75816-19-2Relevant 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.
Tuning the Biological Activity of RGD Peptides with Halotryptophans ?
Kemker, Isabell,Schr?der, David C.,Feiner, Rebecca C.,Müller, Kristian M.,Marion, Antoine,Sewald, Norbert
, p. 586 - 601 (2021/01/14)
An array of l- and d-halotryptophans with different substituents at the indole moiety was synthesized employing either enzymatic halogenation by halogenases or incorporation of haloindoles using tryptophan synthase. Introduction of these Trp derivatives into RGD peptides as a benchmark system was performed to investigate their influence on bioactivity. Halotryptophan-containing RGD peptides display increased affinity toward integrin αvβ3 and enhanced selectivity over integrin α5β1. In addition, bromotryptophan was exploited as a platform for late-stage diversification by Suzuki-Miyaura cross-coupling (SMC), resulting in new-to-nature biaryl motifs. These peptides show enhanced affinity toward αvβ3, good affinity to αvβ8, and remarkable selectivity over α5β1 and αIIbβ3 while featuring fluorogenic properties. Their feasibility as a probe was demonstrated in vitro. Extensive molecular dynamics simulations were undertaken to elucidate NMR and high-performance liquid chromatography (HPLC) data for these late-stage diversified cyclic RGD peptides and to further characterize their conformational preferences.
Complete Stereoinversion of l -Tryptophan by a Fungal Single-Module Nonribosomal Peptide Synthetase
Hai, Yang,Jenner, Matthew,Tang, Yi
supporting information, p. 16222 - 16226 (2019/10/14)
Single-module nonribosomal peptide synthetases (NRPSs) and NRPS-like enzymes activate and transform carboxylic acids in both primary and secondary metabolism and are of great interest due to their biocatalytic potentials. The single-module NRPS IvoA is essential for fungal pigment biosynthesis. Here, we show that IvoA catalyzes ATP-dependent unidirectional stereoinversion of l-tryptophan to d-tryptophan with complete conversion. While the stereoinversion is catalyzed by the epimerization (E) domain, the terminal condensation (C) domain stereoselectively hydrolyzes d-tryptophanyl-S-phosphopantetheine thioester and thus represents a noncanonical C domain function. Using IvoA, we demonstrate a biocatalytic stereoinversion/deracemization route to access a variety of substituted d-tryptophan analogs in high enantiomeric excess.
