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Publikationen - Natur- und Wirkstoffchemie

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Preprints

Fu, N.; Yang, Z.-l.; Pauchet, Y.; Paetz, C.; Brandt, W.; Boland, W.; Burse, A.; A cytochrome P450 from juvenile mustard leaf beetles hydroxylates geraniol, a key step in iridoid biosynthesis bioRxiv (2019) DOI: 10.1101/634485

Juveniles of the leaf beetle Phaedon cochleariae synthesize iridoid via the mevalonate pathway to repel predators. The normal terpenoid biosynthesis is integrated into the dedicated defensive pathway by the ω-hydroxylation of geraniol to 8-hydroxygeraniol. Here we identify and characterize the geraniol 8-hydroxylase as a P450 monooxygenase using integrated transcriptomic and proteomic analyses. In the fat body, 73 individual cytochrome P450s were identified. The double stranded RNA (dsRNA)-mediated knock down of CYP6BH5 led to a significant reduction of 8-hydroxygeraniol-glucoside in the hemolymph and, later, of the chrysomelidial in the defensive secretion. Heterologously expressed CYP6BH5 converted geraniol to 8-hydroxygeraniol. In addition to geraniol, CYP6BH5 also catalyzes other monoterpenols, such as nerol and citronellol, into the corresponding α, ω-dihydroxy compounds.
Publikation

Zoufal, V.; Mairinger, S.; Krohn, M.; Wanek, T.; Filip, T.; Sauberer, M.; Stanek, J.; Traxl, A.; Schuetz, J. D.; Kuntner, C.; Pahnke, J.; Langer, O.; Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[11C]Methylpurine in Mice Mol. Imaging Biol. 21, 306-316, (2019) DOI: 10.1007/s11307-018-1230-y

PurposeMultidrug resistance-associated proteins (MRPs) mediate the hepatobiliary and renal excretion of many drugs and drug conjugates. The positron emission tomography (PET) tracer 6-bromo-7-[11C]methylpurine is rapidly converted in tissues by glutathione-S-transferases into its glutathione conjugate, and has been used to measure the activity of Abcc1 in the brain and the lungs of mice. Aim of this work was to investigate if the activity of MRPs in excretory organs can be measured with 6-bromo-7-[11C]methylpurine.ProceduresWe performed PET scans with 6-bromo-7-[11C]methylpurine in groups of wild-type, Abcc4(−/−) and Abcc1(−/−) mice, with and without pre-treatment with the prototypical MRP inhibitor MK571.Results6-Bromo-7-[11C]methylpurine-derived radioactivity predominantly underwent renal excretion. In blood, MK571 treatment led to a significant increase in the AUC and a decrease in the elimination rate constant of radioactivity (kelimination,blood). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (kuptake,kidney), kelimination,kidney, and the rate constant for tubular secretion of radioactivity (kurine). Experiments in Abcc4(−/−) mice indicated that Abcc4 contributed to renal excretion of 6-bromo-7-[11C]methylpurine-derived radioactivity.ConclusionsOur data suggest that 6-bromo-7-[11C]methylpurine may be useful to assess the activity of MRPs in the kidneys as well as in other organs (brain, lungs), although further work is needed to identify the MRP subtypes involved in the disposition of 6-bromo-7-[11C]methylpurine-derived radioactivity.
Publikation

Yadav, H.; Dreher, D.; Athmer, B.; Porzel, A.; Gavrin, A.; Baldermann, S.; Tissier, A.; Hause, B.; Medicago TERPENE SYNTHASE 10 Is Involved in Defense Against an Oomycete Root Pathogen Plant Physiol. 180, 1598-1613, (2019) DOI: 10.1104/pp.19.00278

In nature, plants interact with numerous beneficial or pathogenic soil-borne microorganisms. Plants have developed various defense strategies to expel pathogenic microbes, some of which function soon after pathogen infection. We used Medicago truncatula and its oomycete pathogen Aphanomyces euteiches to elucidate early responses of the infected root. A. euteiches causes root rot disease in legumes and is a limiting factor in legume production. Transcript profiling of seedlings and adult plant roots inoculated with A. euteiches zoospores for 2 h revealed specific upregulation of a gene encoding a putative sesquiterpene synthase (M. truncatula TERPENE SYNTHASE 10 [MtTPS10]) in both developmental stages. MtTPS10 was specifically expressed in roots upon oomycete infection. Heterologous expression of MtTPS10 in yeast led to production of a blend of sesquiterpenes and sesquiterpene alcohols, with NMR identifying a major peak corresponding to himalachol. Moreover, plants carrying a tobacco (Nicotiana tabacum) retrotransposon Tnt1 insertion in MtTPS10 lacked the emission of sesquiterpenes upon A. euteiches infection, supporting the assumption that the identified gene encodes a multiproduct sesquiterpene synthase. Mttps10 plants and plants with reduced MtTPS10 transcript levels created by expression of an MtTPS10-artificial microRNA in roots were more susceptible to A. euteiches infection than were the corresponding wild-type plants and roots transformed with the empty vector, respectively. Sesquiterpenes produced by expression of MtTPS10 in yeast also inhibited mycelial growth and A. euteiches zoospore germination. These data suggest that sesquiterpene production in roots by MtTPS10 plays a previously unrecognized role in the defense response of M. truncatula against A. euteiches.
Publikation

Westphal, L.; Strehmel, N.; Eschen-Lippold, L.; Bauer, N.; Westermann, B.; Rosahl, S.; Scheel, D.; Lee, J.; pH effects on plant calcium fluxes: lessons from acidification-mediated calcium elevation induced by the γ-glutamyl-leucine dipeptide identified from Phytophthora infestans Sci. Rep. 9, 4733, (2019) DOI: 10.1038/s41598-019-41276-0

Cytosolic Ca2+ ([Ca2+]cyt) elevation is an early signaling response upon exposure to pathogen-derived molecules (so-called microbe-associated molecular patterns, MAMPs) and has been successfully used as a quantitative read-out in genetic screens to identify MAMP receptors or their associated components. Here, we isolated and identified by mass spectrometry the dipeptide γ-Glu-Leu as a component of a Phytophthora infestans mycelium extract that induces [Ca2+]cyt elevation. Treatment of Arabidopsis seedlings with synthetic γ-Glu-Leu revealed stimulatory effects on defense signaling, including a weak enhancement of the expression of some MAMP-inducible genes or affecting the refractory period to a second MAMP elicitation. However, γ-Glu-Leu is not a classical MAMP since pH adjustment abolished these activities and importantly, the observed effects of γ-Glu-Leu could be recapitulated by mimicking extracellular acidification. Thus, although γ-Glu-Leu can act as a direct agonist of calcium sensing receptors in animal systems, the Ca2+-mobilizing activity in plants reported here is due to acidification. Low pH also shapes the Ca2+ signature of well-studied MAMPs (e.g. flg22) or excitatory amino acids such as glutamate. Overall, this work serves as a cautionary reminder that in defense signaling studies where Ca2+ flux measurements are concerned, it is important to monitor and consider the effects of pH.
Publikation

Vasco, A. V.; Méndez, Y.; Porzel, A.; Balbach, J.; Wessjohann, L. A.; Rivera, D. G.; A Multicomponent Stapling Approach to Exocyclic Functionalized Helical Peptides: Adding Lipids, Sugar, PEGs, Labels and Handles to the Lactam Bridge Bioconjugate Chem. 30, 253-259, (2019) DOI: 10.1021/acs.bioconjchem.8b00906

Peptide stapling is traditionally used to lock peptide conformations into α-helical structures using a variety of macrocyclization chemistries. In an endeavor to add a diversity-generating tool to this repertoire, we introduce a multicomponent stapling approach enabling the simultaneous stabilization of helical secondary structures and the exocyclic N-functionalization of the side chain-tethering lactam bridge. This is accomplished by means of a novel solid-phase methodology comprising, for the first time, the on-resin Ugi reaction-based macrocyclization of peptide side chains bearing amino and carboxylic acid groups. The exocyclic diversity elements arise from the isocyanide component used in the Ugi multicomponent stapling protocol, which allows for the incorporation of relevant fragments such as lipids, sugars, polyethylene glycol, fluorescent labels, and reactive handles. We prove the utility of such exocyclic reactive groups in the bioconjugation of a maleimide-armed lactam-bridged peptide to a carrier protein. The on-resin multicomponent stapling proved efficient for the installation of not only one, but also two consecutive lactam bridges having either identical or dissimilar N-functionalities. The easy access to helical peptides with a diverse set of exocyclic functionalities shows prospect for applications in peptide drug discovery and chemical biology.
Publikation

Torres, S.; González-Ramírez, M.; Gavilán, J.; Paz, C.; Palfner, G.; Arnold, N.; Fuentealba, J.; Becerra, J.; Pérez, C.; Cabrera-Pardo, J. R.; Exposure to UV-B Radiation Leads to Increased Deposition of Cell Wall-Associated Xerocomic Acid in Cultures of Serpula himantioides Appl. Environ. Microbiol. 85, e00870-19, (2019) DOI: 10.1128/AEM.00870-19

Many fungi are thought to have developed morphological and physiological adaptations to cope with exposure to UV-B radiation, but in most species, such responses and their protective effects have not been explored. Here, we study the adaptive response to UV-B radiation in the widespread, saprotrophic fungus Serpula himantioides, frequently found colonizing coniferous wood in nature. We report the morphological and chemical responses of S. himantioides to controlled intensities of UV-B radiation, under in vitro culture conditions. Ultraviolet radiation induced a decrease in the growth rate of S. himantioides but did not cause gross morphological changes. Instead, we observed accumulation of pigments near the cell wall with increasing intensities of UV-B radiation. Nuclear magnetic resonance (NMR) and high-performance liquid chromatography-mass spectrometry (HPLC-MS) analyses revealed that xerocomic acid was the main pigment present, both before and after UV-B exposure, increasing from 7 mg/liter to 15 mg/liter after exposure. We show that xerocomic acid is a photoprotective metabolite with strong antioxidant abilities, as evidenced by DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS [2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt], and oxygen radical absorbance capacity (ORAC) assays. Finally, we assessed the capacity of xerocomic acid as a photoprotective agent on HEK293 cells and observed better photoprotective properties than those of β-carotene. Xerocomic acid is therefore a promising natural product for development as a UV-protective ingredient in cosmetic and pharmaceutical products.IMPORTANCE Our study shows the morphological and chemical responses of S. himantioides to controlled doses of UV-B radiation under in vitro culture conditions. We found that increased biosynthesis of xerocomic acid was the main strategy adopted by S. himantioides against UV-B radiation. Xerocomic acid showed strong antioxidant and photoprotective abilities, which has not previously been reported. Our results indicate that upon UV-B exposure, S. himantioides decreases its hyphal growth rate and uses this energy instead to increase the biosynthesis of xerocomic acid, which is allocated near the cell wall. This metabolic switch likely allows xerocomic acid to efficiently defend S. himantioides from UV radiation through its antioxidant and photoprotective properties. The findings further suggest that xerocomic acid is a promising candidate for development as a cosmetic ingredient to protect against UV radiation and should therefore be investigated in depth in the near future both in vitro and in vivo.
Publikation

Soboleva, A.; Mavropulo-Stolyarenko, G.; Karonova, T.; Thieme, D.; Hoehenwarter, W.; Ihling, C.; Stefanov, V.; Grishina, T.; Frolov, A.; Multiple Glycation Sites in Blood Plasma Proteins as an Integrated Biomarker of Type 2 Diabetes Mellitus Int. J. Mol. Sci. 20, 2329, (2019) DOI: 10.3390/ijms20092329

Type 2 diabetes mellitus (T2DM) is one of the most widely spread metabolic diseases. Because of its asymptomatic onset and slow development, early diagnosis and adequate glycaemic control are the prerequisites for successful T2DM therapy. In this context, individual amino acid residues might be sensitive indicators of alterations in blood glycation levels. Moreover, due to a large variation in the half-life times of plasma proteins, a generalized biomarker, based on multiple glycation sites, might provide comprehensive control of the glycemic status across any desired time span. Therefore, here, we address the patterns of glycation sites in highly-abundant blood plasma proteins of T2DM patients and corresponding age- and gender-matched controls by comprehensive liquid chromatography-mass spectrometry (LC-MS). The analysis revealed 42 lysyl residues, significantly upregulated under hyperglycemic conditions. Thereby, for 32 glycation sites, biomarker behavior was demonstrated here for the first time. The differentially glycated lysines represented nine plasma proteins with half-lives from 2 to 21 days, giving access to an integrated biomarker based on multiple protein-specific Amadori peptides. The validation of this biomarker relied on linear discriminant analysis (LDA) with random sub-sampling of the training set and leave-one-out cross-validation (LOOCV), which resulted in an accuracy, specificity, and sensitivity of 92%, 100%, and 85%, respectively.
Publikation

Shumilina, J.; Kusnetsova, A.; Tsarev, A.; Janse van Rensburg, H. C.; Medvedev, S.; Demidchik, V.; Van den Ende, W.; Frolov, A.; Glycation of Plant Proteins: Regulatory Roles and Interplay with Sugar Signalling? Int. J. Mol. Sci. 20, 2366, (2019) DOI: 10.3390/ijms20092366

Glycation can be defined as an array of non-enzymatic post-translational modifications of proteins formed by their interaction with reducing carbohydrates and carbonyl products of their degradation. Initial steps of this process rely on reducing sugars and result in the formation of early glycation products—Amadori and Heyns compounds via Schiff base intermediates, whereas their oxidative degradation or reactions of proteins with α-dicarbonyl compounds yield a heterogeneous group of advanced glycation end products (AGEs). These compounds accompany thermal processing of protein-containing foods and are known to impact on ageing, pathogenesis of diabetes mellitus and Alzheimer’s disease in mammals. Surprisingly, despite high tissue carbohydrate contents, glycation of plant proteins was addressed only recently and its physiological role in plants is still not understood. Therefore, here we summarize and critically discuss the first steps done in the field of plant protein glycation during the last decade. We consider the main features of plant glycated proteome and discuss them in the context of characteristic metabolic background. Further, we address the possible role of protein glycation in plants and consider its probable contribution to protein degradation, methylglyoxal and sugar signalling, as well as interplay with antioxidant defense.
Publikation

Shamraiz, U.; Ahmad, Z.; Badshah, A.; Hussain, H.; Abbas, G.; Ullah, S.; Raza, B.; α-glucosidase inhibition (antidiabetic) of rubidium doped indium sulfide nanomaterials Mater. Res. Express 6, 115051, (2019) DOI: 10.1088/2053-1591/ab4766

Herein, we report the In2S3 and rubidium doped In2S3 (Rb- In2S3) nanostructures and elucidate their role in α-glucosidase inhibition (AIGs). The phase, crystal structure, morphology, and composition of the as prepared In2S3 and Rb- In2S3 nanostructures was characterized by PXRD, SEM, TEM and EDS analysis, respectively. Pure In2S3 were unable to impart significance glucosidase inhibition activity, while the activity was remarkably enhanced with the doping of 5% Rb. The mass percentage of Rb (0.42 μg ml−1) is much lower than the transition metals-based drugs reported in the literature.
Publikation

Shamraiz, U.; Raza, B.; Hussain, H.; Badshah, A.; Green, I. R.; Kiani, F. A.; Al-Harrasi, A.; Gold nanotubes and nanorings: promising candidates for multidisciplinary fields Int. Mater. Rev. 64, 478-512, (2019) DOI: 10.1080/09506608.2018.1554991

Gold is considered as an inert metal and ranks as one of the noblest among all the metals. Progressive importance associated with nanotechnology offers potential development of new methods and controlled morphologies of the anisotropic gold nanostructures to develop its innovative properties and commensurate applications. The unique gold nanostructures are considered for their potential applications in various fields due to their large surface area, excellent adhesion properties and resistance to corrosion. In this review, we will present recent developments for gold nanorings and nanotubes, under the headings of synthesis, properties and potential applications in various fields.
  • Die Leibniz-Gemeinschaft
  • Digitalisierung in der Landwirtschaft
  • Martin-Luther Universität Halle
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