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  -