Elucidation of genes enhancing natural product biosynthesis through co-evolution analysis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1078415 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28019869_1.fastq.gz | Fastqsanger.gz | |||
| SRR28019869_2.fastq.gz | Fastqsanger.gz | |||
| SRR28019870_1.fastq.gz | Fastqsanger.gz | |||
| SRR28019870_2.fastq.gz | Fastqsanger.gz | |||
| SRR28019871_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:Streptomyces has the largest repertoire of natural product biosynthetic gene clusters (BGCs), yet developing a universal engineering strategy for each Streptomyces species is challenging. Given that some Streptomyces species have larger BGC repertoires than others, we hypothesized that a set of genes co-evolved with BGCs to support biosynthetic proficiency must exist in those strains, and that their identification may provide universal strategies to improve the productivity of other strains. We show here that genes co-evolved with natural product BGCs in Streptomyces can be identified by phylogenomics analysis. Among the 597 genes that co-evolved with polyketide BGCs, 11 genes in the “coenzyme” category have been examined, including a gene cluster encoding for the co-factor pyrroloquinoline quinone (PQQ). When the pqq gene cluster was engineered into 11 Streptomyces strains, it enhanced production of 16,385 metabolites, including 36 known natural products with up to 40-fold improvement and several activated silent gene clusters. This study provides a new engineering strategy for improving polyketide production and discovering new biosynthetic gene clusters.
2024-03-01 | GSE256209 | GEO
Project description:Salidroside is a bioactive tyrosine-derived phenolic natural product found in medicinal plants under the Rhodiola genus. In addition to their roles in traditional medicine as anti-fatigue and anti-anoxia adaptogens, Rhodiola total extract and salidroside have also displayed medicinal properties as anti-cardiovascular diseases and anti-cancer agents. The resulting surge in global demand of Rhodiola plants and salidroside has driven some species close to extinction. Here, we report the full elucidation of Rhodiola salidroside biosynthetic pathway utilizing the first comprehensive transcriptomics and metabolomics datasets for Rhodiola rosea. Unlike the previously proposed pathway involving separate decarboxylation and deamination enzymatic steps from tyrosine to the key intermediate 4-hydroxyphenylacetaldehyde, Rhodiola contains a pyridoxal phosphate (PLP)-dependent 4-hydroxyphenylacetaldehyde synthase (4HPAAS) that directly converts tyrosine to 4-hydroxyphenylacetaldehyde. We further identified genes encoding the subsequent 4-hydroxyphenylacetaldehyde reductase (4HPAR) and tyrosol:UDP-glucose 8-O- glucosyltransferase (T8GT), respectively, to complete salidroside biosynthesis in Rhodiola. We show that heterologous production of salidroside can be achieved in yeast Saccharomyces cerevisiae as well as in plant Nicotiana benthamiana through transgenic expression of Rhodiola salidroside biosynthetic genes. This study provides new tools for engineering sustainable production of salidroside in heterologous hosts.
2018-01-25 | MTBLS566 | MetaboLights
Project description:Covering: up to 2017 The participation of non-heme dinuclear iron cluster-containing monooxygenases in natural product biosynthetic pathways has been recognized only recently. At present, two families have been discovered. The archetypal member of the first family, CmlA, catalyzes β-hydroxylation of l-p-aminophenylalanine (l-PAPA) covalently linked to the nonribosomal peptide synthetase (NRPS) CmlP, thereby effecting the first step in the biosynthesis of chloramphenicol by Streptomyces venezuelae. CmlA houses the diiron cluster in a metallo-β-lactamase protein fold instead of the 4-helix bundle fold of nearly every other diiron monooxygenase. CmlA couples O2 activation and substrate hydroxylation via a structural change caused by formation of the l-PAPA-loaded CmlP:CmlA complex. The other new diiron family is typified by two enzymes, AurF and CmlI, which catalyze conversion of aryl-amine substrates to aryl-nitro products with incorporation of oxygen from O2. AurF from Streptomyces thioluteus catalyzes the formation of p-nitrobenzoate from p-aminobenzoate as a precursor to the biostatic compound aureothin, whereas CmlI from S. venezuelae catalyzes the ultimate aryl-amine to aryl-nitro step in chloramphenicol biosynthesis. Both enzymes stabilize a novel type of peroxo-intermediate as the reactive species. The rare 6-electron N-oxygenation reactions of CmlI and AurF involve two progressively oxidized pathway intermediates. The enzymes optimize efficiency by utilizing one of the reaction pathway intermediates as an in situ reductant for the diiron cluster, while simultaneously generating the next pathway intermediate. For CmlI, this reduction allows mid-pathway regeneration of the peroxo intermediate required to complete the biosynthesis. CmlI ensures specificity by carrying out the multistep aryl-amine oxygenation without dissociating intermediate products.
| S-EPMC6051903 | biostudies-literature
Project description:Eukaryotic algae are an extremely diverse category of photosynthetic organisms and some species produce highly potent bioactive compounds poisonous to humans or other animals, most notably observed during harmful algal blooms. These natural products include some of the most poisonous small molecules known and unique cyclic polyethers. However, the diversity and complexity of algal genomes means that sequencing-based research has lagged behind research into more readily sequenced microbes, such as bacteria and fungi. Applying informatics techniques to the algal genomes that are now available reveals new natural product biosynthetic pathways, with different groups of algae containing different types of pathways. There is some evidence for gene clusters and the biosynthetic logic of polyketides enables some prediction of these final products. For other pathways, it is much more challenging to predict the products and there may be many gene clusters that are not identified with the automated tools. These results suggest that there is a great diversity of biosynthetic capacity for natural products encoded in the genomes of algae and suggest areas for future research focus.
| S-EPMC7073580 | biostudies-literature
Project description:Many biologically active small-molecule natural products produced by microorganisms derive their activities from sugar substituents. Changing the structures of these sugars can have a profound impact on the biological properties of the parent compounds. This realization has inspired attempts to derivatize the sugar moieties of these natural products through exploitation of the sugar biosynthetic machinery. This approach requires an understanding of the biosynthetic pathway of each target sugar and detailed mechanistic knowledge of the key enzymes. Scientists have begun to unravel the biosynthetic logic behind the assembly of many glycosylated natural products and have found that a core set of enzyme activities is mixed and matched to synthesize the diverse sugar structures observed in nature. Remarkably, many of these sugar biosynthetic enzymes and glycosyltransferases also exhibit relaxed substrate specificity. The promiscuity of these enzymes has prompted efforts to modify the sugar structures and alter the glycosylation patterns of natural products through metabolic pathway engineering and enzymatic glycodiversification. In applied biomedical research, these studies will enable the development of new glycosylation tools and generate novel glycoforms of secondary metabolites with useful biological activity.
| S-EPMC2796923 | biostudies-literature
Project description:Kinases are annotated in many nucleoside biosynthetic gene clusters but generally are considered responsible only for self-resistance. Here, we report an unexpected 2'-phosphorylation of nucleoside biosynthetic intermediates in the nikkomycin and polyoxin pathways. This phosphorylation is a unique cryptic modification as it is introduced in the third of seven steps during aminohexuronic acid (AHA) nucleoside biosynthesis, retained throughout the pathway's duration, and is removed in the last step of the pathway. Bioinformatic analysis of reported nucleoside biosynthetic gene clusters indicates the presence of cryptic phosphorylation in other pathways and the importance of functional characterization of kinases in nucleoside biosynthetic pathways in general. This study also functionally characterized all of the enzymes responsible for AHA biosynthesis and revealed that AHA is constructed via a unique oxidative C-C bond cleavage reaction. The results indicate a divergent biosynthetic mechanism for three classes of antifungal nucleoside natural products.
| S-EPMC7855722 | biostudies-literature
Project description:Natural products are the result of Nature's exploration of biologically relevant chemical space through evolution and an invaluable source of bioactive small molecules for chemical biology and medicinal chemistry. Novel concepts for the discovery of new bioactive compound classes based on natural product structure may enable exploration of wider biologically relevant chemical space. The pseudo-natural product concept merges the relevance of natural product structure with efficient exploration of chemical space by means of fragment-based compound development to inspire the discovery of new bioactive chemical matter through de novo combination of natural product fragments in unprecedented arrangements. The novel scaffolds retain the biological relevance of natural products but are not obtainable through known biosynthetic pathways which can lead to new chemotypes that may have unexpected or unprecedented bioactivities. Herein, we cover the workflow of pseudo-natural product design and development, highlight recent examples, and discuss a cheminformatic analysis in which a significant portion of biologically active synthetic compounds were found to be pseudo-natural products. We compare the concept to natural evolution and discuss pseudo-natural products as the human-made equivalent, i.e. the chemical evolution of natural product structure.
| S-EPMC8895405 | biostudies-literature
Project description:Gibberellins (GAs) are crucial phytohormones involved in many aspects of plant growth and development, including plant-microbe interactions, which has led to GA production by plant-associated fungi and bacteria as well. While the GA biosynthetic pathways in plants and fungi have been elucidated and found to have arisen independently through convergent evolution, little has been uncovered about GA biosynthesis in bacteria. Some nitrogen-fixing, symbiotic, legume-associated rhizobia, including Bradyrhizobium japonicum-the symbiont of soybean-and Sinorhizobium fredii-a broad-host-nodulating species-contain a putative GA biosynthetic operon, or gene cluster. Through functional characterization of five unknown genes, we demonstrate that this operon encodes the enzymes necessary to produce GA9, thereby elucidating bacterial GA biosynthesis. The distinct nature of these enzymes indicates that bacteria have independently evolved a third biosynthetic pathway for GA production. Furthermore, our results also reveal a central biochemical logic that is followed in all three convergently evolved GA biosynthetic pathways.
| S-EPMC5193102 | biostudies-literature