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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Biosynthesis of l-4-Chlorokynurenine, an Antidepressant Prodrug and a Non-Proteinogenic Amino Acid Found in Lipopeptide Antibiotics

Texto completo
Autor(es):
Luhavaya, Hanna [1] ; Sigrist, Renata [1, 2] ; Chekan, Jonathan R. [1] ; McKinnie, Shaun M. K. [1] ; Moore, Bradley S. [3, 1]
Número total de Autores: 5
Afiliação do(s) autor(es):
[1] Univ Calif San Diego, Scripps Inst Oceanog, Ctr Marine Biotechnol & Biomed, La Jolla, CA 92093 - USA
[2] Univ Campinas UNICAMP, Dept Organ Chem, Cidade Univ Zeferino Vaz S-N, POB 6154, BR-13083970 Campinas, SP - Brazil
[3] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 - USA
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION; v. 58, n. 25, p. 8394-8399, JUN 17 2019.
Citações Web of Science: 5
Resumo

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)

Processo FAPESP: 16/25735-1 - Explorando o potencial metabólico de Streptomyces sp. B1 metabolites: isolamento e caracterização
Beneficiário:Renata Sigrist
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto