterized the enzymes responsible for the conversion of L-tryptophan to L-5-chlorokynurenine, including Lodo315, a tryptophan 2,3-dioxygenase (TDO) enzyme with extensive substrate flexibility. This work expands our current knowledge of TDO enzymes that act on halogenated tryptophan substrates in bacteria and serves as a future basis for bioproduction of chlorinated kynurenine scaffolds.

PMID:42281363 | DOI:10.1021/acs.jnatprod.6c00490