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Publications - Bioorganic Chemistry

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Vattekkatte, A., Garms, S., Brandt, W. & Boland, W. Enhanced structural diversity in terpenoid biosynthesis: enzymes, substrates and cofactors Org Biomol Chem 16, 348-362, (2018) DOI: 10.1039/C7OB02040F

The enormous diversity of terpenes found in nature is generated by enzymes known as terpene synthases, or cyclases. Some are also known for their ability to convert a single substrate into multiple products. This review comprises monoterpene and sesquiterpene synthases that are multiproduct in nature along with the regulation factors that can alter the product specificity of multiproduct terpene synthases without genetic mutations. Variations in specific assay conditions with focus on shifts in product specificity based on change in metal cofactors, assay pH and substrate geometry are described. Alterations in these simple cellular conditions provide the organism with enhanced chemodiversity without investing into new enzymatic architecture. This versatility to modulate product diversity grants organisms, especially immobile ones like plants with access to an enhanced defensive repertoire by simply altering cofactors, pH level and substrate geometry.

Chini, A., Monte, I., Zamarreño, A. M., Hamberg, M., Lassueur, S., Reymond, P., Weiss, S., Stintzi, A., Schaller, A., Porzel, A., García-Mina, J. M. & Solano, R. An OPR3-independent pathway uses 4,5-didehydrojasmonate for jasmonate synthesis. Nat Chem Biol 14, 171-178, (2018) DOI: 10.1038/nchembio.2540

Biosynthesis of the phytohormone jasmonoyl-isoleucine (JA-Ile) requires reduction of the JA precursor 12-oxo-phytodienoic acid (OPDA) by OPDA reductase 3 (OPR3). Previous analyses of the opr3-1 Arabidopsis mutant suggested an OPDA signaling role independent of JA-Ile and its receptor COI1; however, this hypothesis has been challenged because opr3-1 is a conditional allele not completely impaired in JA-Ile biosynthesis. To clarify the role of OPR3 and OPDA in JA-independent defenses, we isolated and characterized a loss-of-function opr3-3 allele. Strikingly, opr3-3 plants remained resistant to necrotrophic pathogens and insect feeding, and activated COI1-dependent JA-mediated gene expression. Analysis of OPDA derivatives identified 4,5-didehydro-JA in wounded wild-type and opr3-3 plants. OPR2 was found to reduce 4,5-didehydro-JA to JA, explaining the accumulation of JA-Ile and activation of JA-Ile-responses in opr3-3 mutants. Our results demonstrate that in the absence of OPR3, OPDA enters the β-oxidation pathway to produce 4,5-ddh-JA as a direct precursor of JA and JA-Ile, thus identifying an OPR3-independent pathway for JA biosynthesis.


Schober, D., Jacob, D., Wilson, M., Cruz, J. A., Marcu, A., Grant, J. R., Moing, A., Deborde, C., de Figueiredo, L. F., Haug, K., Rocca-Serra, P., Easton, J., Ebbels, T. M. D., Hao, J., Ludwig, C., Günther, U. L., Rosato, A., Klein, M. S., Lewis, I. A., Luchinat, C., Jones, A. R., Grauslys, A., Larralde, M., Yokochi, M., Kobayashi, N., Porzel, A., Griffin, J. L., Viant, M. R., Wishart, D. S., Steinbeck, C., Salek, R. M. & Neumann, S. nmrML: A community supported open data standard for the description, storage, and exchange of NMR data. Anal Chem 90, 649–656, (2018) DOI: 10.1021/acs.analchem.7b02795

NMR is a widely used analytical technique with a growing number of repositories available. As a result, demands for a vendor-agnostic, open data format for long-term archiving of NMR data have emerged with the aim to ease and encourage sharing, comparison, and reuse of NMR data. Here we present nmrML, an open XML-based exchange and storage format for NMR spectral data. The nmrML format is intended to be fully compatible with existing NMR data for chemical, biochemical, and metabolomics experiments. nmrML can capture raw NMR data, spectral data acquisition parameters, and where available spectral metadata, such as chemical structures associated with spectral assignments. The nmrML format is compatible with pure-compound NMR data for reference spectral libraries as well as NMR data from complex biomixtures, i.e., metabolomics experiments. To facilitate format conversions, we provide nmrML converters for Bruker, JEOL and Agilent/Varian vendor formats. In addition, easy-to-use Web-based spectral viewing, processing, and spectral assignment tools that read and write nmrML have been developed. Software libraries and Web services for data validation are available for tool developers and end-users. The nmrML format has already been adopted for capturing and disseminating NMR data for small molecules by several open source data processing tools and metabolomics reference spectral libraries, e.g., serving as storage format for the MetaboLights data repository. The nmrML open access data standard has been endorsed by the Metabolomics Standards Initiative (MSI), and we here encourage user participation and feedback to increase usability and make it a successful standard.

Frolov, A., Didio, A., Ihling, C., Chantzeva, V., Grishina, T., Hoehenwarter, W., Sinz, A., Smolikova, G., Bilova, T. & Medvedev, S. The effect of simulated microgravity on the Brassica napus seedling proteome. Funct Plant Biol 45, 440-452, (2018) DOI: 10.1071/FP16378

The magnitude and the direction of the gravitational field represent an important environmental factor affecting plant development. In this context, the absence or frequent alterations of the gravity field (i.e. microgravity conditions) might compromise extraterrestrial agriculture and hence space inhabitation by humans. To overcome the deleterious effects of microgravity, a complete understanding of the underlying changes on the macromolecular level is necessary. However, although microgravity-related changes in gene expression are well characterised on the transcriptome level, proteomic data are limited. Moreover, information about the microgravity-induced changes in the seedling proteome during seed germination and the first steps of seedling development is completely missing. One of the valuable tools to assess gravity-related issues is 3D clinorotation (i.e. rotation in two axes). Therefore, here we address the effects of microgravity, simulated by a two-axial clinostat, on the proteome of 24- and 48-h-old seedlings of oilseed rape (Brassica napus L.). The liquid chromatography-MS-based proteomic analysis and database search revealed 95 up- and 38 downregulated proteins in the tryptic digests obtained from the seedlings subjected to simulated microgravity, with 42 and 52 annotations detected as being unique for 24- and 48-h treatment times, respectively. The polypeptides involved in protein metabolism, transport and signalling were annotated as the functional groups most strongly affected by 3-D clinorotation. 

Reisberg, M., Arnold, N., Porzel, A., Neubert, R. H. H. & Dräger, B. Malusides, novel glucosylceramides isolated from apple pomace (Malus domestica). Z NATURFORSCH C 73, 33-39, (2018) DOI: 10.1515/znc-2017-0059

Three new glucosylceramides (GluCers) named malusides I–III (1–3) were isolated from apple (cultivars of Malus domestica) pomace (fruit material remaining after juice extraction). An unusual oxo/hydroxy group pattern within the sphingadienine (d18:2) type sphingoid base was observed. All compounds contained the same α-hydroxylated fatty acid (h16:0) and a β-D-glucose moiety. Their structures were assigned on the basis of one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) spectroscopic analyses and mass spectrometry (MS) measurements.

Mot, A. C., Prell, E., Klecker, M., Naumann, C., Faden, F., Westermann, B. & Dissmeyer, N. Real‐time detection of N‐end rule‐mediated ubiquitination via fluorescently labeled substrate probe. New Phytolog 217, 613-624, (2018) DOI: 10.1111/nph.14497

The N-end rule pathway has emerged as a major system for regulating protein functions by controlling their turnover in medical, animal and plant sciences as well as agriculture. Although novel functions and enzymes of the pathway have been discovered, the ubiquitination mechanism and substrate specificity of N-end rule pathway E3 ubiquitin ligases have remained elusive. Taking the first discovered bona fide plant N-end rule E3 ligase PROTEOLYSIS1 (PRT1) as a model, we used a novel tool to molecularly characterize polyubiquitination live, in real time.
We gained mechanistic insights into PRT1 substrate preference and activation by monitoring live ubiquitination using a fluorescent chemical probe coupled to artificial substrate reporters. Ubiquitination was measured by rapid in-gel fluorescence scanning as well as in real time by fluorescence polarization.
The enzymatic activity, substrate specificity, mechanisms and reaction optimization of PRT1-mediated ubiquitination were investigated ad hoc instantaneously and with significantly reduced reagent consumption.
We demonstrated that PRT1 is indeed an E3 ligase, which has been hypothesized for over two decades. These results demonstrate that PRT1 has the potential to be involved in polyubiquitination of various substrates and therefore pave the way to understanding recently discovered phenotypes of prt1 mutants.

Edeler, D., Arlt, S., Petković, V., Ludwig, G., Drača, D., Maksimović-Ivanić, D., Mijatović, S. & Kaluđerović, G. N. Delivery of [Ru(η6-p-cymene)Cl2{Ph2P(CH2)3SPh-κP}] using unfunctionalized and mercapto functionalized SBA-15 mesoporous silica: Preparation, characterization and in vitro study. J Inorg Biochem 180, 155-162, (2018) DOI: 10.1016/j.jinorgbio.2017.12.011

SBA-15 (Santa Barbara Amorphous 15) mesoporous silica and its functionalized form (with 3-mercaptopropyltriethoxysilane) SBA-15~SH were used as carriers for [Ru(η6-p-cymene)Cl2{Ph2P(CH2)3SPh-κP}] complex, denoted as [Ru]. Prepared mesoporous silica nanomaterials were characterized by traditional methods. Materials without [Ru] complex did not show any cytotoxic activity against melanoma B16 and B16-F10 cell lines. On the contrary, materials containing [Ru] such as SBA-15¦[Ru] and SBA-15~SH¦[Ru], exhibited very high activity against tested tumor cell lines, moreover with similar inhibitory potential. According to the loaded amount of the [Ru] in SBA-15¦[Ru] and SBA-15~SH¦[Ru] the IC50 values are 1–2 μM depending on the test used, thus in comparison to [Ru] alone the activity of nanomaterials containing [Ru] are elevated 3–6 times in vitro. However, the mechanism of apoptosis induction differs for these two mesoporous silica. Unlike reference [Ru] compound and SBA-15~SH¦[Ru], SBA-15¦[Ru] induces high caspase activation. Discrepancy in mechanism of drugs action at intracellular level points towards an influence of functionalization as well as availability of the drug. Moreover, both SBA-15¦[Ru] and SBA-15~SH¦[Ru] similarly to [Ru] are declining autophagy in B16 cell line.

Melaku, Y., Worku, T., Mekonnen, Y., Schmidt, J., Arnold. N. & Dagne, E. Antiplasmodial Compounds from Leaves of Dodonaea angustifolia Curr Bioactive Comp 13, 268-273, (2017) DOI: 10.2174/1573407213666170403121222

Background: Dodonaea angustifolia is used in Ethiopian traditional medicine to treat malaria. The objective of this work was to conduct bioassay guided fractionation of the leaves of D. angustifolia using Plasmodium berghei infected mice. Methods: The antiplasmodial activity of the extracts and pure compounds were evaluated using the standard Peter’s four-day suppressive method. The structures of isolated compounds were elucidated using chemical and spectroscopic methods. Results: In this study the ethyl acetate soluble portion of the 80% aqueous MeOH extract of the leaves significantly suppressed parasitaemia in Plasmodium berghei infected mice (80.28% at 150 mg/kg). Three active compounds which exhibited significant percent suppression of parasitaemia by 81% at 40 mg/kg, 80% at 50 mg/kg and 70% at 40 mg/kg, respectively were identified. These are the flavanone pinocembrin (1), the flavanol santin (2) and the clerodane diterpene 2-hydroxy-15,16-epoxyceloda-3,13(16),14-trien-18-oic acid (3). Under similar conditions chloroquine suppressed parasitaemia by 100% at 25 mg/kg. Chemical study of the ethanol extract of the leaves yielded 5,7,4'-trihydroxy-3,6-dimethoxyflavone (4), ent-16-hydroxy-labdan-3α,8β-dihydroxy,13(14)-en-15,16-olide (5) and 5,6,7-trihydroxy-3,4'-dimethoxyflavone (6). Compound 6 has not been reported before as a natural product. Conclusion: From the leaves of D. angustifolia three compounds with significant antiplasmodial activities were isolated and characterized, with pinocembrin as the most active compound. 

Greff, A., Porzel, A., Schmidt, J., Palfner, G. & Arnold, N. Pigment pattern of the Chilean mushroom Dermocybe nahuelbutensis Garrido & E. Horak. Rec. Nat. Prod. 11, 547-551, (2017) DOI: 10.25135/rnp.

Fruiting bodies of the Chilean mushroom Dermocybe nahuelbutenis Garrido & E. Horak (syn.: Cortinariusnahuelbutensis (Garrido & E. Horak) E. Valenz. & G. Moreno) were chemically investigated for the first time and afforded the new dimeric anthraqinone 7,7 ' -emodinphyscion (1) beside the know anthraquinones dermolutein (2), endocrocin (3), skyrin (4) and the dimeric pre-anthraquinone derivative flavomannin C (5 ) . The chemotaxonomic significance of the pigments is discussed. 

Loesche, A., Wiese, J., Sommerwerk, S., Simon, V., Brandt, W. & Csuk, R. Repurposing N,N '-bis-(arylamidino)-1,4-piperazinedicarboxamidines: An unexpected class of potent inhibitors of cholinesterases. Eur J Med Chem 125, 430-434, (2017) DOI: 10.1016/j.ejmech.2016.09.051

Drug repurposing (=drug repositioning) is an effective way to cut costs for the development of new therapeutics and to reduce the time-to-market time-span. Following this concept a small library of compounds was screened for their ability to act as inhibitors of acetyl- and butyrylcholinesterase. Picloxydine, an established antiseptic, was shown to be an inhibitor for both enzymes. Systematic variation of the aryl substituents led to analogs possessing almost the same good properties as gold standard galantamine hydrobromide.
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