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Biosynthesis of l-4-chlorokynurenine, an antidepressant prodrug and a non-proteinogenic amino acid found in lipopeptide antibiotics

TitleBiosynthesis of l-4-chlorokynurenine, an antidepressant prodrug and a non-proteinogenic amino acid found in lipopeptide antibiotics
Publication TypeJournal Article
Year of Publication2019
AuthorsLuhavaya H., Sigrist R., Chekan J.R, McKinnie S.MK, Moore BS
Volume58
Pagination8394-8399
Date Published2019/06
Type of ArticleArticle
ISBN Number1433-7851
Accession NumberWOS:000476608700017
Keywordsbiocatalysis; biosynthesis; chemistry; chlorokynurenine; flavin-dependent halogenase; gene-cluster; halogenation; kynurenine; natural; pathway; products; purification; tryptophan degradation
Abstract

l-4-Chlorokynurenine (l-4-Cl-Kyn) is a neuropharmaceutical drug candidate that is in development for the treatment of major depressive disorder. Recently, this amino acid was naturally found as a residue in the lipopeptide antibiotic taromycin. Herein, we report the unprecedented conversion of l-tryptophan into l-4-Cl-Kyn catalyzed by four enzymes in the taromycin biosynthetic pathway from the marine bacterium Saccharomonospora sp. CNQ-490. We used genetic, biochemical, structural, and analytical techniques to establish l-4-Cl-Kyn biosynthesis, which is initiated by the flavin-dependent tryptophan chlorinase Tar14 and its flavin reductase partner Tar15. This work revealed the first tryptophan 2,3-dioxygenase (Tar13) and kynurenine formamidase (Tar16) enzymes that are selective for chlorinated substrates. The substrate scope of Tar13, Tar14, and Tar16 was examined and revealed intriguing promiscuity, thereby opening doors for the targeted engineering of these enzymes as useful biocatalysts.

DOI10.1002/anie.201901571
Student Publication: 
No
Research Topics: 
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