Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Divergent pathways in the biosynthesis of bisindole natural products.

ABSTRACT: Two molecules of the amino acid L-tryptophan are the biosynthetic precursors to a class of natural products named the "bisindoles." Hundreds of these bisindole molecules have been isolated from natural sources, and many of these molecules have potent medicinal properties. Recent studies have clarified the biosynthetic construction of six bisindole molecules, revealing novel enzymatic mechanisms and leading to combinatorial synthesis of new bisindole compounds. Collectively, these results provide a vantage point for understanding how much of the diversity of the bisindole class is generated from a small number of diverging pathways from L-tryptophan, as well as enabling identification of bisindoles that are likely derived via completely distinct biosynthetic pathways.

SUBMITTER: Ryan KS

PROVIDER: S-EPMC2711870 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Divergent pathways in the biosynthesis of bisindole natural products.

Ryan Katherine S KS Drennan Catherine L CL

Chemistry & biology 20090401 4

Two molecules of the amino acid L-tryptophan are the biosynthetic precursors to a class of natural products named the "bisindoles." Hundreds of these bisindole molecules have been isolated from natural sources, and many of these molecules have potent medicinal properties. Recent studies have clarified the biosynthetic construction of six bisindole molecules, revealing novel enzymatic mechanisms and leading to combinatorial synthesis of new bisindole compounds. Collectively, these results provide ...[more]

PMID: 19389622

Similar Datasets

Biosynthesis of alkyne-containing natural products.

Project description:Alkyne-containing natural products are important molecules that are widely distributed in microbes and plants. Inspired by the advantages of acetylenic products used in the fields of medicinal chemistry, organic synthesis and material science, great efforts have focused on discovering the biosynthetic enzymes and pathways for alkyne formation. Here, we summarize the biosyntheses of alkyne-containing natural products and introduce de novo biosynthetic strategies for alkyne-tagged compound production.

| S-EPMC8341276 | biostudies-literature

Biosynthesis of thiocarboxylic acid-containing natural products.

Project description:Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to β-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery.

| S-EPMC6006322 | biostudies-literature

Fosmidomycin biosynthesis diverges from related phosphonate natural products.

Project description:Fosmidomycin and related molecules comprise a family of phosphonate natural products with potent antibacterial, antimalarial and herbicidal activities. To understand the biosynthesis of these compounds, we characterized the fosmidomycin producer, Streptomyces lavendulae, using biochemical and genetic approaches. We were unable to elicit production of fosmidomycin, instead observing the unsaturated derivative dehydrofosmidomycin, which we showed potently inhibits 1-deoxy-D-xylulose-5-phosphate reductoisomerase and has bioactivity against a number of bacteria. The genes required for dehydrofosmidomycin biosynthesis were established by heterologous expression experiments. Bioinformatics analyses, characterization of intermediates and in vitro biochemistry show that the biosynthetic pathway involves conversion of a two-carbon phosphonate precursor into the unsaturated three-carbon product via a highly unusual rearrangement reaction, catalyzed by the 2-oxoglutarate dependent dioxygenase DfmD. The required genes and biosynthetic pathway for dehydrofosmidomycin differ substantially from that of the related natural product FR-900098, suggesting that the ability to produce these bioactive molecules arose via convergent evolution.

| S-EPMC7098449 | biostudies-literature

Engineered biosynthesis of natural products in heterologous hosts.

Project description:Natural products produced by microorganisms and plants are a major resource of antibacterial and anticancer drugs as well as industrially useful compounds. However, the native producers often suffer from low productivity and titers. Here we summarize the recent applications of heterologous biosynthesis for the production of several important classes of natural products such as terpenoids, flavonoids, alkaloids, and polyketides. In addition, we will discuss the new tools and strategies at multi-scale levels including gene, pathway, genome and community levels for highly efficient heterologous biosynthesis of natural products.

| S-EPMC4510016 | biostudies-literature

Biosynthesis of phosphonic and phosphinic acid natural products.

Project description:Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a renewed interest in the biochemistry and biology of these compounds with the cloning of the biosynthetic gene clusters for several family members. This review discusses the commonalities and differences in the molecular logic that lie behind the biosynthesis of these compounds. The current knowledge regarding the metabolic pathways and enzymes involved in the production of a number of natural products, including the approved antibiotic fosfomycin, the widely used herbicide phosphinothricin (PT), and the clinical candidate for treatment of malaria FR-900098, is presented. Many of the enzymes involved in the biosynthesis of these compounds catalyze chemically and biologically unprecedented transformations, and a wealth of new biochemistry has been revealed through their study. These investigations have also suggested new strategies for natural product discovery.

| S-EPMC2729427 | biostudies-literature

Engineered Biosynthesis of Fungal 4-Quinolone Natural Products.

Project description:Quinolone-containing natural products are widely found in bacteria, fungi, and plants. The fungal quinolactacins, which are N-methyl-4-quinolones, display a wide spectrum of biological activities. Here we uncovered a concise nonribosomal peptide synthetase pathway involved in quinolactacin A biosynthesis from Penicillium by using heterologous reconstitution and in vitro enzymatic synthesis. The N-desmethyl analog of quinolactacin A was accessed through the construction of a hybrid bacterial and fungi pathway in the heterologous host.

| S-EPMC8110742 | biostudies-literature

Expansion of bisindole biosynthetic pathways by combinatorial construction.

Project description:Cladoniamides are indolotryptoline natural products that derive from indolocarbazole precursors. Here, we present a microbial platform to artificially redirect the cladoniamide pathway to generate unnatural bisindoles for drug discovery. Specifically, we target glycosyltransferase, halogenase, and oxidoreductase genes from the phylogenetically related indolocarbazole rebeccamycin and staurosporine pathways. We generate a series of novel compounds, reveal details about the substrate specificities of a number of enzymes, and set the stage for future efforts to develop new catalysts and compounds by engineering of bisindole genes. The strategy for structural diversification we use here could furthermore be applied to other natural product families with known biosynthetic genes.

| S-EPMC4564286 | biostudies-literature

A divergent strategy for the synthesis of secologanin derived natural products.

Project description:The syntheses of D,L-geissoschizol, D,L-corynantheidol, D,L-dihydrocorynantheol, D,L-protoemetinol, and D,L-3-epi-protoemetinol have been accomplished from a single synthetic intermediate.

| S-EPMC3037978 | biostudies-literature

Reconstruction of cladoniamide biosynthesis reveals nonenzymatic routes to bisindole diversity.

Project description:Indolotryptolines are bisindole natural products isolated from microbial and eDNA sources. Here, we report the sequence of transformations that convert an indolocarbazole to the indolotryptoline cladoniamide through reconstruction of the four-enzyme cascade in E. coli. This cascade involves, first, conversion of an indolocarbozole to a C4c-C7a cis diol by ClaX1; second, N-methylation by ClaM1; third, rearrangement to the indolotryptoline scaffold by ClaX2; and fourth, installation of an O-methyl group by ClaM3. We furthermore elucidate the origins of minor cladoniamides D-G as the products of nonenzymatic, base-catalyzed opening of the succinimide ring of cladonimiades A-B. Overall, this work reveals the precarious pathway indolocarbazole-derived metabolites must traverse as they are converted into indolotryptoline products and highlights the importance of nonenzymatic chemistry in generating bisindole diversity.

| S-EPMC4613803 | biostudies-literature

Natural products from thioester reductase containing biosynthetic pathways.

Project description:Covering: up to 2018 Thioester reductase domains catalyze two- and four-electron reductions to release natural products following assembly on nonribosomal peptide synthetases, polyketide synthases, and their hybrid biosynthetic complexes. This reductive off-loading of a natural product yields an aldehyde or alcohol, can initiate the formation of a macrocyclic imine, and contributes to important intermediates in a variety of biosyntheses, including those for polyketide alkaloids and pyrrolobenzodiazepines. Compounds that arise from reductase-terminated biosynthetic gene clusters are often reactive and exhibit biological activity. Biomedically important examples include the cancer therapeutic Yondelis (ecteinascidin 743), peptide aldehydes that inspired the first therapeutic proteasome inhibitor bortezomib, and numerous synthetic derivatives and antibody drug conjugates of the pyrrolobenzodiazepines. Recent advances in microbial genomics, metabolomics, bioinformatics, and reactivity-based labeling have facilitated the detection of these compounds for targeted isolation. Herein, we summarize known natural products arising from this important category, highlighting their occurrence in Nature, biosyntheses, biological activities, and the technologies used for their detection and identification. Additionally, we review publicly available genomic data to highlight the remaining potential for novel reductively tailored compounds and drug leads from microorganisms. This thorough retrospective highlights various molecular families with especially privileged bioactivity while illuminating challenges and prospects toward accelerating the discovery of new, high value natural products.

| S-EPMC6146020 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data