ORCID Profile
0000-0003-4957-6388
Current Organisations
Curtin University
,
Centre for Crop Disease Management
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Plant Biology | Plant Cell and Molecular Biology | Plant Developmental and Reproductive Biology | Plant Physiology | Crystallography | Biochemistry and cell biology | Biochemistry and Cell Biology | Structural biology (incl. macromolecular modelling) | Structural Biology (incl. Macromolecular Modelling) | Evolutionary Biology not elsewhere classified | Enzymes | Proteomics and Intermolecular Interactions (excl. Medical Proteomics) | Medical Biochemistry: Proteins And Peptides | Crop and Pasture Protection (Pests, Diseases and Weeds) | Plant Physiology | Genetic Technologies: Transformation, Site-Directed Mutagenesis, Etc. |
ANZSRC Socio-Economic Objective (SEO)
Summer Grains and Oilseeds not elsewhere classified | Expanding Knowledge in the Biological Sciences | Plant Production and Plant Primary Products not elsewhere classified | Plant Extract Crops (e.g. Pyrethrum, Jojoba) | Wheat | Crop Protection Chemicals | Winter Grains and Oilseeds not elsewhere classified | Control of Plant Pests, Diseases and Exotic Species in Farmland, Arable Cropland and Permanent Cropland Environments | Primary plant products not elsewhere classified | Agricultural Chemicals not elsewhere classified | Treatments (e.g. chemicals, antibiotics) | Flora, Fauna and Biodiversity at Regional or Larger Scales | Infectious Diseases
Related Links
Publications
LHP1, the Arabidopsis homologue of HETEROCHROMATIN PROTEIN1, is required for epigenetic silencing of FLC
Publisher: Proceedings of the National Academy of Sciences
Date: 20-03-2006
Abstract: Vernalization is the acceleration of flowering by prolonged cold that aligns the onset of reproductive development with spring conditions. A key step of vernalization in Arabidopsis is the epigenetic silencing of FLOWERING LOCUS C ( FLC ), which encodes a repressor of flowering. The vernalization-induced epigenetic silencing of FLC is associated with histone deacetylation and H3K27me2 and H3K9me2 methylation mediated by VRN/VIN proteins. We have analyzed whether different histone methyltransferases and the chromodomain protein LIKE HETEROCHROMATIN PROTEIN (LHP)1 might play a role in vernalization. No single loss-of-function mutation in the histone methyltransferases studied disrupted the vernalization response however, lhp1 mutants revealed a role for LHP1 in maintaining epigenetic silencing of FLC . Like LHP1, VRN1 functions in both flowering-time control and vernalization. We explored the localization of VRN1 and found it to be associated generally with Arabidopsis chromosomes but not the heterochromatic chromocenters. This association did not depend on vernalization or VRN2 function and was maintained during mitosis but was lost in meiotic chromosomes, suggesting that VRN1 may contribute to chromatin silencing that is not meiotically stable.
Inhibition of chloroplast translation as a new target for herbicides
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1CB00192B
Abstract: The antibiotic linezolid is an effective herbicide pre- and post-emergence. Making a series of analogues, we partly separated its antibacterial and herbicidal activities, making chloroplast translation a potential new herbicide mode of action.
Multiple Roles of Arabidopsis VRN1 in Vernalization and Flowering Time Control
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-07-2002
Abstract: Arabidopsis VRN genes mediate vernalization, the process by which a long period of cold induces a mitotically stable state that leads to accelerated flowering during later development. VRN1 encodes a protein that binds DNA in vitro in a non–sequence-specific manner and functions in stable repression of the major target of the vernalization pathway, the floral repressor FLC . Overexpression of VRN1 reveals a vernalization-independent function for VRN1 , mediated predominantly through the floral pathway integrator FT , and demonstrates that VRN1 requires vernalization-specific factors to target FLC .
Epigenetic Regulation in the Control of Flowering
Publisher: Cold Spring Harbor Laboratory
Date: 2004
Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2021
DOI: 10.1101/2021.11.10.468163
Abstract: Herbicides are vital for modern agriculture, but their utility is threatened by genetic or metabolic resistance in weeds as well as heightened regulatory scrutiny. Of the known herbicide modes of action, 6-hydroxymethyl-7,8-dihydropterin synthase (DHPS) which is involved in folate biosynthesis, is targeted by just one commercial herbicide, asulam. A mimic of the substrate para -aminobenzoic acid, asulam is chemically similar to sulfonamide antibiotics – and while still in widespread use, asulam has faced regulatory scrutiny. With an entire mode of action represented by just one commercial agrochemical, we sought to improve the understanding of its plant target. Here we solve a 2.6 Å resolution crystal structure for Arabidopsis thaliana DHPS that is conjoined to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and reveal a strong structural conservation with bacterial counterparts at the sulfonamide-binding pocket of DHPS. We demonstrate asulam and the antibiotics sulfacetamide and sulfamethoxazole have herbicidal as well as antibacterial activity and explore the structural basis of their potency by modelling these compounds in mitochondrial HPPK/DHPS. Our findings suggest limited opportunity for the rational design of plant selectivity from asulam and that pharmacokinetic or delivery differences between plants and microbes might be the best approaches to safeguard this mode of action.
Herbicidal properties of antimalarial drugs
Publisher: Springer Science and Business Media LLC
Date: 31-03-2017
DOI: 10.1038/SREP45871
Abstract: The evolutionary relationship between plants and the malarial parasite Plasmodium falciparum is well established and underscored by the P. falciparum apicoplast, an essential chloroplast-like organelle. As a result of this relationship, studies have demonstrated that herbicides active against plants are also active against P. falciparum and thus could act as antimalarial drug leads. Here we show the converse is also true many antimalarial compounds developed for human use are highly herbicidal. We found that human antimalarial drugs (e.g. sulfadiazine, sulfadoxine, pyrimethamine, cycloguanil) were lethal to the model plant Arabidopsis thaliana at similar concentrations to market herbicides glufosinate and glyphosate. Furthermore, the physicochemical properties of these herbicidal antimalarial compounds were similar to commercially used herbicides. The implications of this finding that many antimalarial compounds are herbicidal proffers two novel applications: (i) using the genetically tractable A. thaliana to reveal mode-of-action for understudied antimalarial drugs, and (ii) co-opting antimalarial compounds as a new source for much needed herbicide lead molecules.
15N cyclotides by whole plant labeling
Publisher: Wiley
Date: 2008
DOI: 10.1002/BIP.21012
Abstract: Cyclotides are 28-37 amino acid peptides incorporating three disulfide bonds and a cyclic backbone. Their cyclic and knotted topology renders them immune to denaturation by heat or organic solvents and highly resistant to proteolysis. They have a range of interesting and potentially useful pharmaceutical properties and have been proposed as scaffolds within which peptides with drug activities can be stabilized for delivery. Some members of the family also have agricultural applications deriving from their potent insecticidal activity. Labeling peptides with the NMR-active and stable 15N isotope facilitates a range of studies by NMR, including structural and dynamics studies and their use as tracers. However, owing to their head-to-tail cyclized peptide backbone labeled cyclotides are not amenable to conventional recombinant labeling strategies. We have developed an approach to overcome this limitation by growing the cyclotide-bearing plant Oldenlandia affinis on nitrogen-free agar media supplemented with 15N salts and obtaining complete labeling at no detriment to plant biomass. We purified the insecticidal cyclotides kalata B1 and kalata B2 as ex les and provide heteronuclear single quantum coherence (HSQC) NMR spectra for each. This method of labeling cyclotides involves only a fraction of the cost of uniform labeling by solid-phase peptide synthesis.
The alpine violet, Viola biflora, is a rich source of cyclotides with potent cytotoxicity
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.PHYTOCHEM.2007.10.023
Abstract: The cyclotides are currently the largest known family of head-to-tail cyclic proteins. The complex structure of these small plant proteins, which consist of approximately 30 amino acid residues, contains both a circular peptide backbone and a cystine knot, the combination of which produces the cyclic cystine knot motif. To date, cyclotides have been found in plants from the Rubiaceae, Violaceace and Cucurbitaceae families, and are believed to be part of the host defence system. In addition to their insecticidal effect, cyclotides have also been shown to be cytotoxic, anti-HIV, antimicrobial and haemolytic agents. In this study, we show that the alpine violet Viola biflora (Violaceae) is a rich source of cyclotides. The sequences of 11 cyclotides, vibi A-K, were determined by isolation and MS/MS sequencing of proteins and screening of a cDNA library of V. biflora in parallel. For the cDNA screening, a degenerate primer against a conserved (AAFALPA) motif in the cyclotide precursor ER signal sequence yielded a series of predicted cyclotide sequences that were correlated to those of the isolated proteins. There was an apparent discrepancy between the results of the two strategies as only one of the isolated proteins could be identified as a cDNA clone. Finally, to correlate amino acid sequence to cytotoxic potency, vibi D, E, G and H were analysed using a fluorometric microculture cytotoxicity assay using a lymphoma cell line. The IC(50)-values of the bracelet cyclotides vibi E, G and H ranged between 0.96 and 5.0 microM while the Möbius cyclotide vibi D was not cytotoxic at 30 microM.
Cycloquest: Identification of Cyclopeptides via Database Search of Their Mass Spectra against Genome Databases
Publisher: American Chemical Society (ACS)
Date: 28-10-2011
DOI: 10.1021/PR201019Q
Cyclotides: macrocyclic peptides with applications in drug design and agriculture
Publisher: Springer Science and Business Media LLC
Date: 10-2009
DOI: 10.1007/S00018-009-0159-3
Abstract: Cyclotides are disulfide-rich peptides from plants that are exceptionally stable as a result of their unique cyclic cystine knot structural motif. Their natural role is thought to be as plant defence agents, most notably against insect pests, but they also have potential applications in drug design and agriculture. This article identifies gaps in current knowledge on cyclotides and suggests future directions for research into this fascinating family of ultra-stable mini-proteins.
Novel Cyclic Peptides in Seed of Annona muricata are Ribosomally Synthesized
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2019
DOI: 10.1101/647552
Abstract: Small, cyclic peptides are reported to have many bioactivities. In bacteria and fungi they can be made by non-ribosomal peptide synthetases, but in plants they are exclusively ribosomal. Cyclic peptides from the Annona genus possess cytotoxic and anti-inflammatory activities, but their biosynthesis is unknown. The medicinal soursop plant, Annona muricata , contains annomuricatins A (cyclo-PGFVSA) and B (cyclo-PNAWLGT). Here, using de novo transcriptomics and tandem mass spectrometry, we identify a suite of short transcripts for precursor proteins for ten validated annomuricatins, nine of which are novel. In their precursors, annomuricatins are preceded by an absolutely conserved Glu and each peptide sequence has a conserved proto- C -terminal Pro, revealing parallels with the segetalin orbitides from the seed of Vaccaria hispanica , which are processed through ligation by a prolyl oligopeptidase in a transpeptidation reaction.
Mature forms of the major seed storage albumins in sunflower: A mass spectrometric approach
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.JPROT.2016.05.004
Abstract: Seed storage albumins are abundant, water-soluble proteins that are degraded to provide critical nutrients for the germinating seedling. It has been established that the sunflower albumins encoded by SEED STORAGE ALBUMIN 2 (SESA2), SESA20 and SESA3 are the major components of the albumin-rich fraction of the common sunflower Helianthus annuus. To determine the structure of sunflowers most important albumins we performed a detailed chromatographic and mass spectrometric characterization to assess what post-translational processing they receive prior to deposition in the protein storage vacuole. We found that SESA2 and SESA20 each encode two albumins. The first of the two SESA2 albumins (SESA2-1) exists as a monomer of 116 or 117 residues, differing by a threonine at the C-terminus. The second of the two SESA2 albumins (SESA2-2) is a monomer of 128 residues. SESA20 encodes the albumin SESA20-2, which is a 127-residue monomer, whereas SESA20-1 was not abundant enough to be structurally described. SESA3, which has been partly characterized previously, was found in several forms with methylation of its asparagine residues. In contrast to other dicot albumins, which are generally matured into a heterodimer, all the dominant mature sunflower albumins SESA2, SESA20-2, SESA3 and its post-translationally modified analogue SESA3-a are monomeric. Sunflower plants have been bred to thrive in various climate zones making them favored crops to meet the growing worldwide demand by humans for protein. The abundance of seed storage proteins makes them an important source of protein for animal and human nutrition. This study explores the structures of the dominant sunflower napin-type seed storage albumins to understand what structures evolution has favored in the most abundant proteins in sunflower seed.
A comparative study of extraction methods reveals preferred solvents for cystine knot peptide isolation from Momordica cochinchinensis seeds
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.FITOTE.2014.02.016
Abstract: MCoTI-I and MCoTI-II (short for Momordica cochinchinensis Trypsin Inhibitor-I and -II, respectively) are attractive candidates for developing novel intracellular-targeting drugs because both are exceptionally stable and can internalize into cells. These seed-derived cystine knot peptides are ex les of how natural product discovery efforts can lead to biomedical applications. However, discovery efforts are sometimes h ered by the limited availability of seed materials, highlighting the need for efficient extraction methods. In this study, we assessed five extraction methods using M. cochinchinensis seeds, a source of well-characterized cystine knot peptides. The most efficient extraction of nine known cystine knot peptides was achieved by a method based on acetonitrile/water/formic acid (25:24:1), followed by methods based on sodium acetate (20 mM, pH 5.0), ammonium bicarbonate (5 mM, pH 8.0), and boiling water. On average, the yields obtained by these four methods were more than 250-fold higher than that obtained using dichloromethane/methanol (1:1) extraction, a previously applied standard method. Extraction using acetonitrile/water/formic acid (25:24:1) yielded the highest number of reconstructed masses within the majority of plant-derived cystine knot peptide mass range but only accounted for around 50% of the total number of masses, indicating that any single method may result in under-s ling. Applying acetonitrile/water/formic acid (25:24:1), boiling water, and ammonium bicarbonate (5 mM, pH 8.0) extractions either successively or discretely significantly increased the s ling number. Overall, acetonitrile/water/formic acid (25:24:1) can facilitate efficient extraction of cystine-knot peptides from M. cochinchinensis seeds but for discovery purposes the use of a combination of extraction methods is recommended where practical.
Cyclotides are a component of the innate defense of Oldenlandia affinis
Publisher: Wiley
Date: 2010
DOI: 10.1002/BIP.21419
Abstract: Cyclotides are small cysteine-rich plant peptides similar in size and processing to the defensins. Long-term growth of the Rubiaceae family plant Oldenlandia affinis under different conditions reveals a erse cyclotide gene and peptide expression profile, including tissue specificity, suggesting that different cyclotides are regulated differently both spatially and in response to the environment. To determine whether cyclotide precursor gene regulation was dynamic we exposed O. affinis to a range of abiotic, biotic, and hormonal stimuli and monitored Oak1-4 expression over a 48-h period. Unlike some defensins, the genes for cyclotide precursor proteins Oak1-4 did not display dynamic change, indicating that they contribute to the basal defense of O. affinis. Despite this lack of dynamism, the cyclotide profile of plants grown on plates differed markedly from field-grown plants and so prompted attempts to discover novel cyclotides and precursor genes. The two most abundant cyclotides from plate-grown O. affinis were sequenced and one was found to be an unusual linear cyclotide derivative, kalata B20-lin. Degenerate PCR of plate-grown O. affinis obtained five novel cyclotide genes including Oak9 which encodes for kalata B20-lin and appears to have arisen by the presence of a premature stop codon.
DNA Gyrase Is the Target for the Quinolone Drug Ciprofloxacin in Arabidopsis thaliana
Publisher: Elsevier BV
Date: 02-2016
Next generation sequencing and de novo transcriptomics to study gene evolution
Publisher: Springer Science and Business Media LLC
Date: 20-10-2014
Antimalarial drugs as inspiration for herbicides
Publisher: Research Information Ltd.
Date: 10-2020
DOI: 10.1564/V31_OCT_05
Abstract: In addition to good stewardship, the unabated rise in herbicide resistance and dearth of truly new herbicides demands that new molecules be found. Over 30 years ago, a chloroplast-like organelle was found in the malarial parasite Plasmodium falciparum and herbicides demonstrated a close relationship existed to plants. Recently this idea was turned on its head by exploiting the boom in malaria research to search for new herbicide chemistry and it provided interesting starting points for development. The merit of such an approach is underlined by tetflupyrolimet, the first truly novel herbicide in 30 years, and whose target has been a popular subject for antimalarial drug development for 15 years. Which other antimalarial targets, drugs and drug leads might reach across the parasite-plant ide to inspire new herbicides?
Plant asparaginyl endopeptidases and their structural determinants of function
Publisher: Portland Press Ltd.
Date: 05-03-2021
DOI: 10.1042/BST20200908
Abstract: Asparaginyl endopeptidases (AEPs) are versatile enzymes that in biological systems are involved in producing three different catalytic outcomes for proteins, namely (i) routine cleavage by bond hydrolysis, (ii) peptide maturation, including macrocyclisation by a cleavage-coupled intramolecular transpeptidation and (iii) circular permutation involving separate cleavage and transpeptidation reactions resulting in a major reshuffling of protein sequence. AEPs differ in their preference for cleavage or transpeptidation reactions, catalytic efficiency, and preference for asparagine or aspartate target residues. We look at structural analyses of various AEPs that have laid the groundwork for identifying important determinants of AEP function in recent years, with much of the research impetus arising from the potential biotechnological and pharmaceutical applications.
Two proteins for the price of one: Structural studies of the dual-destiny protein preproalbumin with sunflower trypsin inhibitor-1
Publisher: Elsevier BV
Date: 07-2017
Defining the Familial Fold of the Vicilin-Buried Peptide Family
Publisher: American Chemical Society (ACS)
Date: 30-09-2020
Physical clustering of FLC alleles during Polycomb-mediated epigenetic silencing in vernalization
Publisher: Cold Spring Harbor Laboratory
Date: 09-2013
Abstract: Vernalization, the promotion of flowering by cold, involves Polycomb-mediated epigenetic silencing of FLOWERING LOCUS C ( FLC ). Cold progressively promotes cell-autonomous switching to a silenced state. Here, we used live-cell imaging of FLC-lacO to monitor changes in nuclear organization during vernalization. FLC-lacO alleles physically cluster during the cold and generally remain so after plants are returned to warm. Clustering is dependent on the Polycomb trans -factors necessary for establishment of the FLC silenced state but not on LIKE HETEROCHROMATIN PROTEIN 1, which functions to maintain silencing. These data support the view that physical clustering may be a common feature of Polycomb-mediated epigenetic switching mechanisms.
A herbicide structure-activity analysis of the antimalarial lead compound MMV007978 against Arabidopsis thaliana
Publisher: Wiley
Date: 05-03-2018
DOI: 10.1002/PS.4872
Abstract: To fight herbicide-resistant weeds, new herbicides are needed particularly ones with new modes of action. Building on the revelation that many antimalarial drugs are herbicidal, here we focus on the Medicines for Malaria Venture antimalarial lead compound MMV007978 that has herbicidal activity against the model plant Arabidopsis thaliana. Twenty-two variations of the lead compound thiophenyl motif revealed that change was tolerated provided ring size and charge were retained. MMV007978 was active against select monocot and dicot weeds, and physiological profiling indicated that its mode of action is related to germination and cell ision. Of interest is the fact that the compound has a profile that is currently not found among known herbicides. We demonstrate that the antimalarial compound MMV007978 is also herbicidal and that exploiting lead compounds that are often understudied could lead to the identification of interesting herbicidal scaffolds. Further structural investigation of MMV007978 could provide improved herbicidal chemistries with a potential new mode of action. © 2018 Society of Chemical Industry.
Systematic, small-scale screening with Arabidopsis reveals herbicides synergies that extend to lettuce
Publisher: Wiley
Date: 10-07-2021
DOI: 10.1002/PS.6533
Abstract: Combining herbicides into a mixture is a common approach used to overcome the potential for herbicide resistance in weeds. Many herbicide mixtures can be antagonistic and they are rarely synergistic. Here, 24 commercial herbicides, each representing a different mode of action were used to create a matrix of all 276 unique combinations to search for new synergies in agar using Arabidopsis thaliana . Herbicides were used at an appropriate sublethal dose such that any synergies gave visible growth inhibition. We found five synergies including three new ones, namely mesotrione–norflurazon, mesotrione–clethodim and clomazone–paraquat. All three were reproducible in soil‐grown conditions. Interestingly, the three new combinations all included a bleaching herbicide, suggesting that synergy might be a class‐specific phenomenon. We also found that mesotrione–norflurazon and mesotrione–clethodim combinations were also synergistic against lettuce ( Lactuca sativa ), but not tef ( Eragrostis tef ). Our study shows that screening herbicide mixtures against A. thaliana is an efficient approach for finding rare herbicide synergies.
A tripartite approach identifies the major sunflower seed albumins
Publisher: Springer Science and Business Media LLC
Date: 14-01-2016
DOI: 10.1007/S00122-015-2653-3
Abstract: We have used a combination of genomic, transcriptomic, and proteomic approaches to identify the napin-type albumin genes in sunflower and define their contributions to the seed albumin pool. Seed protein content is determined by the expression of what are typically large gene families. A major class of seed storage proteins is the napin-type, water soluble albumins. In this work we provide a comprehensive analysis of the napin-type albumin content of the common sunflower (Helianthus annuus) by analyzing a draft genome, a transcriptome and performing a proteomic analysis of the seed albumin fraction. We show that although sunflower contains at least 26 genes for napin-type albumins, only 15 of these are present at the mRNA level. We found protein evidence for 11 of these but the albumin content of mature seeds is dominated by the encoded products of just three genes. So despite high genetic redundancy for albumins, only a small sub-set of this gene family contributes to total seed albumin content. The three genes identified as producing the majority of sunflower seed albumin are potential future candidates for manipulation through genetics and breeding.
An interstitial peptide is readily processed from within seed proteins
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.PLANTSCI.2019.05.001
Abstract: The importance of de novo protein evolution is apparent, but most ex les are de novo coding transcripts evolving from silent or non-coding DNA. The peptide macrocycle SunFlower Trypsin Inhibitor 1 (SFTI-1) evolved over 45 million years from genetic expansion within the N-terminal 'discarded' region of an ancestral seed albumin precursor. SFTI-1 and its adjacent albumin are both processed into separate, mature forms by asparaginyl endopeptidase (AEP). Here to determine whether the evolution of SFTI-1 in a latent region of its precursor was critical, we used a transgene approach in A. thaliana analysed by peptide mass spectrometry and RT-qPCR. SFTI could emerge from alternative locations within preproalbumin as well as emerge with precision from unrelated seed proteins via AEP-processing. SFTI production was possible with the adjacent albumin, but peptide levels dropped greatly without the albumin. The ability for SFTI to be processed from multiple sequence contexts and different proteins suggests that to make peptide, it was not crucial for the genetic expansion that gave rise to SFTI and its family to be within a latent protein region. Interstitial peptides, evolving like SFTI within existing proteins, might be more widespread and as a mechanism, SFTI exemplifies a stable, new, functional peptide that did not need a new gene to evolve de novo.
Cycloquest: identification of cyclopeptides via database search of their mass spectra against genome databases.
Publisher: American Chemical Society (ACS)
Date: 07-09-2011
DOI: 10.1021/PR200323A
Solution NMR and racemic crystallography provide insights into a novel structural class of cyclic plant peptides
Publisher: Cold Spring Harbor Laboratory
Date: 28-07-2021
DOI: 10.1101/2021.07.28.454061
Abstract: Head-to-tail cyclic and disulfide-rich peptides are natural products with applications in drug design. Among these are the PawS-Derived Peptides (PDPs) produced in seeds of the daisy plant family. PDP-23 is a unique member of this class in that it is twice the typical size and adopts two β-hairpins separated by a hinge region. The β-hairpins - both stabilised by a single disulfide bond - fold together into a V-shaped tertiary structure creating a hydrophobic core. In water two PDP-23 molecules merge their hydrophobic cores to form a square prism quaternary structure. Here, we synthesised PDP-23 and its enantiomer comprising all D-amino acids, which allowed us to confirm these solution NMR structural data by racemic crystallography. Furthermore, we discovered the related PDP-24. NMR analysis showed that PDP-24 does not form a dimeric structure and it has poor water solubility, but in less polar solvents adopts near identical secondary and tertiary structure to PDP-23. The natural role of these peptides in plants remains enigmatic, as we did not observe any antimicrobial or insecticidal activity. However, the plasticity of these larger PDPs and their ability to change structure under different conditions make them appealing peptide drug scaffolds.
Orientation and Location of the Cyclotide Kalata B1 in Lipid Bilayers Revealed by Solid-State NMR
Publisher: Elsevier BV
Date: 02-2017
The genetic origin of evolidine, the first cyclopeptide discovered in plants, and related orbitides
Publisher: Elsevier BV
Date: 10-2020
Diverse cyclic seed peptides in the Mexican zinnia (Zinnia haageana)
Publisher: Wiley
Date: 11-2016
DOI: 10.1002/BIP.22901
Abstract: A new family of small plant peptides was recently described and found to be widespread throughout the Millereae and Heliantheae tribes of the sunflower family Asteraceae. These peptides originate from the post-translational processing of unusual seed-storage albumin genes, and have been termed PawS-derived peptides (PDPs). The prototypic family member is a 14-residue cyclic peptide with potent trypsin inhibitory activity named SunFlower Trypsin Inhibitor (SFTI-1). In this study we present the features of three new PDPs discovered in the seeds of the sunflower species Zinnia haageana by a combination of de novo transcriptomics and liquid chromatography-mass spectrometry. Two-dimensional solution NMR spectroscopy was used to elucidate their structural characteristics. All three Z. haageana peptides have well-defined folds with a head-to-tail cyclized peptide backbone and a single disulfide bond. Although two possess an anti-parallel β-sheet structure, like SFTI-1, the Z. haageana peptide PDP-21 has a more irregular backbone structure. Despite structural similarities with SFTI-1, PDP-20 was not able to inhibit trypsin, thus the functional roles of these peptides is yet to be discovered. Defining the structural features of the small cyclic peptides found in the sunflower family will be useful for guiding the exploitation of these peptides as scaffolds for grafting and protein engineering applications.
Solution NMR and racemic crystallography provide insights into a novel structural class of cyclic plant peptides
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1CB00155H
Abstract: Larger members of the PawS-Derived family of cyclic plant peptides form complex structures. The graphical abstract shows the racemic crystal structure of the homodimeric PDP-23 as well as the solution NMR structure of PDP-24.
Florigen takes two to tango
Publisher: Springer Science and Business Media LLC
Date: 19-09-2011
DOI: 10.1038/NCHEMBIO.666
Refining physico-chemical rules for herbicides using an antimalarial library
Publisher: Cold Spring Harbor Laboratory
Date: 27-10-2020
DOI: 10.1101/2020.10.27.356576
Abstract: Successful herbicides, like drugs, have physico-chemical properties that usually fall within certain limits. A recent analysis of 334 herbicides showed similar properties to the ‘rule of five’ for human orally-delivered drugs, but herbicides erged from this for proton donors, partition coefficients and molecular weight. To refine rules for herbicides, we exploited the close evolutionary relationship between P. falciparum and plants by screening the Malaria Box, a 400-compound library composed of novel chemical scaffolds with activity against blood stage malaria parasite Plasmodium falciparum . A high proportion (52 of 400) were herbicidal to Arabidopsis thaliana on agar plates. Thirty-nine of these 52 herbicidal compounds were tested on soil and 16 compounds were herbicidal. These data were used to predict whether a herbicidal hit found on agar will work on soil-grown plants. The physico-chemical parameters were weighted to logP and formal charge and used to generate weighted scores to a large chemical library of liver-stage effective antimalarial leads. Of the six top-scoring compounds, one had a potency comparable to commercial herbicides. This novel compound MMV1206386 had no close structural matches among commercial herbicides. Physiological profiling suggested that MMV1206386 has a new mode of action and overall demonstrates how weighted rules can help during herbicide discovery programs.
Cosuppression of eukaryotic release factor 1-1 in Arabidopsis affects cell elongation and radial cell division
Publisher: Oxford University Press (OUP)
Date: 19-08-2005
Abstract: The role of the eukaryotic release factor 1 (eRF1) in translation termination has previously been established in yeast however, only limited characterization has been performed on any plant homologs. Here, we demonstrate that cosuppression of eRF1-1 in Arabidopsis (Arabidopsis thaliana) has a profound effect on plant morphology, resulting in what we term the broomhead phenotype. These plants primarily exhibit a reduction in internode elongation causing the formation of a broomhead-like cluster of malformed siliques at the top of the inflorescence stem. Histological analysis of broomhead stems revealed that cells are reduced in height and display ectopic lignification of the phloem cap cells, some phloem sieve cells, and regions of the fascicular cambium, as well as enhanced lignification of the interfascicular fibers. We also show that cell ision in the fascicular cambial regions is altered, with the majority of vascular bundles containing cambial cells that are disorganized and possess enlarged nuclei. This is the first attempt at functional characterization of a release factor in vivo in plants and demonstrates the importance of eRF1-1 function in Arabidopsis.
An Orbitide from Ratibida columnifera Seed Containing 16 Amino Acid Residues
Publisher: American Chemical Society (ACS)
Date: 08-08-2019
DOI: 10.1021/ACS.JNATPROD.9B00111
Abstract: Cyclic peptides are abundant in plants and have attracted interest due to their bioactivity and potential as drug scaffolds. Orbitides are head-to-tail cyclic peptides that are ribosomally synthesized, post-translationally modified, and lack disulfide bonds. All known orbitides contain 5-12 amino acid residues. Here we describe PLP-53, a novel orbitide from the seed of
Structural basis of ribosomal peptide macrocyclization in plants
Publisher: eLife Sciences Publications, Ltd
Date: 31-01-2018
DOI: 10.7554/ELIFE.32955
Abstract: Constrained, cyclic peptides encoded by plant genes represent a new generation of drug leads. Evolution has repeatedly recruited the Cys-protease asparaginyl endopeptidase (AEP) to perform their head-to-tail ligation. These macrocyclization reactions use the substrates amino terminus instead of water to deacylate, so a peptide bond is formed. How solvent-exposed plant AEPs macrocyclize is poorly understood. Here we present the crystal structure of an active plant AEP from the common sunflower, Helianthus annuus. The active site contained electron density for a tetrahedral intermediate with partial occupancy that predicted a binding mode for peptide macrocyclization. By substituting catalytic residues we could alter the ratio of cyclic to acyclic products. Moreover, we showed AEPs from other species lacking cyclic peptides can perform macrocyclization under favorable pH conditions. This structural characterization of AEP presents a logical framework for engineering superior enzymes that generate macrocyclic peptide drug leads.
The genetic origin of evolidine, the first cyclopeptide discovered in plants, and related orbitides
Publisher: Cold Spring Harbor Laboratory
Date: 12-06-2020
DOI: 10.1101/2020.06.10.145326
Abstract: Cyclic 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 erse 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 erse family of peptides is encoded by sequences like these across the Rutaceae.
Targeting plant DIHYDROFOLATE REDUCTASE with antifolates and mechanisms for genetic resistance
Publisher: Wiley
Date: 28-06-2018
DOI: 10.1111/TPJ.13983
Abstract: The folate biosynthetic pathway and its key enzyme dihydrofolate reductase (DHFR) is a popular target for drug development due to its essential role in the synthesis of DNA precursors and some amino acids. Despite its importance, little is known about plant DHFRs, which, like the enzymes from the malarial parasite Plasmodium, are bifunctional, possessing DHFR and thymidylate synthase (TS) domains. Here using genetic knockout lines we confirmed that either DHFR-TS1 or DHFR-TS2 (but not DHFR-TS3) was essential for seed development. Screening mutated Arabidopsis thaliana seeds for resistance to antimalarial DHFR-inhibitor drugs pyrimethamine and cycloguanil identified causal lesions in DHFR-TS1 and DHFR-TS2, respectively, near the predicted substrate-binding site. The different drug resistance profiles for the plants, enabled by the G137D mutation in DHFR-TS1 and the A71V mutation in DHFR-TS2, were consistent with biochemical studies using recombinant proteins and could be explained by structural models. These findings provide a great improvement in our understanding of plant DHFR-TS and suggest how plant-specific inhibitors might be developed, as DHFR is not currently targeted by commercial herbicides.
Structural Characterization of the PawL-Derived Peptide Family, an Ancient Subfamily of Orbitides
Publisher: American Chemical Society (ACS)
Date: 21-10-2021
DOI: 10.1021/ACS.JNATPROD.1C00672
Abstract: Plants are an excellent source of bioactive peptides, often with disulfide bonds and/or a cyclic backbone. While focus has predominantly been directed at disulfide-rich peptides, a large family of small, cyclic plant peptides lacking disulfide bonds, known as orbitides, has been relatively ignored. A recently discovered subfamily of orbitides is the PawL-derived peptides (PLPs), produced during the maturation of precursors for seed storage albumins. Although their evolutionary origins have been dated, in-depth exploration of the family's structural characteristics and potential bioactivities remains to be conducted. Here we present an extensive and systematic characterization of the PLP family. Nine PLPs were chosen and prepared by solid phase peptide synthesis. Their structural features were studied using solution NMR spectroscopy, and seven were found to possess regions of backbone order. Ordered regions consist of β-turns, with some PLPs adopting two well-defined β-turns within sequences as short as seven residues, which are largely the result of side chain interactions. Our data highlight that the sequence ersity within this family results in equally erse structures. None of these nine PLPs showed antibacterial or antifungal activity.
Natural structural diversity within a conserved cyclic peptide scaffold
Publisher: Springer Science and Business Media LLC
Date: 10-2016
DOI: 10.1007/S00726-016-2333-X
Abstract: We recently isolated and described the evolutionary origin of a erse class of small single-disulfide bonded peptides derived from Preproalbumin with SFTI-1 (PawS1) proteins in the seeds of flowering plants (Asteraceae). The founding member of the PawS derived peptide (PDP) family is the potent trypsin inhibitor SFTI-1 (sunflower trypsin inhibitor-1) from Helianthus annuus, the common sunflower. Here we provide additional structures and describe the structural ersity of this new class of small peptides, derived from solution NMR studies, in detail. We show that although most have a similar backbone framework with a single disulfide bond and in many cases a head-to-tail cyclized backbone, they all have their own characteristics in terms of projections of side-chains, flexibility and physiochemical properties, attributed to the variety of their sequences. Small cyclic and constrained peptides are popular as drug scaffolds in the pharmaceutical industry and our data highlight how amino acid side-chains can fine-tune conformations in these promising peptides.
A fungal tolerance trait and selective inhibitors proffer HMG-CoA reductase as a herbicide mode-of-action
Publisher: Springer Science and Business Media LLC
Date: 22-09-2022
DOI: 10.1038/S41467-022-33185-0
Abstract: Decades of intense herbicide use has led to resistance in weeds. Without innovative weed management practices and new herbicidal modes of action, the unabated rise of herbicide resistance will undoubtedly place further stress upon food security. HMGR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is the rate limiting enzyme of the eukaryotic mevalonate pathway successfully targeted by statins to treat hypercholesterolemia in humans. As HMGR inhibitors have been shown to be herbicidal, HMGR could represent a mode of action target for the development of herbicides. Here, we present the crystal structure of a HMGR from Arabidopsis thaliana (AtHMG1) which exhibits a wider active site than previously determined structures from different species. This plant conserved feature enables the rational design of specific HMGR inhibitors and we develop a tolerance trait through sequence analysis of fungal gene clusters. These results suggest HMGR to be a viable herbicide target modifiable to provide a tolerance trait.
Improved herbicide discovery using physico-chemical rules refined by antimalarial library screening
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1RA00914A
Abstract: Trawling hundreds of antimalarials for herbicides, we develop a weighted scoring system for the phys-chem ‘rules’ of herbicide-likeness. Using this, we discover the antimalarial MMV1206386 is herbicidal via a novel mode of action.
Structural basis for a natural circular permutation in proteins
Publisher: Cold Spring Harbor Laboratory
Date: 29-10-2020
DOI: 10.1101/2020.10.28.360099
Abstract: Over 30 years ago, an intriguing post-translational modification was discovered to be responsible for creating concanavalin A (conA), a carbohydrate-binding protein found in the seeds of jack bean ( Canavalia ensiformis ) and commercially used for carbohydrate chromatography. Biosynthesis of conA involves what was then an unprecedented rearrangement in amino acid sequence, whereby the N-terminal half of the gene-encoded conA precursor is swapped to become the C-terminal half of conA. The cysteine protease, asparaginyl endopeptidase (AEP), was shown to be involved, but its mechanism was not fully elucidated. To understand the structural basis and consequences of conA circular permutation, we generated a recombinant jack bean conA precursor (pro-conA) plus jack bean AEP (CeAEP1) and solved crystal structures for each to 2.1 Å and 2.7 Å respectively. By reconstituting the biosynthesis of conA in vitro , we prove CeAEP1 alone can perform both the cleavage and cleavage-coupled transpeptidation to form conA. CeAEP1 structural analysis reveals how it is capable of carrying out both these reactions. Biophysical assays illustrated that conA is more thermally and pH stable than pro-conA, consistent with fewer intermolecular interactions between subunits in the pro-conA crystal structure. These findings elucidate the consequences of circular permutation in the only post-translation ex le known to occur in nature.
Cyclic peptides arising by evolutionary parallelism via asparaginyl-endopeptidase-mediated biosynthesis
Publisher: Oxford University Press (OUP)
Date: 07-2012
Protocol: A simple phenol-based method for 96-well extraction of high quality RNA from Arabidopsis
Publisher: Springer Science and Business Media LLC
Date: 13-03-2011
Abstract: Many experiments in modern plant molecular biology require the processing of large numbers of s les for a variety of applications from mutant screens to the analysis of natural variants. A severe bottleneck to many such analyses is the acquisition of good yields of high quality RNA suitable for use in sensitive downstream applications such as real time quantitative reverse-transcription-polymerase chain reaction (real time qRT-PCR). Although several commercial kits are available for high-throughput RNA extraction in 96-well format, only one non-kit method has been described in the literature using the commercial reagent TRIZOL. We describe an unusual phenomenon when using TRIZOL reagent with young Arabidopsis seedlings. This prompted us to develop a high-throughput RNA extraction protocol (HTP96) adapted from a well established phenol:chloroform-LiCl method (P:C-L) that is cheap, reliable and requires no specialist equipment. With this protocol 192 high quality RNA s les can be prepared in 96-well format in three hours (less than 1 minute per s le) with less than 1% loss of s les. We demonstrate that the RNA derived from this protocol is of high quality and suitable for use in real time qRT-PCR assays. The development of the HTP96 protocol has vastly increased our s le throughput, allowing us to fully exploit the large s le capacity of modern real time qRT-PCR thermocyclers, now commonplace in many labs, and develop an effective high-throughput gene expression platform. We propose that the HTP96 protocol will significantly benefit any plant scientist with the task of obtaining hundreds of high quality RNA extractions.
Evidence for Ancient Origins of Bowman-Birk Inhibitors from Selaginella moellendorffii
Publisher: Oxford University Press (OUP)
Date: 03-2017
DOI: 10.1105/TPC.16.00831
Global asymptotic stability analysis for delayed neural networks using a matrix-based quadratic convex approach
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.NEUNET.2014.02.012
Abstract: This paper is concerned with global asymptotic stability for a class of generalized neural networks with interval time-varying delays by constructing a new Lyapunov-Krasovskii functional which includes some integral terms in the form of ∫(t-h)(t)(h-t-s)(j)ẋ(T)(s)Rjẋ(s)ds(j=1,2,3). Some useful integral inequalities are established for the derivatives of those integral terms introduced in the Lyapunov-Krasovskii functional. A matrix-based quadratic convex approach is introduced to prove not only the negative definiteness of the derivative of the Lyapunov-Krasovskii functional, but also the positive definiteness of the Lyapunov-Krasovskii functional. Some novel stability criteria are formulated in two cases, respectively, where the time-varying delay is continuous uniformly bounded and where the time-varying delay is differentiable uniformly bounded with its time-derivative bounded by constant lower and upper bounds. These criteria are applicable to both static neural networks and local field neural networks. The effectiveness of the proposed method is demonstrated by two numerical ex les.
A systematic approach for finding herbicide synergies
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2021
DOI: 10.1101/2021.02.08.430187
Abstract: Combining herbicides into a double dose is a common approach to overcome the potential for herbicide resistance by weeds. Many herbicide mixtures can be antagonistic and they are rarely synergistic. Here, 24 commercial herbicides, each representing a mode of action were used to create a matrix of all 276 unique combinations to search for new synergies in agar with Arabidopsis thaliana . Herbicides were used at an appropriate sub-lethal dose such that any synergies gave visible growth inhibition. We found five synergies including three new ones, namely mesotrione-norflurazon, mesotrione-clethodim and paraquat-clomazone. All three new synergies were reproducible in soil-grown conditions. Interestingly, all three new combinations included a bleaching herbicide, suggesting synergy might be a class specific phenomenon. We also found that mesotrione-norflurazon and mesotrione-clethodim combinations remained synergistic against lettuce (Lactuca sativa) , but not tef (Eragrostis tef) . Our study shows that screening herbicide mixtures against A. thaliana is an efficient approach for finding rare herbicide synergies.
Defining the familial fold of the vicilin-buried peptide family
Publisher: Cold Spring Harbor Laboratory
Date: 28-05-2020
DOI: 10.1101/2020.05.26.118075
Abstract: Plants and their seeds have been shown to be a rich source of cystine-stabilized peptides. Recently a new family of plant seed peptides whose sequences are buried within precursors for seed storage vicilins was identified. Members of this Vicilin Buried Peptide (VBP) family are found in distantly related plant species including the monocot date palm, as well as dicotyledonous species like pumpkin and sesame. Genetic evidence for their widespread occurrence indicates that they are of ancient origin. Limited structural studies have been conducted on VBP family members, but two members have been shown to adopt a helical hairpin fold. We here present an extensive characterization of VBPs using solution NMR spectroscopy, to better understand their structural features. Four peptides were produced by solid phase peptide synthesis and shown to adopt a helix-loop-helix hairpin fold, as a result of the I-IV/II-III ladder-like connectivity of their disulfide bonds. Inter-helix interactions, including hydrophobic contacts and salt bridges, are critical for the fold stability and control the angle at which the anti-parallel α-helices interface. Activities reported for VBPs include trypsin inhibitory activity and inhibition of ribosomal function, however their erse structural features despite a common fold suggest additional bioactivities yet to be revealed are likely.
The evolution of Momordica cyclic peptides.
Publisher: Oxford University Press (OUP)
Date: 06-11-2015
Abstract: Cyclic proteins have evolved for millions of years across all kingdoms of life to confer structural stability over their acyclic counterparts while maintaining intrinsic functional properties. Here, we show that cyclic miniproteins (or peptides) from Momordica (Cucurbitaceae) seeds evolved in species that erged from an African ancestor around 19 Ma. The ability to achieve head-to-tail cyclization of Momordica cyclic peptides appears to have been acquired through a series of mutations in their acyclic precursor coding sequences following recent and independent gene expansion event(s). Evolutionary analysis of Momordica cyclic peptides reveals sites that are under selection, highlighting residues that are presumably constrained for maintaining their function as potent trypsin inhibitors. Molecular dynamics of Momordica cyclic peptides in complex with trypsin reveals site-specific residues involved in target binding. In a broader context, this study provides a basis for selecting Momordica species to further investigate the biosynthesis of the cyclic peptides and for constructing libraries that may be screened against evolutionarily related serine proteases implicated in human diseases.
Cyclic Peptides in Seed of Annona muricata Are Ribosomally Synthesized
Publisher: American Chemical Society (ACS)
Date: 02-04-2020
Evolutionary Origins of a Bioactive Peptide Buried within Preproalbumin
Publisher: Oxford University Press (OUP)
Date: 03-2014
Abstract: The de novo evolution of proteins is now considered a frequented route for biological innovation, but the genetic and biochemical processes that lead to each newly created protein are often poorly documented. The common sunflower (Helianthus annuus) contains the unusual gene PawS1 (Preproalbumin with SFTI-1) that encodes a precursor for seed storage albumin however, in a region usually discarded during albumin maturation, its sequence is matured into SFTI-1, a protease-inhibiting cyclic peptide with a motif homologous to unrelated inhibitors from legumes, cereals, and frogs. To understand how PawS1 acquired this additional peptide with novel biochemical functionality, we cloned PawS1 genes and showed that this dual destiny is over 18 million years old. This new family of mostly backbone-cyclic peptides is structurally erse, but the protease-inhibitory motif was restricted to peptides from sunflower and close relatives from its subtribe. We describe a widely distributed, potential evolutionary intermediate PawS-Like1 (PawL1), which is matured into storage albumin, but makes no stable peptide despite possessing residues essential for processing and cyclization from within PawS1. Using sequences we cloned, we retrodict the likely stepwise creation of PawS1's additional destiny within a simple albumin precursor. We propose that relaxed selection enabled SFTI-1 to evolve its inhibitor function by converging upon a successful sequence and structure.
Structural and biochemical analyses of concanavalin A circular permutation by jack bean asparaginyl endopeptidase
Publisher: Oxford University Press (OUP)
Date: 08-05-2021
Abstract: Over 30 years ago, an intriguing posttranslational modification was found responsible for creating concanavalin A (conA), a carbohydrate-binding protein from jack bean (Canavalia ensiformis) seeds and a common carbohydrate chromatography reagent. ConA biosynthesis involves what was then an unprecedented rearrangement in amino-acid sequence, whereby the N-terminal half of the gene-encoded conA precursor (pro-conA) is swapped to become the C-terminal half of conA. Asparaginyl endopeptidase (AEP) was shown to be involved, but its mechanism was not fully elucidated. To understand the structural basis and consequences of circular permutation, we generated recombinant jack bean pro-conA plus jack bean AEP (CeAEP1) and solved crystal structures for each to 2.1 and 2.7 Å, respectively. By reconstituting conA biosynthesis in vitro, we prove CeAEP1 alone can perform both cleavage and cleavage-coupled transpeptidation to form conA. CeAEP1 structural analysis reveals how it is capable of carrying out both reactions. Biophysical assays illustrated that pro-conA is less stable than conA. This observation was explained by fewer intermolecular interactions between subunits in the pro-conA crystal structure and consistent with a difference in the prevalence for tetramerization in solution. These findings elucidate the consequences of circular permutation in the only posttranslation ex le known to occur in nature.
The PHD Finger Protein VRN5 Functions in the Epigenetic Silencing of Arabidopsis FLC
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.CUB.2006.11.052
Abstract: Vernalization, the acceleration of flowering by the prolonged cold of winter, ensures that plants flower in favorable spring conditions. During vernalization in Arabidopsis, cold temperatures repress FLOWERING LOCUS C (FLC) expression in a mechanism involving VERNALIZATION INSENSITIVE 3 (VIN3), and this repression is epigenetically maintained by a Polycomb-like chromatin regulation involving VERNALIZATION 2 (VRN2), a Su(z)12 homolog, VERNALIZATION 1 (VRN1), and LIKE-HETEROCHROMATIN PROTEIN 1. In order to further elaborate how cold repression triggers epigenetic silencing, we have targeted mutations that result in FLC misexpression both at the end of the prolonged cold and after subsequent development. This identified VERNALIZATION 5 (VRN5), a PHD finger protein and homolog of VIN3. Our results suggest that during the prolonged cold, VRN5 and VIN3 form a heterodimer necessary for establishing the vernalization-induced chromatin modifications, histone deacetylation, and H3 lysine 27 trimethylation required for the epigenetic silencing of FLC. Double mutant and FLC misexpression analyses reveal additional VRN5 functions, both FLC-dependent and -independent, and indicate a spatial complexity to FLC epigenetic silencing with VRN5 acting as a common component in multiple pathways.
Binary vectors for sense and antisense expression of arabidopsis ESTs
Publisher: Springer Science and Business Media LLC
Date: 1998
Exploiting the Evolutionary Relationship between Malarial Parasites and Plants To Develop New Herbicides
Publisher: Wiley
Date: 12-07-2017
Abstract: Herbicide resistance is driving a need to develop new herbicides. The evolutionary relationship between apicomplexan parasites, such as those causing malaria, and plants is close enough that many antimalarial drugs are herbicidal and so represent novel scaffolds for herbicide development. Using a compound library from the Medicines for Malaria Venture, the model plant Arabidopsis thaliana, and a physicochemical database of known herbicides, a compound was discovered that showed post-emergence herbicidal activity equal to commercial herbicides. Using structure-activity analysis, important points for its potency were found. The compound was also tested and found to be active against common crop weeds. Physiological profiling suggested the compound was a photosystem II inhibitor, representing a new scaffold for herbicide development. Overall this approach demonstrates the viability of using antimalarial compounds as lead compounds for the development of much needed new herbicides.
De Novo Peptide Sequencing Reveals Many Cyclopeptides in the Human Gut and Other Environments
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.CELS.2019.11.007
Abstract: Cyclic and branch cyclic peptides (cyclopeptides) represent a class of bioactive natural products that include many antibiotics and anti-tumor compounds. Despite the recent advances in metabolomics analysis, still little is known about the cyclopeptides in the human gut and their possible interactions due to a lack of computational analysis pipelines that are applicable to such compounds. Here, we introduce CycloNovo, an algorithm for automated de novo cyclopeptide analysis and sequencing that employs de Bruijn graphs, the workhorse of DNA sequencing algorithms, to identify cyclopeptides in spectral datasets. CycloNovo reconstructed 32 previously unreported cyclopeptides (to the best of our knowledge) in the human gut and reported over a hundred cyclopeptides in other environments represented by various spectra on Global Natural Products Social Molecular Network (GNPS). behsaz/cyclonovo.
Cyclotides associate with leaf vasculature and are the products of a novel precursor in Petunia (Solanaceae)
Publisher: Elsevier BV
Date: 08-2012
Developing ciprofloxacin analogues against plant DNA gyrase: a novel herbicide mode of action
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7CC09518J
Abstract: The development of ciprofloxacin analogues against plant DNA gyrase, a novel herbicidal target, with increased herbicidal activity and diminished antibacterial activity is described.
Expression, purification and preliminary X-ray diffraction studies of VERNALIZATION1(208-341) from Arabidopsis thaliana
Publisher: International Union of Crystallography (IUCr)
Date: 26-02-2009
A family of small, cyclic peptides buried in preproalbumin since the Eocene epoch
Publisher: Wiley
Date: 02-2018
DOI: 10.1002/PLD3.42
Vernalization requires epigenetic silencing of FLC by histone methylation
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.1038/NATURE02269
Antibiotic resistance lessons for the herbicide resistance crisis
Publisher: Wiley
Date: 18-03-2021
DOI: 10.1002/PS.6357
Abstract: The challenges of resistance to antibiotics and resistance to herbicides have much in common. Antibiotic resistance became a risk in the 1950s, but a concerted global effort to manage it did not begin until after 2000. Widespread herbicide use began during the 1950s and was soon followed by an unabated rise in resistance. Here, we examine what lessons for combatting herbicide resistance could be learnt from the global, coordinated efforts of all stakeholders to avert the antibiotic resistance crisis. © 2021 Society of Chemical Industry.
Peptide Macrocyclization by a Bifunctional Endoprotease
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.CHEMBIOL.2015.04.010
Abstract: Proteases usually cleave peptides, but under some conditions, they can ligate them. Seeds of the common sunflower contain the 14-residue, backbone-macrocyclic peptide sunflower trypsin inhibitor 1 (SFTI-1) whose maturation from its precursor has a genetic requirement for asparaginyl endopeptidase (AEP). To provide more direct evidence, we developed an in situ assay and used (18)O-water to demonstrate that SFTI-1 is excised and simultaneously macrocyclized from its linear precursor. The reaction is inefficient in situ, but a newfound breakdown pathway can mask this inefficiency by reducing the internal disulfide bridge of any acyclic-SFTI to thiols before degrading it. To confirm AEP can directly perform the excision/ligation, we produced several recombinant plant AEPs in E. coli, and one from jack bean could catalyze both a typical cleavage reaction and cleavage-dependent, intramolecular transpeptidation to create SFTI-1. We propose that the evolution of ligating endoproteases enables plants like sunflower and jack bean to stabilize bioactive peptides.
An interactive database to explore herbicide physicochemical properties
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00469A
Abstract: An interactive database containing the physicochemical properties of successful herbicidal compounds that allows rapid comparison to potential, new herbicidal compounds is presented.
Macrocyclization by asparaginyl endopeptidases
Publisher: Wiley
Date: 21-03-2017
DOI: 10.1111/NPH.14511
Abstract: Contents Summary 923 I. Introduction 923 II. Plant AEPs with macrocyclizing ability 924 III. Mechanism of macrocyclization by AEPs 925 IV. Conclusions 927 Acknowledgements 927 References 927 SUMMARY: Plant asparaginyl endopeptidases (AEPs) are important for the post-translational processing of seed storage proteins via cleavage of precursor proteins. Some AEPs also function as peptide bond-makers during the biosynthesis of several unrelated classes of cyclic peptides, namely the kalata-type cyclic peptides, PawS-Derived Peptides and cyclic knottins. These three families of gene-encoded peptides have different evolutionary origins, but all have recruited AEPs for their maturation. In the last few years, the field has advanced rapidly, with the biochemical characterization of three plant AEPs capable of peptide macrocyclization, and insights have been gained from the first AEP crystal structures, albeit mammalian ones. Although the biochemical studies have improved our understanding of the mechanism of action, the focus now is to understand what changes in AEP sequence and structure enable some plant AEPs to perform macrocyclization reactions.
NMR assignment and secondary structure of the C-terminal DNA binding domain of Arabidopsis thaliana VERNALIZATION1
Publisher: Springer Science and Business Media LLC
Date: 08-05-2012
DOI: 10.1007/S12104-011-9313-6
Abstract: VERNALIZATION1 (VRN1) is a multidomain DNA binding protein from Arabidopsis thaliana that is required for the acceleration of flowering time in response to prolonged cold treatment a physiological process called vernalization. VRN1 is a 39 kDa protein comprised of two B3 domains flanking a putative nuclear localization sequence and two PEST domains. Here we report the (1)H, (13)C and (15)N resonance assignments of the 134 residue C-terminal region of VRN1, comprising a B3 DNA binding domain of the REM family and an upstream region that is highly conserved among VRN1 homologs from other dicotyledonous plant species.
Seed storage albumins: biosynthesis, trafficking and structures
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/FP14035
Abstract: Seed storage albumins are water-soluble and highly abundant proteins that are broken-down during seed germination to provide nitrogen and sulfur for the developing seedling. During seed maturation these proteins are subject to post-translational modifications and trafficking before they are deposited in great quantity and with great stability in dedicated vacuoles. This review will cover the subcellular movement, biochemical processing and mature structures of seed storage napins.
A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action
Publisher: Cold Spring Harbor Laboratory
Date: 19-04-2022
DOI: 10.1101/2022.04.18.488698
Abstract: Decades of intense herbicide use has led to resistance in weeds. Without innovative weed management practices and new herbicidal modes of action, the unabated rise of herbicide resistance will undoubtedly place further stress upon food security. HMGR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is the rate limiting enzyme of the eukaryotic mevalonate pathway successfully targeted by statins to treat hypercholesterolemia in humans. As HMGR inhibitors have been shown to be herbicidal, HMGR could represent a new mode of action target for the development of herbicides. Here we present the crystal structure of a HMGR from Arabidopsis thaliana (AtHMG1) which exhibits a wider active site than previously determined structures from different species. This plant conserved feature enabled the rational design of specific HMGR inhibitors, for which we engineered a tolerance trait through sequence analysis of fungal gene clusters. These results suggest HMGR to be a viable herbicide target modifiable to provide a tolerance trait.
Circular proteins from Melicytus (Violaceae) refine the conserved protein and gene architecture of cyclotides
Publisher: Royal Society of Chemistry (RSC)
Date: 2009
DOI: 10.1039/B823020J
Abstract: Cyclotides are cyclic disulfide rich mini-proteins found in various Rubiaceae (coffee family), Violaceae (violet family) and Cucurbitaceae (squash family) plant species. Within the Violaceae, cyclotides have been found in numerous species of the genus Viola as well as species from two other genera, namely Hybanthus and Leonia. This is the first in-depth report of cyclotides in the genus Melicytus (Violaceae). We present the chromatographic profiles of extracts of eight Melicytus species and one Melicytus hybrid that were found to contain these circular peptides. We isolated and characterised five novel cyclotides (mra1 to mra5) from the aerial parts of a common New Zealand tree, Melicytus ramiflorus. All five peptides show the characteristics of the bracelet subfamily of cyclotides. Furthermore, we isolated 17 non-redundant cDNA clones from the leaves of Melicytus ramiflorus encoding cyclotide prepropeptides. This detailed report on the presence of cyclotides in several species of the genus Melicytus further strengthens our hypothesis that cyclotides are ubiquitous in Violaceae family plants and provides additional insight into the biochemical processing mechanisms that produce the cyclic protein backbone of this unique family of ultra-stable plant proteins.
ARABIDOPSIS TRITHORAX1 Dynamically RegulatesFLOWERING LOCUS CActivation via Histone 3 Lysine 4 Trimethylation
Publisher: Oxford University Press (OUP)
Date: 03-2008
Abstract: Trithorax function is essential for epigenetic maintenance of gene expression in animals, but little is known about trithorax homologs in plants. ARABIDOPSIS TRITHORAX1 (ATX1) was shown to be required for the expression of homeotic genes involved in flower organogenesis. Here, we report a novel function of ATX1, namely, the epigenetic regulation of the floral repressor FLOWERING LOCUS C (FLC). Downregulation of FLC accelerates the transition from vegetative to reproductive development in Arabidopsis thaliana. In the atx1 mutant, FLC levels are reduced and the FLC chromatin is depleted of trimethylated, but not dimethylated, histone 3 lysine 4, suggesting a specific trimethylation function of ATX1. In addition, we found that ATX1 directly binds the active FLC locus before flowering and that this interaction is released upon the transition to flowering. This dynamic process stands in contrast with the stable maintenance of homeotic gene expression mediated by trithorax group proteins in animals but resembles the dynamics of plant Polycomb group function.
Cyclotide Isolation and Characterization
Publisher: Elsevier
Date: 2012
Multiple pathways in the decision to flower: Enabling, promoting, and resetting
Publisher: Oxford University Press (OUP)
Date: 12-03-2004
DOI: 10.1105/TPC.015958
Exploiting the Evolutionary Relationship between Malarial Parasites and Plants To Develop New Herbicides
Publisher: Wiley
Date: 12-07-2017
Herbicidal activity of fluoroquinolone derivatives
Publisher: Wiley
Date: 09-2021
DOI: 10.1002/PLD3.348
Abstract: Development of herbicides with novel modes of action is crucial for weed control and to hinder herbicide resistance. An attractive novel herbicidal target is plant DNA gyrase, which has been demonstrated to be effectively inhibited by the known antimicrobial ciprofloxacin. Despite this good herbicidal activity, ciprofloxacin is not suitable as a herbicide due to its antimicrobial activity therefore, a erse library of analogues was analyzed to gain insight into the aspects required for herbicidal activity. This analysis revealed that significant structural modifications were tolerated and that the fluoride at C‐6 and a cyclic amino group at C‐7 were not crucial for herbicidal activity. The analysis also revealed that these modifications also affected the antibacterial activity with one compound demonstrating good herbicidal activity and weak antibacterial activity, against both Gram‐positive and Gram‐negative bacteria.
An Ancient Peptide Family Buried within Vicilin Precursors
Publisher: American Chemical Society (ACS)
Date: 11-04-2019
DOI: 10.1021/ACSCHEMBIO.9B00167
Abstract: New proteins can evolve by duplication and ergence or de novo, from previously noncoding DNA. A recently observed mechanism is for peptides to evolve within a "host" protein and emerge by proteolytic processing. The first ex les of such interstitial peptides were ones hosted by precursors for seed storage albumin. Interstitial peptides have also been observed in precursors for seed vicilins, but current evidence for vicilin-buried peptides (VBPs) is limited to seeds of the broadleaf plants pumpkin and macadamia. Here, an extensive sequence analysis of vicilin precursors suggested that peptides buried within the N-terminal region of preprovicilins are widespread and truly ancient. Gene sequences indicative of interstitial peptides were found in species from Amborellales to eudicots and include important grass and legume crop species. We show the first protein evidence for a monocot VBP in date palm seeds as well as protein evidence from other crops including the common tomato, sesame and pumpkin relatives, cucumber, and the sponge loofah ( Luffa aegyptiaca). Their excision was consistent with asparaginyl endopeptidase-mediated maturation, and sequences were confirmed by tandem mass spectrometry. Our findings suggest that the family is large and ancient and that based on the NMR solution structures for loofah Luffin P1 and tomato VBP-8, VBPs adopt a helical hairpin fold stapled by two internal disulfide bonds. The first VBPs characterized were a protease inhibitor, antimicrobials, and a ribosome inactivator. The age and evolutionary retention of this peptide family suggest its members play important roles in plant biology.
Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam
Publisher: Elsevier BV
Date: 07-2022
Buried treasure: biosynthesis, structures and applications of cyclic peptides hidden in seed storage albumins
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7NP00066A
Abstract: SFTI-1 and related peptide natural products emerge from a hiding place in seed storage proteins to inspire pharmaceutical design.
A chameleonic macrocyclic peptide with drug delivery applications
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1SC00692D
Abstract: The cyclic peptide PDP-23 adopts a different structure depending on conditions. In water it forms a dimer, but can unfold allowing its hydrophobic core to interact with membranes. PDP-23 shows promise as a cell penetrating scaffold for drug delivery.
Structural Characterization of the PawL-Derived Peptide Family, an Ancient Subfamily of Orbitides
Publisher: Cold Spring Harbor Laboratory
Date: 19-07-2021
DOI: 10.1101/2021.07.18.452857
Abstract: Plants are an excellent source of bioactive peptides, often with disulfide bonds and/or a cyclic backbone. While focus has predominantly been directed at disulfide-rich peptides, a large family of small, cyclic but non-disulfide bonded plant peptides, known as orbitides, has been relatively ignored. A recently discovered subfamily of orbitides is the PawL-Derived Peptides (PLPs), produced during the maturation of precursors for seed storage albumins. Although their evolutionary origins have been dated, in-depth exploration of the family’s structural characteristics and potential bioactivities remains to be conducted. Here we present an extensive and systematic characterization of the PLP family. Nine PLPs were chosen and prepared by solid phase peptide synthesis. Their structural features were studied using solution NMR spectroscopy and seven were found to possess regions of backbone order. Ordered regions consist of β-turns, with some PLPs adopting two well-defined β-turns within sequences as short as seven residues, which are largely the result of side chain interactions. Our data highlight that the sequence ersity within this family results in equally erse molecular scaffolds. None of these nine PLPs showed antibacterial or antifungal activity.
The macrocyclizing protease butelase 1 remains auto-catalytic and reveals the structural basis for ligase activity
Publisher: Wiley
Date: 28-03-2019
DOI: 10.1111/TPJ.14293
Abstract: Plant asparaginyl endopeptidases (AEPs) are expressed as inactive zymogens that perform maturation of seed storage protein upon cleavage-dependent autoactivation in the low-pH environment of storage vacuoles. The AEPs have attracted attention for their macrocyclization reactions, and have been classified as cleavage or ligation specialists. However, we have recently shown that the ability of AEPs to produce either cyclic or acyclic products can be altered by mutations to the active site region, and that several AEPs are capable of macrocyclization given favorable pH conditions. One AEP extracted from Clitoria ternatea seeds (butelase 1) is classified as a ligase rather than a protease, presenting an opportunity to test for loss of cleavage activity. Here, making recombinant butelase 1 and rescuing an Arabidopsis thaliana mutant lacking AEP, we show that butelase 1 retains cleavage functions in vitro and in vivo. The in vivo rescue was incomplete, consistent with some trade-off for butelase 1 specialization toward macrocyclization. Its crystal structure showed an active site with only subtle differences from cleaving AEPs, suggesting the many differences in its peptide-binding region are the source of its efficient macrocyclization. All considered, it seems that either butelase 1 has not fully specialized or a requirement for autocatalytic cleavage is an evolutionary constraint upon macrocyclizing AEPs.
Total Synthesis of the Antimalarial Ascidian Natural Product Albopunctatone
Publisher: American Chemical Society (ACS)
Date: 09-07-2019
DOI: 10.1021/ACS.ORGLETT.9B01838
Abstract: The first approaches to the 10'-anthronyl-2-anthraquinone skeleton have been devised, allowing two syntheses of the marine natural product albopunctatone. Both routes involve regioselective addition of a nucleophilic masked anthraquinone to a protected chrysazin derivative the best affords albopunctatone in five steps and 35% overall yield. Albopunctatone exhibits potent inhibitory activity against
Rapid isolation of high-quality RNA from symbiotic dinoflagellates
Publisher: Informa UK Limited
Date: 07-1998
Sequencing Orbitides by Acid-Mediated Ring Cleavage Followed by Tandem Mass Spectrometry
Publisher: American Chemical Society (ACS)
Date: 30-09-2019
DOI: 10.1021/ACS.JPROTEOME.9B00516
Abstract: Homodetic cyclic peptides have aroused interest because of their pharmacological potential. Sequencing cyclic peptides is difficult-Edman degradation is not possible as there is no N-terminus, NMR requires quantities that are hard to gather from native s les, and tandem mass spectrometry data are difficult to interpret due to the peptide ring opening at multiple points. Sequencing can be simplified by cleaving the peptide ring at a specific peptide bond. Partial acid hydrolysis is a possible solution, but to date sequencing by this method has only been demonstrated for linear peptides and cyclotides, which are larger cyclic peptides (∼30 amino acids) with three disulfide bonds. This study tests whether partial acid hydrolysis could be used to aid sequencing of Cys-less cyclic peptides with fewer than ten amino acid residues. We show that, with the right combination of temperature and acid, ring cleavage occurs and offers relatively simple MS/MS spectra amenable to sequencing. We describe how this method was used in our recent study in which we sequenced annomuricatin D (cyclo-GHSIFPPIP) from seeds of the soursop,
Cyclotides as a basis for drug design
Publisher: Informa Healthcare
Date: 21-02-2012
DOI: 10.1517/17460441.2012.661554
Abstract: Cyclotides are plant-made defence proteins with a head-to-tail cyclic backbone combined with a conserved, six cystine knot. They have a range of biological activities, including uterotonic and anti-HIV activity, which have attracted attention to their potential pharmaceutical applications. Furthermore, their unique structures and high stability make them appealing as peptide-based templates for drug design applications. Methods have been developed for their production, including solid phase peptide synthesis as well as recombinant methods. This article reviews the recent literature associated with therapeutic applications of naturally occurring and synthetically modified cyclotides. It includes applications of cyclotides and cyclotide-like molecules as peptide-based drug leads and diagnostic agents. The ultra-stable cyclotides are promising templates for drug development applications and are currently being assessed for the potential breadth of their applications. For synthetic versions of cyclotides to enter human clinical trials further studies to examine their biopharmaceutical properties and toxicities are required. However, several promising proof-of-concept studies have established that pharmaceutically relevant bioactive peptide sequences can be grafted into cyclotide frameworks and thereby stabilised, while maintaining biological activity. These studies include ex les directed at cancer, cardiovascular disease and infectious diseases. Solid phase peptide synthesis has been the preferred approach for making pharmaceutically modified cyclotides so far, but promising progress is being made in biological approaches to cyclotide production.
Inhibition of chloroplast translation as a new target for herbicides
Publisher: Cold Spring Harbor Laboratory
Date: 28-09-2021
DOI: 10.1101/2021.09.28.462089
Abstract: The rise in herbicide resistance over recent decades threatens global agriculture and food security and so discovery of new modes of action is increasingly important. Here we reveal linezolid, an oxazolidinone antibiotic that inhibits microbial translation, is also herbicidal. To validate the herbicidal mode of action of linezolid we confirmed its micromolar inhibition is specific to chloroplast translation and did not affect photosynthesis directly. To assess the herbicide potential of linezolid, testing against a range of weed and crop species found it effective pre- and post-emergence. Using structure-activity analysis we identified the critical elements for herbicidal activity, but importantly also show, using antimicrobial susceptibility assays, that separation of antibacterial and herbicidal activities was possible. Overall these results validate chloroplast translation as a viable herbicidal target.
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