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Publikationen - Natur- und Wirkstoffchemie

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Publikation

Dippe, M.; Davari, M. D.; Weigel, B.; Heinke, R.; Vogt, T.; Wessjohann, L. A.; Altering the regiospecificity of a catechol O‐methyltransferase through rational design: Vanilloid vs. isovanilloid motifs in the B‐ring of flavonoids ChemCatChem 14, e202200511, (2022) DOI: 10.1002/cctc.202200511

Rational re-design of the substrate pocket of phenylpropanoid-flavonoid O-methyltransferase (PFOMT) from Mesembryanthe-mum crystallinum, an enzyme that selectively methylates the 3’-position (= meta-position) in catechol-moieties of flavonoids to guiacol-moieties, provided the basis for the generation of variants with opposite, i. e. 4’- (para-) regioselectivity and enhanced catalytic efficiency. A double variant (Y51R/N202W) identified through a newly developed colorimetric assay efficiently modified the para-position in flavanone and flavano-nol substrates, providing access to the sweetener molecule hesperetin and other rare plant flavonoids having an isovanil-loid motif.
Publikation

Michels, K.; Heinke, R.; Schöne, P.; Kuipers, O. P.; Arnold, N.; Wessjohann, L. A.; A fluorescence-based bioassay for antibacterials and its application in screening natural product extracts J. Antibiot. 68, 734-740, (2015) DOI: 10.1038/ja.2015.71

The reliable assessment of the biological activity of a minor component embedded in a complex matrix of several hundred compounds is a difficult but common task in the search for natural product-based antibiotics, for example, by bioassay-guided fractionation. To quantify the antibiotic properties, it is necessary to assess the cell viability. Direct measurements use CFU counts, OD measurements or detection via fluorescent or reducible dyes. However, natural extracts often already possess intrinsic dye, fluorescent, reducing or protein denaturing properties, or they contain insoluble compounds or general protein-binding (tanning) polyphenols as disturbing features, while at the same time very little of the selective antibiotic sought after is present. A promising alternative is provided by intrinsically produced bright fluorescent proteins. In this paper, a rapid, robust and concentration-dependent assay for screening antibiotics with genetically modified mutants of Bacillus subtilis 168 (PabrB-iyfp) is presented. The Gram-positive bacteria exhibit a native fluorescence during their exponential growth phase due to the expression of improved yellow fluorescent protein. To demonstrate the applicability in the field of natural product research, several compounds and extracts were screened for antibacterial activity, with an emphasis on those from the fungal genus Hygrophorus (waxy caps).
Publikation

Brauer, M. C. N.; Neves Filho, R. A. W.; Westermann, B.; Heinke, R.; Wessjohann, L. A.; Synthesis of antibacterial 1,3-diyne-linked peptoids from an Ugi-4CR/Glaser coupling approach Beilstein J. Org. Chem. 11, 25-30, (2015) DOI: 10.3762/bjoc.11.4

A library of ten 1,3-diyne-linked peptoids has been synthesized through an Ugi four-component reaction (U-4CR) followed by a copper-catalysed alkyne homocoupling (Glaser reaction). The short and chemoselective reaction sequence allows generating diverse (pseudo) dimeric peptoids. A combinatorial version allows the one-pot preparation of, e.g., six-compound-libraries of homo- and heterodimers verified by ESI-MS and HPLC. In a preliminary evaluation, some compounds display moderate activity against the Gram-positive bacterium Bacillus subtilis.
Publikation

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.
Publikation

Heinke, R.; Schöne, P.; Arnold, N.; Wessjohann, L.; Schmidt, J.; Metabolite Profiling and Fingerprinting of Suillus Species (Basidiomycetes) by Electrospray Mass Spectrometry Eur. J. Mass Spectrom. 20, 85-97, (2014) DOI: 10.1255/ejms.1235

The genus Suillus is known for the occurrence of a series of prenylated phenols and boviquinones. The extracts of four different Suillus species (S. bovinus, S. granulatus, S. tridentinus and S. variegatus) were investigated by using rapid ultra-performance liquid chromatography/electrospray ionization mass spectrometry (UPLC/ESI-MS) and direct infusion electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS). While direct infusion ESI-FT-ICR mass spectra give a fast overview concerning the elemental compositions of the compounds and, therefore, hints to the main metabolites, UPLC/ESI-tandem mass spectrometry is shown to be a useful tool for their identification. A principal component analysis (PCA) and hierarchical cluster analysis (HCA) based on the UPLC/ESI-MS clearly showed that the metabolite profiles can be used not only for the identification and classification of such fungi but also as a sophisticated and powerful tool for the chemotaxonomy of fungi. Furthermore, a clear discrimination of various types of biological samples (fruiting bodies versus mycelial cultures) is also possible. The orthogonal partial least squares (OPLS) two-class models of both UPLC/ESI-MS and ESI-FT-ICR-MS possess a clear differentiation of two compared Suillus species representing the between class variation and the within class variation. Based on generated S-plots and loading plots, statistically significant metabolites could be identified as potential biomarker for one species.
Publikation

Farag, M. A.; Mohsen, M.; Heinke, R.; Wessjohann, L. A.; Metabolomic fingerprints of 21 date palm fruit varieties from Egypt using UPLC/PDA/ESI–qTOF-MS and GC–MS analyzed by chemometrics Food Res. Int. 64, 218-226, (2014) DOI: 10.1016/j.foodres.2014.06.021

Date palm fruits of the species Phoenix dactylifera exhibit a great diversity in sensory attributes including skin color, smell and taste. This study attempts to elucidate the primary and secondary metabolite profiles of 21 date varieties from Egypt. A major difficulty is sugar rich matrix and skin-fibers embedding the secondary metabolites. A total of 49 metabolites extracted from the fruit skin were evaluated in a UPLC/PDA/ESI–qTOF-MS based metabolomics study. The total phenolic contents of the varieties varied from 233 to 1897 mg/100 g (2.3–19 g/kg) dry weight. The predominant flavones were glycosides of luteolin and apigenin, quercetin conjugates were the principal flavonols, whereas caffeoyl shikimic acid was the main hydroxycinnamic acid conjugate. Aside from these major phenolic classes, a group of sphingolipids, fatty and other organic acids was also identified. The total non-fatty organic acid content correlates with reported shelf lives. GC–MS was further utilized to localize primary metabolites in fruits (i.e. sugars and organic acids) with glucose and fructose accounting for up to 95% of TIC among most varieties. Principal component and clustering analyses reveal that flavonols and sugars, both contribute the most to variety classification. This study provides the most complete map for polyphenol & sugar distribution in Egyptian date fruit varieties. By describing the metabolite profiles in a diverse dataset of P. dactylifera, this study provides the basis for future investigations of date fruit nutritional value beyond providing energy and its potential for nutraceutical enhancement or storability.
Publikation

Heinke, R.; Arnold, N.; Wessjohann, L.; Schmidt, J.; Negative ion tandem mass spectrometry of prenylated fungal metabolites and their derivatives Anal. Bioanal. Chem. 405, 177-189, (2013) DOI: 10.1007/s00216-012-6498-1

Liquid chromatography negative ion electrospray ionisation tandem mass spectrometry has been used for characterisation of naturally occurring prenylated fungal metabolites and synthetic derivatives. The fragmentation studies allow an elucidation of the decomposition pathways for these compounds. It could be shown, that the prenyl side chain is degraded by successive radical losses of C5 units. Both the benzoquinones and the phenolic derivatives display significant key ions comprising the aromatic ring. In some cases, the formation of significant oxygen-free key ions could be evidenced by high-resolution MS/MS measurements. Furthermore, the different types of basic skeletons, benzoquinones and phenol type as well as cyclic prenylated compounds, can be differentiated by their MS/MS behaviour.
Publikation

Westermann, B.; Dörner, S.; Brauch, S.; Schaks, A.; Heinke, R.; Stark, S.; van Delft, F. L.; van Berkel, S. S.; CuAAC-mediated diversification of aminoglycoside–arginine conjugate mimics by non-reducing di- and trisaccharides Carbohyd. Res. 371, 61-67, (2013) DOI: 10.1016/j.carres.2013.02.003

Di- and triguanidinylation of trehalose, sucrose, and melizitose has been achieved via a Huisgen-cycloaddition approach. They can serve as aminoglycoside–arginine conjugate mimics, which has been demonstrated by their biological profiles in assays against Bacillus subtilis. For comparative studies, tetraguanidinylated neamine and kanamycin derivatives have also been synthesized and evaluated
Publikation

Heinke, R.; Franke, K.; Michels, K.; Wessjohann, L.; Ali, N. A. A.; Schmidt, J.; Analysis of furanocoumarins from Yemenite Dorstenia species by liquid chromatography/electrospray tandem mass spectrometry J. Mass Spectrom. 47, 7-22, (2012) DOI: 10.1002/jms.2017

A series of prevailing prenylated furanocoumarins from leaves of Dorstenia gigas and Dorstenia foetida (Moraceae) were investigated by liquid chromatography/electrospray tandem mass spectrometry. The mass spectral behavior of the furanocoumarins under positive ion electrospray conditions is discussed using both an ion trap and a triple quadrupole system. It is demonstrated that both methods represent valuable tools not only for the rapid classification of this type of compounds, but also with respect to their substitution pattern.
Publikation

Heinke, R.; Franke, K.; Porzel, A.; Wessjohann, L. A.; Awadh Ali, N. A.; Schmidt, J.; Furanocoumarins from Dorstenia foetida Phytochemistry 72, 929-934, (2011) DOI: 10.1016/j.phytochem.2011.03.008

The linear furanocoumarins 5-(2,3-epoxy-3-methyl-butoxy)-chalepensin, 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)-psoralen-diacetate (7), 5-methoxy-3-[3-(β-d-glucopyranosyloxy)-2-acetyloxy-3-methyl-butyl]-psoralen and 5-(3-methyl-2,3-dihydroxybutyloxy)-3-[3-(β-d-glucopyranosyloxy)-2-hydroxy-3-methyl-butyl]-psoralen, and the coumarin derivative 7-hydroxy-5-methoxy-6-carboxymethyl-3-[3-(β-d-glucopyranosyloxy)-2-hydroxy-3-methyl-butyl]-coumarin were isolated from the leaves of Dorstenia foetida (Moraceae) along with the known compounds psoralen, bergapten, isopimpinellin, phellopterin, 5-methoxychalepensin and turbinatocoumarin. Further furanocoumarins were characterized by ESI-MS/MS investigations. The nonpolar extracts of D. foetida exhibit antifungal, antibacterial and cytotoxic activity, however, no anthelminthic activity.
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