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Exploring the Diversity of Cysteine-Rich Natural Product Peptides via MS/MS Fingerprint Ions.

ABSTRACT: Natural product extracts present inherently complex matrices in which the identification of novel bioactive peptide species is challenged by low-abundance masses and significant structural and sequence diversity. Additionally, discovery efforts often result in the re-identification of known compounds, where modifications derived in vivo or during sample handling may obscure true sequence identity. Herein, we identify mass spectral (MS²) "fingerprint" ions characteristic of cyclotides, a diverse and biologically active family of botanical cysteine-rich peptides, based on regions of high sequence homology. We couple mass shift analysis with MS² spectral fingerprint ions cross referenced with CyBase-a cyclotide database-to discern unique mass species in Viola communis extracts from mass species that are likely already characterized and those with common modifications. The approach is extended to a related class of cysteine-rich peptides, the trypsin inhibitors, using the characterized botanical species Lagenaria siceraria. Coupling the observation of highly abundant MS² ions with mass shift analysis, we identify a new set of small, highly disulfide-bound cysteine-rich L. siceraria peptides.

SUBMITTER: Parsley NC

PROVIDER: S-EPMC7816094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Exploring the diversity of cysteine-rich natural product peptides via MS/MS fingerprint ions

Project description:Stable and commonly bioactive cysteine-rich peptides (CRPs) have are typically discovered via mass shift analysis. However, the accurate assessment of unique CRP species in a given botanical species is often challenged by same mass species, post-translational modifications or modifications derived from sample handling, and incomplete MS2 fragmentation. Mass spectral fingerprint ions can be leveraged to gain additional information about a mass species prior to full sequence characterization and with only poor quality MS2 spectra. Herein we identify sets of mass spectral fingerprint ions characteristic of the CRP cyclotide family, which may indicate a mass belongs to a specific cyclotide subfamily, and “tell-tale” ions that are of importance when discriminating putative cyclotide species, including common oxidation and over-alkylation ions observed experimentally. Cyclotide-containing V. communis material is used as proof-of-principle, where experimental cyclotide fingerprint ions are explored. Fingerprint ions derived from a third type of CRP, the trypsin inhibitors, are assessed in the gourd L. siceraria. Combining mass shift analysis with the identification of prominent MS2 fingerprint ions is then used to identify three novel CRPs. We demonstrate that abundant mass spectral fingerprint ions can be used to quickly discern masses of interest in complex matrices and masses that are already characterized, aiding prioritization of the most promising novel mass species in a natural product sample for characterization.

2020-09-04 | PXD019501 | Pride

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Project description:Cyclotides are plant cyclic cysteine-rich peptides (CRPs). The cyclic nature is reported to be gene-determined with a precursor containing a cyclization-competent domain which contains an essential C-terminal Asn/Asp (Asx) processing signal recognized by a cyclase. Linear forms of cyclotides are rare and are likely uncyclizable because they lack this essential C-terminal Asx signal (uncyclotide). Here we show that in the cyclotide-producing plant Clitoria ternatea, both cyclic and acyclic products, collectively named cliotides, can be bioprocessed from the same cyclization-competent precursor. Using an improved peptidomic strategy coupled with the novel Asx-specific endopeptidase butelase 2 to linearize cliotides at a biosynthetic ligation site for transcriptomic analysis, we characterized 272 cliotides derived from 38 genes. Several types of post-translational modifications of the processed cyclotides were observed, including deamidation, oxidation, hydroxylation, dehydration, glycosylation, methylation, and truncation. Taken together, our results suggest that cyclotide biosynthesis involves 'fuzzy' processing of precursors into both cyclic and linear forms as well as post-translational modifications to achieve molecular diversity, which is a commonly found trait of natural product biosynthesis.

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Atypical DNA methylation of genes encoding cysteine-rich peptides in Arabidopsis thaliana

Project description:In plants, transposons and non-protein-coding repeats are epigenetically silenced by CG and non-CG methylation. This pattern of methylation is mediated in part by small RNAs and two specialized RNA polymerases, Pol IV and Pol V, in a process called RNA-directed DNA methylation. By contrast, many protein-coding genes transcribed by Pol II contain in their gene bodies exclusively CG methylation that is independent of small RNAs and Pol IV/Pol V activities. It is unclear how the different methylation machineries distinguish between transposons and genes. Here we report on a group of atypical genes that display in their coding region a transposon-like methylation pattern, which is associated with gene silencing in sporophytic tissues. We performed a methylation-sensitive amplification polymorphism analysis to search for targets of RNA-directed DNA methylation in Arabidopsis thaliana and identified several members of a gene family encoding cysteine-rich peptides (CRPs). We also examined small RNA abundance at individual CRP genes in the wild type plant, nrpd1, and rdr2 mutant plants.

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