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Preprints

Thum, A.; Mönchgesang, S.; Westphal, L.; Lübken, T.; Rosahl, S.; Neumann, S.; Posch, S.; Supervised Penalized Canonical Correlation Analysis arXiv (2014)

The canonical correlation analysis (CCA) is commonly used to analyze data sets with paired data, e.g. measurements of gene expression and metabolomic intensities of the same experiments. This allows to find interesting relationships between the data sets, e.g. they can be assigned to biological processes. However, it can be difficult to interpret the processes and often the relationships observed are not related to the experimental design but to some unknown parameters.Here we present an extension of the penalized CCA, the supervised penalized approach (spCCA), where the experimental design is used as a third data set and the correlation of the biological data sets with the design data set is maximized to find interpretable and meaningful canonical variables. The spCCA was successfully tested on a data set of Arabidopsis thaliana with gene expression and metabolite intensity measurements and resulted in eight significant canonical variables and their interpretation. We provide an R-package under the GPL license.
Publications

Pecher, P.; Eschen-Lippold, L.; Herklotz, S.; Kuhle, K.; Naumann, K.; Bethke, G.; Uhrig, J.; Weyhe, M.; Scheel, D.; Lee, J.; The Arabidopsis thaliana mitogen-activated protein kinases MPK3 and MPK6 target a subclass of ‘VQ-motif’-containing proteins to regulate immune responses New Phytol. 203, 592-606, (2014) DOI: 10.1111/nph.12817

Mitogen‐activated protein kinase (MAPK) cascades play key roles in plant immune signalling, and elucidating their regulatory functions requires the identification of the pathway‐specific substrates.We used yeast two‐hybrid interaction screens, in vitro kinase assays and mass spectrometry‐based phosphosite mapping to study a family of MAPK substrates. Site‐directed mutagenesis and promoter‐reporter fusion studies were performed to evaluate the impact of substrate phosphorylation on downstream signalling.A subset of the Arabidopsis thaliana VQ‐motif‐containing proteins (VQPs) were phosphorylated by the MAPKs MPK3 and MPK6, and renamed MPK3/6‐targeted VQPs (MVQs). When plant protoplasts (expressing these MVQs) were treated with the flagellin‐derived peptide flg22, several MVQs were destabilized in vivo. The MVQs interact with specific WRKY transcription factors. Detailed analysis of a representative member of the MVQ subset, MVQ1, indicated a negative role in WRKY‐mediated defence gene expression – with mutation of the VQ‐motif abrogating WRKY binding and causing mis‐regulation of defence gene expression.We postulate the existence of a variety of WRKY‐VQP‐containing transcriptional regulatory protein complexes that depend on spatio‐temporal VQP and WRKY expression patterns. Defence gene transcription can be modulated by changing the composition of these complexes – in part – through MAPK‐mediated VQP degradation.
Publications

Pantelić, N.; Zmejkovski, B. B.; Stanojković, T. P.; Jeftić, V. V.; Radić, G. P.; Trifunović, S. R.; Kaluđerović, G. N.; Sabo, T. J.; Synthesis and high in vitro cytotoxicity of some (S,S)-ethylenediamine-N,N’-di-2-propanoate dihydrochloride esters J. Serb. Chem. Soc. 79, 649-658, (2014) DOI: 10.2298/JSC130512022P

A novel (S,S)-R2eddip ester, O,O′-diisopentyl-(S,S)-ethylenediamine-N,N′-di-2-propanoate dihydrochloride (1) was synthesized and characterized by IR, 1H- and 13C-NMR spectroscopy, mass spectroscopy and elemental analysis. In vitro antitumor action of 1, and two more R2eddip esters, dialkyl (S,S)-ethylenediamine-N,N′-di-2-propanoate dihydrochlorides, obtained before (alkyl = n-Bu or n-Pe, 2 and 3, respectively), was determined against cervix adenocarcinoma (HeLa), human melanoma (Fem-x), human chronic myelogenous leukemia (K562) cells, and a non-cancerous cell line human embryonic lung fibroblast (MRC-5), using the microculture tetrazolium test MTT assay. Esters 1–3 showed higher cytotoxicity and better selectivity in comparison to cisplatin, used as reference compound. The highest activity was expressed by 1, with IC50(Fem-x) value of 1.51±0.09 μM.
Publications

Pahnke, J.; Fröhlich, C.; Paarmann, K.; Krohn, M.; Bogdanovic, N.; Årsland, D.; Winblad, B.; Cerebral ABC Transporter-common Mechanisms May Modulate Neurodegenerative Diseases and Depression in Elderly Subjects Arch. Med. Res. 45, 738-743, (2014) DOI: 10.1016/j.arcmed.2014.10.010

In elderly subjects, depression and dementia often coincide but the actual reason is currently unknown. Does a causal link exist or is it just a reactive effect of the knowledge to suffer from dementia? The ABC transporter superfamily may represent a causal link between these mental disorders. Since the transporters ABCB1 and ABCC1 have been discovered as major β-amyloid-exporting molecules at the blood–brain barrier and ABCC1 was found to be directly activated by St. John's wort (SJW), depression and dementia certainly share an important pathophysiologic link. It was recognized that herbal anti-depressant formulations made from SJW are at least as effective for the treatment of unipolar depression in old age as classical pharmacotherapy, while having fewer side effects (Cochrane reports, 2008). SJW is known to activate various metabolizing and transport systems in the body, with cytochrome P450 enzymes and ABC transporters being most important.Does the treatment of depression in elderly subjects using pharmacological compounds or phytomedical extracts target a mechanism that also accounts for peptide storage in Alzheimer's disease and perhaps other proteopathies of the brain?In this review we summarize recent data that point to a common mechanism and present the first promising causal treatment results of demented elderly subjects with distinct SJW extracts. Insufficient trans-barrier clearance may indeed present a common problem in all the proteopathies of the brain where toxic peptides are deposited in a location-specific manner. Thus, activation of efflux molecules holds promise for future treatment of this large group of devastating disorders.
Publications

Otto, A.; Porzel, A.; Schmidt, J.; Wessjohann, L.; Arnold, N.; Penarines A–F, (nor-)sesquiterpene carboxylic acids from Hygrophorus penarius (Basidiomycetes) Phytochemistry 108, 229-233, (2014) DOI: 10.1016/j.phytochem.2014.09.005

Five sesquiterpene carboxylic acids (1–5) and one nor-sesquiterpene carboxylic acid (6) of the very rare ventricosane type, named penarines A–F, were isolated from fruiting bodies of the basidiomycete Hygrophorus penarius (Hygrophoraceae). This is the first report of (nor)-sesquiterpenes isolated from basidiocarps of the family Hygrophoraceae. Their structures were elucidated on the basis of extensive 1D (1H, 13C) and 2D (HSQC, HMBC, COSY, ROESY) NMR spectroscopic analyses as well as high-resolution mass spectrometry studies. Additionally, the only known member of this rare type of sesquiterpenes, ventricos-7(13)-ene (7), could be identified via headspace GC–MS analysis in a fruiting body of H. penarius. Compounds 1–6 were devoid of remarkable antifungal activity against Cladosporium cucumerinum. Additionally, the cytotoxic activities of compounds 1 and 2 were evaluated against the human prostate cancer cell line PC-3 and the colon cancer cell line HT-29 showing no significant cytotoxic activity.
Publications

Olkhov, R. V.; Weissenborn, M. J.; Flitsch, S. L.; Shaw, A. M.; Glycosylation Characterization of Human and Porcine Fibrinogen Proteins by Lectin-Binding Biophotonic Microarray Imaging Anal. Chem. 86, 621-628, (2014) DOI: 10.1021/ac402872t

Lectin binding has been studied using the particle plasmon light-scattering properties of gold nanoparticles printed into an array format. Performance of the kinetic assay is evaluated from a detailed analysis of the binding of concanavalin A (ConA) and wheat germ agglutinin (WGA) to their target monosaccharides indicating affinity constants in the order of KD ∼10 nM for the lectin-monosaccharide interaction. The detection limits for the lectins following a 200 s injection time were determined as 10 ng/mL or 0.23 nM and 100 ng/mL or 0.93 nM, respectively. Subsequently, a nine-lectin screen was performed on the porcine and human fibrinogen glycoproteins. The observed spectra of lectin-protein specific binding rates result in characteristic patterns that evidently correlate with the structure of the glycans and allow one to distinguish between glycosylation of the porcine and human fibrinogens. The array technology has the potential to perform a multilectin screen of large numbers of proteins providing information on protein glycosylation and their microheterogeneity.
Publications

Nakamura, Y.; Paetz, C.; Brandt, W.; David, A.; Rendón-Anaya, M.; Herrera-Estrella, A.; Mithöfer, A.; Boland, W.; Synthesis of 6-Substituted 1-oxoindanoyl Isoleucine Conjugates and Modeling Studies with the COI1-JAZ Co-Receptor Complex of Lima Bean J. Chem. Ecol. 40, 687-699, (2014) DOI: 10.1007/s10886-014-0469-2

The conjugates of 6-substituted 1-oxoindanoyl carboxylic acids with L-isoleucine are mimics of the plant hormone (+)-7-iso-JA-L-Ile (3) that controls and regulates secondary metabolism and stress responses. In order to generate ligands that can be used as hormone-like compounds possessing different biological activities, an efficient and short synthesis of 6-bromo-1-oxoindane-4-carboxylic acid opens a general route to 6-Br-1-oxoindanoyl L-isoleucine conjugate (Br-In-L-Ile) (9a) as a key intermediate for several bioactive 6-halogen-In-L-Ile analogs (7a, 8a, 10a). The 6-ethynyl-In-L-Ile analog (11a) might be a valuable tool to localize macromolecular receptor molecules by click-chemistry. The activities of In-Ile derivatives were evaluated by assays inducing the release of volatile organic compounds (VOCs) in lima bean (Phaseolus lunatus). Each compound showed slightly different VOC induction patterns. To correlate such differences with structural features, modeling studies of In-Ile derivatives with COI-JAZa/b/c co-receptors of P. lunatus were performed. The modeling profits from the rigid backbone of the 1-oxoindanonoyl conjugates, which allows only well defined interactions with the receptor complex.
Publications

Müller, H.; Heinze, M.; Heinke, R.; Schmidt, J.; Roos, W.; Self-regulation of phytoalexin production: a non-biosynthetic enzyme controls alkaloid biosynthesis in cultured cells of Eschscholzia californica Plant Cell Tiss. Organ Cult. 119, 661-676, (2014) DOI: 10.1007/s11240-014-0565-6

Benzophenanthridine alkaloids are strong antimicrobials of Papaveraceae and attractive lead compounds for drug development. The cytotoxicity of these compounds requires the producing plant to limit the pathogen-triggered burst of biosynthesis. Cells of Eschscholzia californica excrete early benzophenanthridines to the cell wall, followed by re-uptake and reduction in the cytoplasm by the detoxifying enzyme sanguinarine reductase. We now discovered that this enzyme is a core component of self-control in alkaloid production. RNAi-based silencing of sanguinarine reductase gave rise to mutants that either show a complete stop of elicitor-triggered alkaloid production or a burst of biosynthesis that severalfold surpasses the wild type level. These unexpected phenotypes reflect impacts of substrate or product of sanguinarine reductase: the substrate, sanguinarine, inhibits phospholipase A2 at the plasma membrane, an initial component of the signal path towards expression of biosynthetic enzymes. The product, dihydrosanguinarine, inhibits enzymes of early biosynthesis, prior to reticuline formation. By tuning these steady states, sanguinarine reductase adjusts the capacity of alkaloid biosynthesis: a minimum activity is sufficient to prevent the blockade of the induction pathway by sanguinarine, while the full activity of the same enzyme causes a limitation of the biosynthetic flow via dihydrosanguinarine.
Publications

Monte, I.; Hamberg, M.; Chini, A.; Gimenez-Ibanez, S.; García-Casado, G.; Porzel, A.; Pazos, F.; Boter, M.; Solano, R.; Rational design of a ligand-based antagonist of jasmonate perception Nat. Chem. Biol. 10, 671-676, (2014) DOI: 10.1038/nchembio.1575

(+)-7-iso-Jasmonoyl-L-isoleucine (JA-Ile) regulates developmental and stress responses in plants. Its perception involves the formation of a ternary complex with the F-box COI1 and a member of the JAZ family of co-repressors and leads to JAZ degradation. Coronatine (COR) is a bacterial phytotoxin that functionally mimics JA-Ile and interacts with the COI1-JAZ co-receptor with higher affinity than JA-Ile. On the basis of the co-receptor structure, we designed ligand derivatives that spatially impede the interaction of the co-receptor proteins and, therefore, should act as competitive antagonists. One derivative, coronatine-O-methyloxime (COR-MO), has strong activity in preventing the COI1-JAZ interaction, JAZ degradation and the effects of JA-Ile or COR on several JA-mediated responses in Arabidopsis thaliana. Moreover, it potentiates plant resistance, preventing the effect of bacterially produced COR during Pseudomonas syringae infections in different plant species. In addition to the utility of COR-MO for plant biology research, our results underscore its biotechnological potential for safer and sustainable agriculture.
Publications

Meesters, C.; Mönig, T.; Oeljeklaus, J.; Krahn, D.; Westfall, C. S.; Hause, B.; Jez, J. M.; Kaiser, M.; Kombrink, E.; A chemical inhibitor of jasmonate signaling targets JAR1 in Arabidopsis thaliana Nat. Chem. Biol. 10, 830-836, (2014) DOI: 10.1038/nchembio.1591

Jasmonates are lipid-derived plant hormones that regulate plant defenses and numerous developmental processes. Although the biosynthesis and molecular function of the most active form of the hormone, (+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile), have been unraveled, it remains poorly understood how the diversity of bioactive jasmonates regulates such a multitude of plant responses. Bioactive analogs have been used as chemical tools to interrogate the diverse and dynamic processes of jasmonate action. By contrast, small molecules impairing jasmonate functions are currently unknown. Here, we report on jarin-1 as what is to our knowledge the first small-molecule inhibitor of jasmonate responses that was identified in a chemical screen using Arabidopsis thaliana. Jarin-1 impairs the activity of JA-Ile synthetase, thereby preventing the synthesis of the active hormone, JA-Ile, whereas closely related enzymes are not affected. Thus, jarin-1 may serve as a useful chemical tool in search for missing regulatory components and further dissection of the complex jasmonate signaling networks.
  • Die Leibniz-Gemeinschaft
  • Digitalization in agriculture
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