Chekan, Jonathan R.
McKinnie, Shaun M. K.
Moore, Bradley S.
Número total de Autores: 5
Afiliação do(s) autor(es):
 Univ Calif San Diego, Scripps Inst Oceanog, Ctr Marine Biotechnol & Biomed, La Jolla, CA 92093 - USA
 Univ Campinas UNICAMP, Dept Organ Chem, Cidade Univ Zeferino Vaz S-N, POB 6154, BR-13083970 Campinas, SP - Brazil
 Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 - USA
Número total de Afiliações: 3
Tipo de documento:
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION;
JUN 17 2019.
Citações Web of Science:
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. (AU)