TY - JOUR A1 - Pavashe, Prashant A1 - Elamparuthi, Elangovan A1 - Hettrich, Cornelia A1 - Moeller, Heiko M. A1 - Linker, Torsten T1 - Synthesis of 2-Thiocarbohydrates and Their Binding to Concanavalin A JF - The journal of organic chemistry N2 - A convenient and general synthesis of 2-thiocarbohydrates via cerium ammonium nitrate oxidation of the thiocyanate ion is described. Radical addition to glycals proceeds with excellent regio- and good stereoselectivities in only one step, deprotection affords water-soluble 2-thio saccharides. Binding studies to Con A have been performed by isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR spectroscopy. The 2-thiomannose derivative binds even stronger to Con A than the natural substrate, offering opportunities for new lectin or enzyme inhibitors. Y1 - 2016 U6 - https://doi.org/10.1021/acs.joc.6b00987 SN - 0022-3263 VL - 81 SP - 8595 EP - 8603 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Schildknecht, Stefan A1 - Pape, Regina A1 - Meiser, Johannes A1 - Karreman, Christiaan A1 - Strittmatter, Tobias A1 - Odermatt, Meike A1 - Cirri, Erica A1 - Friemel, Anke A1 - Ringwald, Markus A1 - Pasquarelli, Noemi A1 - Ferger, Boris A1 - Brunner, Thomas A1 - Marx, Andreas A1 - Moeller, Heiko M. A1 - Hiller, Karsten A1 - Leist, Marcel T1 - Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP+ by Transporter-Independent Export of the Intermediate MPDP+ JF - Antioxidants & redox signaling N2 - Aims: 1-Methyl-4-phenyl-tetrahydropyridine (MPTP) is among the most widely used neurotoxins for inducing experimental parkinsonism. MPTP causes parkinsonian symptoms in mice, primates, and humans by killing a subpopulation of dopaminergic neurons. Extrapolations of data obtained using MPTP-based parkinsonism models to human disease are common; however, the precise mechanism by which MPTP is converted into its active neurotoxic metabolite, 1-methyl-4-phenyl-pyridinium (MPP+), has not been fully elucidated. In this study, we aimed to address two unanswered questions related to MPTP toxicology: (1) Why are MPTP-converting astrocytes largely spared from toxicity? (2) How does MPP+ reach the extracellular space? Results: In MPTP-treated astrocytes, we discovered that the membrane-impermeable MPP+, which is generally assumed to be formed inside astrocytes, is almost exclusively detected outside of these cells. Instead of a transporter-mediated export, we found that the intermediate, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), and/or its uncharged conjugate base passively diffused across cell membranes and that MPP+ was formed predominately by the extracellular oxidation of MPDP+ into MPP+. This nonenzymatic extracellular conversion of MPDP+ was promoted by O-2, a more alkaline pH, and dopamine autoxidation products. Innovation and Conclusion: Our data indicate that MPTP metabolism is compartmentalized between intracellular and extracellular environments, explain the absence of toxicity in MPTP-converting astrocytes, and provide a rationale for the preferential formation of MPP+ in the extracellular space. The mechanism of transporter-independent extracellular MPP+ formation described here indicates that extracellular genesis of MPP+ from MPDP is a necessary prerequisite for the selective uptake of this toxin by catecholaminergic neurons. Y1 - 2015 U6 - https://doi.org/10.1089/ars.2015.6297 SN - 1523-0864 SN - 1557-7716 VL - 23 IS - 13 SP - 1001 EP - 1016 PB - Liebert CY - New Rochelle ER - TY - JOUR A1 - Victora, Andrea A1 - Moeller, Heiko M. A1 - Exner, Thomas E. T1 - Accurate ab initio prediction of NMR chemical shifts of nucleic acids and nucleic acids/protein complexes JF - Nucleic acids research N2 - NMR chemical shift predictions based on empirical methods are nowadays indispensable tools during resonance assignment and 3D structure calculation of proteins. However, owing to the very limited statistical data basis, such methods are still in their infancy in the field of nucleic acids, especially when non-canonical structures and nucleic acid complexes are considered. Here, we present an ab initio approach for predicting proton chemical shifts of arbitrary nucleic acid structures based on state-of-the-art fragment-based quantum chemical calculations. We tested our prediction method on a diverse set of nucleic acid structures including double-stranded DNA, hairpins, DNA/protein complexes and chemically-modified DNA. Overall, our quantum chemical calculations yield highly/very accurate predictions with mean absolute deviations of 0.3-0.6 ppm and correlation coefficients (r(2)) usually above 0.9. This will allow for identifying misassignments and validating 3D structures. Furthermore, our calculations reveal that chemical shifts of protons involved in hydrogen bonding are predicted significantly less accurately. This is in part caused by insufficient inclusion of solvation effects. However, it also points toward shortcomings of current force fields used for structure determination of nucleic acids. Our quantum chemical calculations could therefore provide input for force field optimization. Y1 - 2014 U6 - https://doi.org/10.1093/nar/gku1006 SN - 0305-1048 SN - 1362-4962 VL - 42 IS - 22 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Hildebrand, Viet A1 - Heydenreich, Matthias A1 - Laschewsky, Andre A1 - Moeller, Heiko M. A1 - Müller-Buschbaum, Peter A1 - Papadakis, Christine M. A1 - Schanzenbach, Dirk A1 - Wischerhoff, Erik T1 - "Schizophrenic" self-assembly of dual thermoresponsive block copolymers bearing a zwitterionic and a non-ionic hydrophilic block JF - Polymer : the international journal for the science and technology of polymers N2 - Several series of presumed dual thermo-responsive diblock copolymers consisting of one non-ionic and one zwitterionic block were synthesized via consecutive reversible addition-fragmentation chain transfer (RAFT) polymerization. For all copolymers, poly(N-isopropylmethacrylamide) was chosen as non-ionic block that shows a coil-to-globule collapse transition of the lower critical solution temperature (LCST) type. In contrast, the chemical structure of zwitterionic blocks, which all belonged to the class of poly(sulfobetaine methacrylate)s, was varied broadly, in order to tune their coil-to-globule collapse transition of the upper critical solution temperature (UCST) type. All polymers were labeled with a solvatochromic fluorescent end-group. The dual thermo-responsive behavior and the resulting multifarious temperature-dependent self-assembly in aqueous solution were mapped by temperature resolved turbidimetry, H-1 NMR spectroscopy, dynamic light scattering (DLS), and fluorescence spectroscopy. Depending on the relative positions between the UCST-type and LCST-type transition temperatures, as well as on the width of the window in-between, all the four possible modes of stimulus induced micellization can be realized. This includes classical induced micellization due to a transition from a double hydrophilic, or respectively, from a double hydrophobic to an amphiphilic state, as well as "schizophrenic" behavior, where the core- and shell-forming blocks are inverted. The exchange of the roles of the hydrophilic and hydrophobic block in the amphiphilic states is possible through a homogeneous intermediate state or a heterogeneous one. (C) 2017 Elsevier Ltd. All rights reserved. KW - RAFT polymerization KW - Block copolymer KW - Sulfobetaine methacrylate KW - Responsive polymer KW - LCST KW - UCST KW - Schizophrenic self-assembly Y1 - 2017 U6 - https://doi.org/10.1016/j.polymer.2017.06.063 SN - 0032-3861 SN - 1873-2291 VL - 122 SP - 347 EP - 357 PB - Elsevier CY - Oxford ER -