Kaiser M

References (13)

Title : Chemoproteomics Reveals the Pan-HER Kinase Inhibitor Neratinib To Target an Arabidopsis Epoxide Hydrolase Related to Phytohormone Signaling - Ninck_2023_ACS.Chem.Biol__
Author(s) : Ninck S , Halder V , Krahn JH , Beisser D , Resch S , Dodds I , Scholtysik R , Bormann J , Sewald L , Gupta MD , Heilmann G , Bhandari DD , Morimoto K , Buscaill P , Hause B , van der Hoorn RAL , Kaschani F , Kaiser M
Ref : ACS Chemical Biology , : , 2023
Abstract : Plant phytohormone pathways are regulated by an intricate network of signaling components and modulators, many of which still remain unknown. Here, we report a forward chemical genetics approach for the identification of functional SA agonists in Arabidopsis thaliana that revealed Neratinib (Ner), a covalent pan-HER kinase inhibitor drug in humans, as a modulator of SA signaling. Instead of a protein kinase, chemoproteomics unveiled that Ner covalently modifies a surface-exposed cysteine residue of Arabidopsis epoxide hydrolase isoform 7 (AtEH7), thereby triggering its allosteric inhibition. Physiologically, the Ner application induces jasmonate metabolism in an AtEH7-dependent manner as an early response. In addition, it modulates PATHOGENESIS RELATED 1 (PR1) expression as a hallmark of SA signaling activation as a later effect. AtEH7, however, is not the exclusive target for this physiological readout induced by Ner. Although the underlying molecular mechanisms of AtEH7-dependent modulation of jasmonate signaling and Ner-induced PR1-dependent activation of SA signaling and thus defense response regulation remain unknown, our present work illustrates the powerful combination of forward chemical genetics and chemical proteomics for identifying novel phytohormone signaling modulatory factors. It also suggests that marginally explored metabolic enzymes such as epoxide hydrolases may have further physiological roles in modulating signaling.
ESTHER : Ninck_2023_ACS.Chem.Biol__
PubMedSearch : Ninck_2023_ACS.Chem.Biol__
PubMedID: 37115018
Gene_locus related to this paper: arath-T14P8.15

Title : Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9 - Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
Author(s) : Carvalho LAR , Ross B , Fehr L , Bolgi O , Wohrle S , Lum KM , Podlesainski D , Vieira AC , Kiefersauer R , Felix R , Rodrigues T , Lucas SD , Gross O , Geiss-Friedlander R , Cravatt BF , Huber R , Kaiser M , Moreira R
Ref : Angew Chem Int Ed Engl , : , 2022
Abstract : Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-beta-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date.
ESTHER : Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
PubMedSearch : Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
PubMedID: 36089535
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : Identification of fungal lignocellulose-degrading biocatalysts secreted by Phanerochaete chrysosporium via activity-based protein profiling - Schmerling_2022_Commun.Biol_5_1254
Author(s) : Schmerling C , Sewald L , Heilmann G , Witfeld F , Begerow D , Jensen K , Brsen C , Kaschani F , Overkleeft HS , Siebers B , Kaiser M
Ref : Commun Biol , 5 :1254 , 2022
Abstract : Activity-based protein profiling (ABPP) has emerged as a versatile biochemical method for studying enzyme activity under various physiological conditions, with applications so far mainly in biomedicine. Here, we show the potential of ABPP in the discovery of biocatalysts from the thermophilic and lignocellulose-degrading white rot fungus Phanerochaete chrysosporium. By employing a comparative ABPP-based functional screen, including a direct profiling of wood substrate-bound enzymes, we identify those lignocellulose-degrading carbohydrate esterase (CE1 and CE15) and glycoside hydrolase (GH3, GH5, GH16, GH17, GH18, GH25, GH30, GH74 and GH79) enzymes specifically active in presence of the substrate. As expression of fungal enzymes remains challenging, our ABPP-mediated approach represents a preselection procedure for focusing experimental efforts on the most promising biocatalysts. Furthermore, this approach may also allow the functional annotation of domains-of-unknown functions (DUFs). The ABPP-based biocatalyst screening described here may thus allow the identification of active enzymes in a process of interest and the elucidation of novel biocatalysts that share no sequence similarity to known counterparts.
ESTHER : Schmerling_2022_Commun.Biol_5_1254
PubMedSearch : Schmerling_2022_Commun.Biol_5_1254
PubMedID: 36385496

Title : N-oxide alkaloids from Crinum amabile (Amaryllidaceae) - Tallini_2018_Molecules_23_1277
Author(s) : Tallini LR , Torras-Claveria L , Borges WS , Kaiser M , Viladomat F , Zuanazzi JAS , Bastida J
Ref : Molecules , 23 :1277 , 2018
Abstract : Natural products play an important role in the development of new drugs. In this context, the Amaryllidaceae alkaloids have attracted considerable attention in view of their unique structural features and various biological activities. In this study, twenty-three alkaloids were identified from Crinum amabile by GC-MS and two new structures (augustine N-oxide and buphanisine N-oxide) were structurally elucidated by NMR. Anti-parasitic and cholinesterase (AChE and BuChE) inhibitory activities of six alkaloids isolated from this species, including the two new compounds, are described herein. None of the alkaloids isolated from C. amabile gave better results than the reference drugs, so it was possible to conclude that the N-oxide group does not increase their therapeutic potential.
ESTHER : Tallini_2018_Molecules_23_1277
PubMedSearch : Tallini_2018_Molecules_23_1277
PubMedID: 29861456

Title : Hippeastrum reticulatum (Amaryllidaceae): Alkaloid Profiling, Biological Activities and Molecular Docking - Tallini_2017_Molecules_22_
Author(s) : Tallini LR , Osorio EH , Santos VDD , Borges WS , Kaiser M , Viladomat F , Zuanazzi JAS , Bastida J
Ref : Molecules , 22 : , 2017
Abstract : The Amaryllidaceae family has proven to be a rich source of active compounds, which are characterized by unique skeleton arrangements and a broad spectrum of biological activities. The aim of this work was to perform the first detailed study of the alkaloid constituents of Hippeastrum reticulatum (Amaryllidaceae) and to determine the anti-parasitological and cholinesterase (AChE and BuChE) inhibitory activities of the epimers (6alpha-hydroxymaritidine and 6beta-hydroxymaritidine). Twelve alkaloids were identified in H. reticulatum: eight known alkaloids by GC-MS and four unknown (6alpha-hydroxymaritidine, 6beta-hydroxymaritidine, reticulinine and isoreticulinine) by NMR. The epimer mixture (6alpha-hydroxymaritidine and 6beta-hydroxymaritidine) showed low activity against all protozoan parasites tested and weak AChE-inhibitory activity. Finally, a molecular docking analysis of AChE and BuChE proteins showed that isoreticulinine may be classified as a potential inhibitory molecule since it can be stabilized in the active site through hydrogen bonds, pi-pi stacking and hydrophobic interactions.
ESTHER : Tallini_2017_Molecules_22_
PubMedSearch : Tallini_2017_Molecules_22_
PubMedID: 29232852

Title : Harnessing fungal nonribosomal cyclodepsipeptide synthetases for mechanistic insights and tailored engineering - Steiniger_2017_Chem.Sci_8_7834
Author(s) : Steiniger C , Hoffmann S , Mainz A , Kaiser M , Voigt K , Meyer V , Sussmuth RD
Ref : Chem Sci , 8 :7834 , 2017
Abstract : Nonribosomal peptide synthetases represent potential platforms for the design and engineering of structurally complex peptides. While previous focus has been centred mainly on bacterial systems, fungal synthetases assembling drugs like the antifungal echinocandins, the antibacterial cephalosporins or the anthelmintic cyclodepsipeptide (CDP) PF1022 await in-depth exploitation. As various mechanistic features of fungal CDP biosynthesis are only partly understood, effective engineering of NRPSs has been severely hampered. By combining protein truncation, in trans expression and combinatorial swapping, we assigned important functional segments of fungal CDP synthetases and assessed their in vivo biosynthetic capabilities. Hence, artificial assembly line components comprising of up to three different synthetases were generated. Using Aspergillus niger as a heterologous expression host, we obtained new-to-nature octa-enniatin (4 mg L(-1)) and octa-beauvericin (10.8 mg L(-1)), as well as high titers of the hybrid CDP hexa-bassianolide (1.3 g L(-1)) with an engineered ring size. The hybrid compounds showed up to 12-fold enhanced antiparasitic activity against Leishmania donovani and Trypanosoma cruzi compared to the reference drugs miltefosine and benznidazole, respectively. Our findings thus contribute to a rational engineering of iterative nonribosomal assembly lines.
ESTHER : Steiniger_2017_Chem.Sci_8_7834
PubMedSearch : Steiniger_2017_Chem.Sci_8_7834
PubMedID: 29163920

Title : A photorhabdus natural product inhibits insect juvenile hormone epoxide hydrolase - Nollmann_2015_Chembiochem_16_766
Author(s) : Nollmann FI , Heinrich AK , Brachmann AO , Morisseau C , Mukherjee K , Casanova-Torres AM , Strobl F , Kleinhans D , Kinski S , Schultz K , Beeton ML , Kaiser M , Chu YY , Phan Ke L , Thanwisai A , Bozhuyuk KA , Chantratita N , Gotz F , Waterfield NR , Vilcinskas A , Stelzer EH , Goodrich-Blair H , Hammock BD , Bode HB
Ref : Chembiochem , 16 :766 , 2015
Abstract : Simple urea compounds ("phurealipids") have been identified from the entomopathogenic bacterium Photorhabdus luminescens, and their biosynthesis was elucidated. Very similar analogues of these compounds have been previously developed as inhibitors of juvenile hormone epoxide hydrolase (JHEH), a key enzyme in insect development and growth. Phurealipids also inhibit JHEH, and therefore phurealipids might contribute to bacterial virulence.
ESTHER : Nollmann_2015_Chembiochem_16_766
PubMedSearch : Nollmann_2015_Chembiochem_16_766
PubMedID: 25711603

Title : Calcium responses to synaptically activated bursts of action potentials and their synapse-independent replay in cultured networks of hippocampal neurons - Bengtson_2013_Biochim.Biophys.Acta_1833_1672
Author(s) : Bengtson CP , Kaiser M , Obermayer J , Bading H
Ref : Biochimica & Biophysica Acta , 1833 :1672 , 2013
Abstract : Both synaptic N-methyl-d-aspartate (NMDA) receptors and voltage-operated calcium channels (VOCCs) have been shown to be critical for nuclear calcium signals associated with transcriptional responses to bursts of synaptic input. However the direct contribution to nuclear calcium signals from calcium influx through NMDA receptors and VOCCs has been obscured by their concurrent roles in action potential generation and synaptic transmission. Here we compare calcium responses to synaptically induced bursts of action potentials with identical bursts devoid of any synaptic contribution generated using the pre-recorded burst as the voltage clamp command input to replay the burst in the presence of blockers of action potentials or ionotropic glutamate receptors. Synapse independent replays of bursts produced nuclear calcium responses with amplitudes around 70% of their original synaptically generated signals and were abolished by the L-type VOCC blocker, verapamil. These results identify a major direct source of nuclear calcium from local L-type VOCCs whose activation is boosted by NMDA receptor dependent depolarization. The residual component of synaptically induced nuclear calcium signals which was both VOCC independent and NMDA receptor dependent showed delayed kinetics consistent with a more distal source such as synaptic NMDA receptors or internal stores. The dual requirement of NMDA receptors and L-type VOCCs for synaptic activity-induced nuclear calcium dependent transcriptional responses most likely reflects a direct somatic calcium influx from VOCCs whose activation is amplified by synaptic NMDA receptor-mediated depolarization and whose calcium signal is boosted by a delayed input from distal calcium sources mostly likely entry through NMDA receptors and release from internal stores. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.
ESTHER : Bengtson_2013_Biochim.Biophys.Acta_1833_1672
PubMedSearch : Bengtson_2013_Biochim.Biophys.Acta_1833_1672
PubMedID: 23360982

Title : A para-nitrophenol phosphonate probe labels distinct serine hydrolases of Arabidopsis - Nickel_2012_Bioorg.Med.Chem_20_601
Author(s) : Nickel S , Kaschani F , Colby T , van der Hoorn RA , Kaiser M
Ref : Bioorganic & Medicinal Chemistry , 20 :601 , 2012
Abstract : Activity-based protein profiling represents a powerful methodology to probe the activity state of enzymes under various physiological conditions. Here we present the development of a para-nitrophenol phosphonate activity-based probe with structural similarities to the potent agrochemical paraoxon. We demonstrate that this probes labels distinct serine hydrolases with the carboxylesterase CXE12 as the predominant target in Arabidopsis thaliana. The designed probe features a distinct labeling pattern and therefore represents a promising chemical tool to investigate physiological roles of selected serine hydrolases such as CXE12 in plant biology.
ESTHER : Nickel_2012_Bioorg.Med.Chem_20_601
PubMedSearch : Nickel_2012_Bioorg.Med.Chem_20_601
PubMedID: 21763150

Title : Selective inhibition of plant serine hydrolases by agrochemicals revealed by competitive ABPP - Kaschani_2012_Bioorg.Med.Chem_20_597
Author(s) : Kaschani F , Nickel S , Pandey B , Cravatt BF , Kaiser M , van der Hoorn RA
Ref : Bioorganic & Medicinal Chemistry , 20 :597 , 2012
Abstract : Organophosphate and -phosphonates and their thio derivatives are often used in agroindustry as herbicides and insecticides, but their potential off-targets in the plant are poorly investigated. Here, we use competitive activity-based protein profiling (ABPP) of serine hydrolases (SHs) to detect targets of these agrochemicals and other compounds in Arabidopsis thaliana. Using broad-range and specific probes, and by overexpression of various SHs in planta, we are able to confirm eight SH-compound interactions, including selective inhibition of carboxylesterase CXE12, prolyloligopeptidase, methylesterase MES2 and tripeptidyl peptidase TPP2. These observations can be used for the design of novel probes and selective inhibitors and may help to assess physiological effects of agrochemicals on crop plants.
ESTHER : Kaschani_2012_Bioorg.Med.Chem_20_597
PubMedSearch : Kaschani_2012_Bioorg.Med.Chem_20_597
PubMedID: 21764588

Title : Effects of distinct collybistin isoforms on the formation of GABAergic synapses in hippocampal neurons - Korber_2012_Mol.Cell.Neurosci_50_250
Author(s) : Korber C , Richter A , Kaiser M , Schlicksupp A , Mukusch S , Kuner T , Kirsch J , Kuhse J
Ref : Molecular & Cellular Neurosciences , 50 :250 , 2012
Abstract : Collybistin (Cb) is a brain specific guanine nucleotide exchange factor that interacts with the inhibitory postsynaptic scaffold protein gephyrin. Cb is essential for the postsynaptic clustering of gephyrin and major GABA(A) receptor subtypes during the formation and maintenance of GABAergic synapses in the hippocampus and other areas of the forebrain. In the rat, four distinct splice variants (Cb1, Cb2(SH3-), Cb2(SH3+) and Cb3), have been described, which differ in their C-termini (Cb1-3) and in respect of the SH3-domain that is absent in Cb2(SH3-). In the human brain, only a single isoform (hPEM2) corresponding to Cb3, was found to be expressed. This has been implicated in neurological defects such as hyperekplexia, epilepsy, anxiety, aggression and mental retardation. In this study, we address the functional significance of the differentially spliced Cb isoforms by generating a shRNA-mediated knock-down of endogenous Cb in hippocampal cultured neurons that is subsequently rescued by the expression of distinct Cb isoforms. We found that the Cb knock-down induced impairment in GABAergic neurotransmission could be rescued by the expression of any of the Cb isoforms, independent of their C-termini or the presence of the SH3-domain in the N-terminal region. Thus, the different Cb isoforms all confer basic functionality.
ESTHER : Korber_2012_Mol.Cell.Neurosci_50_250
PubMedSearch : Korber_2012_Mol.Cell.Neurosci_50_250
PubMedID: 22659578

Title : Whole genome survey of copy number variation in the spontaneously hypertensive rat: relationship to quantitative trait loci, gene expression, and blood pressure - Charchar_2010_Hypertension_55_1231
Author(s) : Charchar FJ , Kaiser M , Bingham AJ , Fotinatos N , Ahmady F , Tomaszewski M , Samani NJ
Ref : Hypertension , 55 :1231 , 2010
Abstract : Copy number variation has emerged recently as an important genetic mechanism leading to phenotypic heterogeneity. The aim of our study was to determine whether copy number variants (CNVs) exist between the spontaneously hypertensive rat (SHR) and its control strain, the Wistar-Kyoto rat, whether these map to quantitative trait loci in the rat and whether CNVs associate with gene expression or blood pressure differences between the 2 strains. We performed a comparative genomic hybridization assay between SHR and Wistar-Kyoto strains using a whole-genome array. In total, 16 CNVs were identified and validated (6 because of a relative loss of copy number in the SHR and 10 because of a relative gain). CNVs were present on rat autosomes 1, 3, 4, 6, 7, 10, 14, and 17 and varied in size from 10.0 kb to 1.6 Mb. Most of these CNVs mapped to chromosomal regions within previously identified quantitative trait loci, including those for blood pressure in the SHR. Transcriptomic experiments confirmed differences in the renal expression of several genes (including Ms4a6a, Ndrg3, Egln1, Cd36, Sema3a, Ugt2b, and Idi21) located in some of the CNVs between SHR and Wistar-Kyoto rats. In F(2) animals derived from an SHRxWistar-Kyoto cross, we also found a significant increase in blood pressure associated with an increase in copy number in the Egln1 gene. Our findings suggest that CNVs may play a role in the susceptibility to hypertension and related traits in the SHR.
ESTHER : Charchar_2010_Hypertension_55_1231
PubMedSearch : Charchar_2010_Hypertension_55_1231
PubMedID: 20231529

Title : Leishmanicidal and cholinesterase inhibiting activities of phenolic compounds from Allanblackia monticola and Symphonia globulifera - Lenta_2007_Molecules_12_1548
Author(s) : Lenta BN , Vonthron-Senecheau C , Weniger B , Devkota KP , Ngoupayo J , Kaiser M , Naz Q , Choudhary MI , Tsamo E , Sewald N
Ref : Molecules , 12 :1548 , 2007
Abstract : In a preliminary antiprotozoal screening of several Clusiaceae species, the methanolic extracts of Allanblackia monticola and Symphonia globulifera showed high in vitro leishmanicidal activity. Further bioguided phytochemical investigation led to the isolation of four benzophenones: guttiferone A (1), garcinol (2), cambogin (3) and guttiferone F (4), along with three xanthones: allanxanthone A (5), xanthone V1 (6) and globulixanthone C (7) as active constituents. Compounds 1 and 6 were isolated from S. globulifera leaves, while compounds 2-5 were obtained from A. monticola fruits. Guttiferone A (1) and F (4) showed particulary strong leishmanicidal activity in vitro, with IC50 values (0.2 microM and 0.16 microM, respectively) comparable to that of the reference compound, miltefosine (0.46 microM). Although the leishmanicidal activity is promising, the cytotoxicity profile of these compounds prevent at this state further in vivo biological evaluation. In addition, all the isolated compounds were tested in vitro for their anticholinesterase properties. The four benzophenones showed potent anticholinesterase properties towards acetylcholinesterase (AChE) and butylcholinesterase (AChE). For AChE, the IC50 value (0.66 microM) of garcinol (2) was almost equal to that of the reference compound galanthamine (0.50 microM). Furthermore, guttiferone A (1) and guttiferone F (4) (IC50 = 2.77 and 3.50 microM, respectively) were more active than galanthamine (IC50 = 8.5) against BChE.
ESTHER : Lenta_2007_Molecules_12_1548
PubMedSearch : Lenta_2007_Molecules_12_1548
PubMedID: 17960072