scholarly journals Novel cyclic peptides from lethal Amanita species through a genomic approach, and major peptide toxins in the ectomycorrhizal association

2020 ◽  
Author(s):  
Hong Luo ◽  
Shengwen Zhou ◽  
Xincan Li ◽  
Xuan Li ◽  
Zuo H. Chen ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Rna Seq ◽  
The Past ◽  
A Genome ◽  
Mycorrhizal Association ◽  
Genomic Approach ◽  
Peptide Toxins ◽  
Microbiome Profiling

Abstract Background: Most species in the genus Amanita are ectomycorrhizal fungi, and the cyclic peptide toxins that some species produce are notoriously deadly. In total, around 25 of these peptides were found in the fruiting bodies over the past 82 years, and whether any of them are present in the mycorrhizae is unknown. Reportedly, sequenced lethal Amanita genomes harbor a significant number of precursor genes of MSDIN family, indicating there could be a much larger capacity for cyclic peptide production in these mushrooms. However, it is largely unknown that to what extent these genes are transcribed, and further, translated into true cyclic peptides.Method: In this study, three poisonous Amanita species, A. rimosa, A. exitialis and A. subjunquillea, were sequenced through PacBio and Illumina techniques. For expression analysis, one strain of A. subjunquillea was sequenced through RNA-Seq. A genome-guided approach was adopted to identify cyclic peptides by coupling predicted toxin-biosynthetic genes with mass spectrometry (MS and MS/MS). To investigate whether any of the toxins were express in the microbiome, profiling of known major toxins was conducted on A. subjunquillea mycorrhizae via HRMS and gene cloning.Results: The resultant genomes showed significant potential to produce known and unknown cyclic peptides. Together with our 2 previously sequenced genomes, in total 37 unknown MSDIN genes were discovered. Expression of over 90% of the MSDIN genes was demonstrated in two strains of A. subjunquillea. Through the genome-guided approach, 12 MSDIN genes were found to produce true, novel cyclic peptides with no additional posttranslational modifications. When the ectomycorrhizae of A. subjunquillea were analyzed by MS, all major toxins were detected. The corresponding MSDINs for these cyclic peptides were successfully cloned directly from the mycorrhizae.Conclusions: The genome-guided approach provided a speedy method to identify cyclic peptides both in Amanita mushrooms and in the ectomycorrhizae. In this study, a significant number of novel MSDIN genes were discovered, most of which were found to be expressed in the tested species. The identification of the 12 novel cyclic peptides strongly suggests that Amanita species possess a much larger reservoir of these peptides than previously thought. This is the first report to demonstrate that the cyclic peptides in Amanita species are expressed in the mycorrhizal association. All four major toxins, α-amanitin, β-amanitin, phallacidin and phalloidin, are found to be present in the symbiosis, offering new clues to their biological function(s).

scholarly journals Novel Cyclic Peptides from Lethal Amanita Mushrooms through a Genome-Guided Approach

2021 ◽  
Vol 7 (3) ◽  
pp. 204
Author(s):  
Shengwen Zhou ◽  
Xincan Li ◽  
Yunjiao Lüli ◽  
Xuan Li ◽  
Zuo H. Chen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Amino Acid Residues ◽  
Fragment Ions ◽  
Peptide Pair ◽  
A Genome ◽  
Peptide Toxins ◽  
Poisonous Mushrooms ◽  
Large Peptide

Most species in the genus Amanita are ectomycorrhizal fungi comprising both edible and poisonous mushrooms. Some species produce potent cyclic peptide toxins, such as α-amanitin, which places them among the deadliest organisms known to mankind. These toxins and related cyclic peptides are encoded by genes of the “MSDIN” family (named after the first five amino acid residues of the precursor peptides), and it is largely unknown to what extent these genes are expressed in the basidiocarps. In the present study, Amanita rimosa and Amanita exitialis were sequenced through the PacBio and Illumina techniques. Together with our two previously sequenced genomes, Amanita subjunquillea and Amanita pallidorosea, in total, 46 previously unknown MSDIN genes were discovered. The expression of over 80% of the MSDIN genes was demonstrated in A. subjunquillea. Through a combination of genomics and mass spectrometry, 12 MSDIN genes were shown to produce novel cyclic peptides. To further confirm the results, three of the cyclic peptides were chemically synthesized. The tandem mass spectrometry (MS/MS) spectra of the natural and the synthetic peptides shared a majority of the fragment ions, demonstrating an identical structure between each peptide pair. Collectively, the results suggested that the genome-guided approach is reliable for identifying novel cyclic peptides in Amanita species and that there is a large peptide reservoir in these mushrooms.

scholarly journals The genetic origin of evolidine, the first cyclopeptide discovered in plants, and related orbitides

2020 ◽  
Vol 295 (42) ◽  
pp. 14510-14521 ◽  
Author(s):  
Mark F. Fisher ◽  
Colton D. Payne ◽  
Thaveshini Chetty ◽  
Darren Crayn ◽  
Oliver Berkowitz ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
De Novo ◽  
Forest Tree ◽  
Whole Genome Sequencing Data ◽  
The Novel ◽  
Rna Seq ◽  
Sequencing Data ◽  
The Family

Cyclic peptides are reported to have antibacterial, antifungal, and other bioactivities. Orbitides are a class of cyclic peptides that are small, head-to-tail cyclized, composed of proteinogenic amino acids and lack disulfide bonds; they are also known in several genera of the plant family Rutaceae. Melicope xanthoxyloides is the Australian rain forest tree of the Rutaceae family in which evolidine, the first plant cyclic peptide, was discovered. Evolidine (cyclo-SFLPVNL) has subsequently been all but forgotten in the academic literature, so to redress this we used tandem MS and de novo transcriptomics to rediscover evolidine and decipher its biosynthetic origin from a short precursor just 48 residues in length. We also identified another six M. xanthoxyloides orbitides using the same techniques. These peptides have atypically diverse C termini consisting of residues not recognized by either of the known proteases plants use to macrocyclize peptides, suggesting new cyclizing enzymes await discovery. We examined the structure of two of the novel orbitides by NMR, finding one had a definable structure, whereas the other did not. Mining RNA-seq and whole genome sequencing data from other species of the Rutaceae family revealed that a large and diverse family of peptides is encoded by similar sequences across the family and demonstrates how powerful de novo transcriptomics can be at accelerating the discovery of new peptide families.

scholarly journals The genetic origin of evolidine, the first cyclopeptide discovered in plants, and related orbitides

2020 ◽  
Author(s):  
Mark F. Fisher ◽  
Colton Payne ◽  
Thaveshini Chetty ◽  
Darren Crayn ◽  
Oliver Berkowitz ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
De Novo ◽  
Forest Tree ◽  
Whole Genome Sequencing Data ◽  
Resonance Spectroscopy ◽  
The Novel ◽  
Rna Seq ◽  
Sequencing Data

AbstractCyclic peptides are reported to have antibacterial, antifungal and other bioactivities. Several genera of the Rutaceae family are known to produce orbitides, which are small head-to-tail cyclic peptides composed of proteinogenic amino acids and lacking disulfide bonds. Melicope xanthoxyloides is an Australian rain forest tree of the Rutaceae family in which evolidine - the first plant cyclic peptide - was discovered. Evolidine (cyclo-SFLPVNL) has subsequently been all but forgotten in the academic literature, but here we use tandem mass spectrometry to rediscover evolidine and using de novo transcriptomics we show its biosynthetic origin to be from a short precursor just 48 residues in length. In all, seven M. xanthoxyloides orbitides were found and they had atypically diverse C-termini consisting of residues not recognized by either of the known proteases plants use to macrocyclize peptides. Two of the novel orbitides were studied by nuclear magnetic resonance spectroscopy and although one had definable structure, the other did not. By mining RNA-seq and whole genome sequencing data from other species, it was apparent that a large and diverse family of peptides is encoded by sequences like these across the Rutaceae.

A Target-Based Method for Designing Heterochiral Cyclic Peptide Binders: De Novo Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
Cyclic Peptide ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

scholarly journals The state of the art in soybean transcriptomics resources and gene coexpression networks

2021 ◽  
Author(s):  
Fabricio Almeida-Silva ◽  
Kanhu C Moharana ◽  
Thiago M Venancio
Keyword(s):  
State Of The Art ◽  
The State ◽  
Gene Coexpression Network ◽  
Rna Seq ◽  
Transcriptomic Data ◽  
The Past ◽  
Gene Coexpression ◽  
Genomics Research ◽  
Public Repositories ◽  
Coexpression Networks

Abstract In the past decade, over 3000 samples of soybean transcriptomic data have accumulated in public repositories. Here, we review the state of the art in soybean transcriptomics, highlighting the major microarray and RNA-seq studies that investigated soybean transcriptional programs in different tissues and conditions. Further, we propose approaches for integrating such big data using gene coexpression network and outline important web resources that may facilitate soybean data acquisition and analysis, contributing to the acceleration of soybean breeding and functional genomics research.

scholarly journals Snails In Silico: A Review of Computational Studies on the Conopeptides

Marine Drugs ◽  
2019 ◽  
Vol 17 (3) ◽  
pp. 145 ◽  
Author(s):  
Rachael Mansbach ◽  
Timothy Travers ◽  
Benjamin McMahon ◽  
Jeanne Fair ◽  
S. Gnanakaran
Keyword(s):  
Posttranslational Modifications ◽  
High Throughput Screening ◽  
Molecular Mechanisms ◽  
Defense Mechanism ◽  
Docking Studies ◽  
Chemical Diversity ◽  
Machine Learning Techniques ◽  
Peptide Toxins ◽  
Dynamics Simulations ◽  
And Function

Marine cone snails are carnivorous gastropods that use peptide toxins called conopeptides both as a defense mechanism and as a means to immobilize and kill their prey. These peptide toxins exhibit a large chemical diversity that enables exquisite specificity and potency for target receptor proteins. This diversity arises in terms of variations both in amino acid sequence and length, and in posttranslational modifications, particularly the formation of multiple disulfide linkages. Most of the functionally characterized conopeptides target ion channels of animal nervous systems, which has led to research on their therapeutic applications. Many facets of the underlying molecular mechanisms responsible for the specificity and virulence of conopeptides, however, remain poorly understood. In this review, we will explore the chemical diversity of conopeptides from a computational perspective. First, we discuss current approaches used for classifying conopeptides. Next, we review different computational strategies that have been applied to understanding and predicting their structure and function, from machine learning techniques for predictive classification to docking studies and molecular dynamics simulations for molecular-level understanding. We then review recent novel computational approaches for rapid high-throughput screening and chemical design of conopeptides for particular applications. We close with an assessment of the state of the field, emphasizing important questions for future lines of inquiry.

scholarly journals Improvement on Permeability of Cyclic Peptide/Peptidomimetic: Backbone N-Methylation as A Useful Tool

Marine Drugs ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. 311
Author(s):  
Yang Li ◽  
Wang Li ◽  
Zhengshuang Xu
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Three Dimensional ◽  
Conformational Space ◽  
Cell Permeability ◽  
Relative Importance ◽  
Intrinsic Properties ◽  
Surface Areas ◽  
Synthetic Methodologies ◽  
Three Dimensional Configuration

Peptides have a three-dimensional configuration that can adopt particular conformations for binding to proteins, which are well suited to interact with larger contact surface areas on target proteins. However, low cell permeability is a major challenge in the development of peptide-related drugs. In recent years, backbone N-methylation has been a useful tool for manipulating the permeability of cyclic peptides/peptidomimetics. Backbone N-methylation permits the adjustment of molecule’s conformational space. Several pathways are involved in the drug absorption pathway; the relative importance of each N-methylation to total permeation is likely to differ with intrinsic properties of cyclic peptide/peptidomimetic. Recent studies on the permeability of cyclic peptides/peptidomimetics using the backbone N-methylation strategy and synthetic methodologies will be presented in this review.

scholarly journals Ribosomal biosynthesis of the cyclic peptide toxins of Amanita mushrooms

Biopolymers ◽  
2010 ◽  
Vol 94 (5) ◽  
pp. 659-664 ◽  
Author(s):  
Jonathan D. Walton ◽  
Heather E. Hallen-Adams ◽  
Hong Luo
Keyword(s):  
Cyclic Peptide ◽  
Peptide Toxins ◽  
Amanita Mushrooms

scholarly journals A Transcriptomic Approach to the Metabolism of Tetrapyrrolic Photosensitizers in a Marine Annelid

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3924
Author(s):  
Maria Leonor Santos ◽  
Mariaelena D’Ambrosio ◽  
Ana P. Rodrigo ◽  
A. Jorge Parola ◽  
Pedro M. Costa
Keyword(s):  
Metabolic Pathways ◽  
Molecular Networks ◽  
Bile Pigments ◽  
Rna Seq ◽  
The Past ◽  
Wide Range ◽  
Genes Encoding ◽  
Organ Specific ◽  
Bright Green ◽  
Green Coloration

The past decade has seen growing interest in marine natural pigments for biotechnological applications. One of the most abundant classes of biological pigments is the tetrapyrroles, which are prized targets due their photodynamic properties; porphyrins are the best known examples of this group. Many animal porphyrinoids and other tetrapyrroles are produced through heme metabolic pathways, the best known of which are the bile pigments biliverdin and bilirubin. Eulalia is a marine Polychaeta characterized by its bright green coloration resulting from a remarkably wide range of greenish and yellowish tetrapyrroles, some of which have promising photodynamic properties. The present study combined metabolomics based on HPLC-DAD with RNA-seq transcriptomics to investigate the molecular pathways of porphyrinoid metabolism by comparing the worm’s proboscis and epidermis, which display distinct pigmentation patterns. The results showed that pigments are endogenous and seemingly heme-derived. The worm possesses homologs in both organs for genes encoding enzymes involved in heme metabolism such as ALAD, FECH, UROS, and PPOX. However, the findings also indicate that variants of the canonical enzymes of the heme biosynthesis pathway can be species- and organ-specific. These differences between molecular networks contribute to explain not only the differential pigmentation patterns between organs, but also the worm’s variety of novel endogenous tetrapyrrolic compounds.

ChemInform Abstract: Head-to-Tail Cyclic Peptides and Cyclic Peptide Libraries

ChemInform ◽  
2000 ◽  
Vol 31 (47) ◽  
pp. no-no
Author(s):  
Arno F. Spatola ◽  
Peteris Romanovskis
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Libraries
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