6548-09-0Relevant articles and documents
An Obligate Peptidyl Brominase Underlies the Discovery of Highly Distributed Biosynthetic Gene Clusters in Marine Sponge Microbiomes
Nguyen, Nguyet A.,Lin, Zhenjian,Mohanty, Ipsita,Garg, Neha,Schmidt, Eric W.,Agarwal, Vinayak
supporting information, p. 10221 - 10231 (2021/07/26)
Marine sponges are prolific sources of bioactive natural products, several of which are produced by bacteria symbiotically associated with the sponge host. Bacteria-derived natural products, and the specialized bacterial symbionts that synthesize them, are not shared among phylogenetically distant sponge hosts. This is in contrast to nonsymbiotic culturable bacteria in which the conservation of natural products and natural product biosynthetic gene clusters (BGCs) is well established. Here, we demonstrate the widespread conservation of a BGC encoding a cryptic ribosomally synthesized and post-translationally modified peptide (RiPP) in microbiomes of phylogenetically and geographically dispersed sponges from the Pacific and Atlantic oceans. Detection of this BGC was enabled by mining for halogenating enzymes in sponge metagenomes, which, in turn, allowed for the description of a broad-spectrum regiospecific peptidyl tryptophan-6-brominase which possessed no chlorination activity. In addition, we demonstrate the cyclodehydrative installation of azoline heterocycles in proteusin RiPPs. This is the first demonstration of halogenation and cyclodehydration for proteusin RiPPs and the enzymes catalyzing these transformations were found to competently interact with other previously described proteusin substrate peptides. Within a sponge microbiome, many different generalized bacterial taxa harbored this BGC with often more than 50 copies of the BGC detected in individual sponge metagenomes. Moreover, the BGC was found in all sponges queried that possess high diversity microbiomes but it was not detected in other marine invertebrate microbiomes. These data shed light on conservation of cryptic natural product biosynthetic potential in marine sponges that was not detected by traditional natural product-to-BGC (meta)genome mining.
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.
Non-natural tryptophan derivative synthesis method
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Paragraph 0026-0028; 0035-0037, (2017/08/27)
The invention relates to the field of organic synthesis, and discloses a non-natural tryptophan derivative synthesis method. Indole derivatives serve as raw materials. The synthesis method includes the steps: (1) dissolving the indole derivatives, 2-nitrine ethyl acrylate and bismuth trifluoromethanesulfonate in organic solvents, performing reaction for 2-6 hours, performing quenching reaction after complete reaction, extracting reaction liquid, and washing and drying an organic phase to obtain a compound 2; (2) dissolving the compound 2 in alcohol, dripping alkali solution, continuing reaction for 1.5-5 hours, performing concentration after complete reaction, extracting the reaction liquid, adjusting the pH (potential of hydrogen) of an aqueous phase to be 4-5, filtering the aqueous phase and taking solid to obtain a compound 3; (3) dissolving the compound 3 in alcohol, adding palladium carbon catalysts, leading in hydrogen, performing reaction for 6-10 hours, filtering the solution after complete reaction, and concentrating and recrystallizing filtrate. The synthesis method has the advantages that the raw materials are easily obtained, reaction conditions are mild, yield is high, production is easily amplified, and cost can be reduced.
