33468-35-8Relevant articles and documents
Targeted Enzyme Engineering Unveiled Unexpected Patterns of Halogenase Stabilization
Minges, Hannah,Schnepel, Christian,B?ttcher, Dominique,Wei?, Martin S.,Spro?, Jens,Bornscheuer, Uwe T.,Sewald, Norbert
, p. 818 - 831 (2019/12/24)
Halogenases are valuable biocatalysts for selective C?H activation, but despite recent efforts to broaden their application scope by means of protein engineering, improvement of thermostability and catalytic efficiency is still desired. A directed evoluti
Biosynthesis of l-4-Chlorokynurenine, an Antidepressant Prodrug and a Non-Proteinogenic Amino Acid Found in Lipopeptide Antibiotics
Luhavaya, Hanna,Sigrist, Renata,Chekan, Jonathan R.,McKinnie, Shaun M. K.,Moore, Bradley S.
supporting information, p. 8394 - 8399 (2019/05/21)
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.
An Unusual Flavin-Dependent Halogenase from the Metagenome of the Marine Sponge Theonella swinhoei WA
Smith, Duncan R. M.,Uria, Agustinus R.,Helfrich, Eric J. N.,Milbredt, Daniela,Van Pée, Karl-Heinz,Piel, J?rn,Goss, Rebecca J. M.
, p. 1281 - 1287 (2017/05/29)
Uncultured bacteria from sponges have been demonstrated to be responsible for the generation of many potent, bioactive natural products including halogenated metabolites.1 The identification of gene clusters from the metagenomes of such bacterial communities enables the discovery of enzymes that mediate new and useful chemistries and allows insight to be gained into the biogenesis of potentially pharmacologically important natural products. Here we report a new pathway to the keramamides (krm); the first functional evidence for the existence of a distinct producer in the Theonella swinhoei WA chemotype is revealed, and a key enzyme on the pathway, a unique flavin-dependent halogenase with a broad substrate specificity, with potential as a useful new biocatalytic tool, is described.
