Angewandte Chemie - International Edition, volume 58, issue 25, pages 8394-8399
Biosynthesis of l ‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics
Luhavaya Hanna
1
,
Sigrist Renata
1, 2
,
Chekan Jonathan R.
1
,
McKinnie Shaun M.K.
1
,
Moore Bradley Matthys
1, 3
1
Center for Marine Biotechnology and BiomedicineScripps Institution of OceanographyUniversity of California, San Diego La Jolla CA 92093 USA
|
2
Department of Organic ChemistryUniversity of Campinas UNICAMPCidade Universitária Zeferino Vaz s/n P.O. Box 6154 13083-970 Campinas SP Brazil
|
3
Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of California San Diego La Jolla CA 92093 USA
|
Publication type: Journal Article
Publication date: 2019-06-17
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 16.6
ISSN: 14337851, 15213773
PubMed ID:
30963655
General Chemistry
Catalysis
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.
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- We do not take into account publications that without a DOI.
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Luhavaya H. et al. Biosynthesis of l ‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics // Angewandte Chemie - International Edition. 2019. Vol. 58. No. 25. pp. 8394-8399.
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Luhavaya H., Sigrist R., Chekan J. R., McKinnie S. M., Moore B. M. Biosynthesis of l ‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics // Angewandte Chemie - International Edition. 2019. Vol. 58. No. 25. pp. 8394-8399.
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TY - JOUR
DO - 10.1002/anie.201901571
UR - https://doi.org/10.1002%2Fanie.201901571
TI - Biosynthesis of l ‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics
T2 - Angewandte Chemie - International Edition
AU - Luhavaya, Hanna
AU - Sigrist, Renata
AU - Chekan, Jonathan R.
AU - McKinnie, Shaun M.K.
AU - Moore, Bradley Matthys
PY - 2019
DA - 2019/06/17 00:00:00
PB - Wiley
SP - 8394-8399
IS - 25
VL - 58
PMID - 30963655
SN - 1433-7851
SN - 1521-3773
ER -
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@article{2019_Luhavaya,
author = {Hanna Luhavaya and Renata Sigrist and Jonathan R. Chekan and Shaun M.K. McKinnie and Bradley Matthys Moore},
title = {Biosynthesis of l ‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics},
journal = {Angewandte Chemie - International Edition},
year = {2019},
volume = {58},
publisher = {Wiley},
month = {jun},
url = {https://doi.org/10.1002%2Fanie.201901571},
number = {25},
pages = {8394--8399},
doi = {10.1002/anie.201901571}
}
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MLA
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Luhavaya, Hanna, et al. “Biosynthesis of l ‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics.” Angewandte Chemie - International Edition, vol. 58, no. 25, Jun. 2019, pp. 8394-8399. https://doi.org/10.1002%2Fanie.201901571.