Pharmaceutical Chemistry

Diplom, 1987, Free University Berlin (Germany); Ph.D., 1990, Technical University Berlin (Germany)

Office: 236C Simons
Phone: (785)864-4880
FAX: (785)864-5736
schoneic@ukans.edu

Mechanisms of free radical reactions, protein stability, anticancer agents

Professor Schöneich's research focuses on the oxidative post-translational modification of proteins in vitro and in vivo. These are generally carried out by reactive oxygen species and/or reactive nitrogen species. In vivo, such oxidative modifications accompany physiological disorders associated with biological aging or disease. While major scientific advances have been made through the sequencing of the human genome, it has been recognized that in many cases only the detailed characterization and quantification of the protein complement (the "proteome") will lead to an accurate understanding of human disease. Moreover, in addition to quantification of the expression levels of certain proteins a detailed map of their post-translational modifications is necessary. Such research is carried out in our group. We are using state-of-the-art analytical proteomics and tandem mass spectrometry techniques to characterize post-translationally modified proteins in tissue. Experiments involve two-dimensional gel--electrophoresis and two-dimensional HPLC separations, coupled to MALDI-TOF or electrospray ionization mass spectrometry analysis on either Q-TOF2 or ion trap instrumentation. We are currently involved in the building of an interdisciplinary "Proteomics Center" at the University of Kansas, which, by Fall 2003, will be equipped with the newest generations of MALDI-TOF/TOF, MALDI-QqTOF and linear ion trap instruments. For the quantification of distinct post-translational modifications, we are designing specific labeling chemistries, which allow the targeted enrichment of specifically modified peptides from complex biological samples. For example, we have recently characterized specific S-glutathiolated sequences of a membrane protein, the sarco/endoplasmic reticulum Ca-ATPase, as a result of exposure to the biological messenger nitric oxide (NO). An additional focus of our research is to understand the actual mechanisms of oxidation, and the effect of protein structure on these reactions. In vivo, only selected proteins suffer oxidative modifications, which may be the result of chemical selectivity, protein structure, the rates of protein turnover, and/or specific protein-protein interactions.
In vitro, i.e. in pharmaceutical formulations, protein oxidation presents an important stability problem. We are interested to generate a database which relates oxidation sensitivity to specific structural elements of proteins. With such a database at hand, we can potentially predict the stability of new protein products, facilitating pharmaceutical development. To achieve such a database, we are studying oxidative protein stability for proteins in (a) solution, (b) in polymeric matrices, and (c) in the solid state.

T. Nauser and C. Schöneich, "Thiyl Radicals Abstract Hydrogen Atoms from the (alpha)C-H Bonds in Model Peptides: Absolute Rate Constants and Effect of Amino Acid Structure," J. Am. Chem. Soc., 125: 2042–2043 (2003).

V. S. Sharov, N. A. Galeva, T. V. Knyushko, D. J. Bigelow, T. D. Williams and C. Schöneich, "Two-dimensional separation of the membrane protein sarcoplasmic reticulum Ca-ATPase for high-performance liquid chromatography-tandem mass spectrometry analysis of posttranslational protein modifications," Anal. Biochem., 308: 328–335 (2002).

C. Schöneich, "Redox processes of methionine relevant to beta-amyloid oxidation and Alzheimer's disease," Arch. Biochem. Biophys., 397: 370–376 (2002).

C. Schöneich and T. D. Williams, "Cu(II)-catalyzed oxidation of beta-amyloid peptide targets His13 and His14 over His6: Detection of 2-Oxo-histidine by HPLC-MS/MS," Chem. Res. Toxicol., 15: 717–722 (2002).

D. Pogocki and C. Schöneich, "Computational characterization of sulfur-cxygen-bonded sulfuranyl radicals derived from alkyl- and (carboxyalkyl)thiopropionic acids: evidence for sigma-type radicals," J. Org. Chem., 67: 1526–1535 (2002).

D. Pogocki and C. Schoneich, "Redox properties of Met(35) in neurotoxic beta-amyloid peptide. A molecular modeling study," Chem. Res. Toxicol., 15: 408–418 (2002).

J. Kanski, M. Aksenova, C. Schöneich and D. A. Butterfield, "Substitution of isoleucine-31 by helical-breaking proline abolishes oxidative stress and neurotoxic properties of Alzheimer's amyloid beta- peptide," Free Radic. Biol. Med., 32: 1205–1211 (2002).

S. W. Hovorka, T. D. Williams and C. Schöneich, "Characterization of the metal-binding site of bovine growth hormone through site-specific metal-catalyzed oxidation and high-performance liquid chromatography-tandem mass spectrometry," Anal. Biochem., 300: 206–211 (2002).

S. W. Hovorka, H. Biesiada, T. D. Williams, A. Huhmer and C. Schöneich, "High sensitivity of Zn2+ insulin to metal-catalyzed oxidation: detection of 2-oxo-histidine by tandem mass spectrometry," Pharm. Res., 19: 530–537 (2002).

S. W. Hovorka, M. J. Hageman and C. Schöneich, "Oxidative degradation of a sulfonamide-containing 5,6-dihydro-4-hydroxy- 2-pyrone in aqueous/organic cosolvent mixtures," Pharm. Res., 19: 538–545 (2002).

T. Adachi, R. Matsui, S. Xu, M. Kirber, H. L. Lazar, V. S. Sharov, C. Schöneich and R. A. Cohen, ":Antioxidant improves smooth muscle sarco/endoplasmic reticulum Ca2+-ATPase function and lowers tyrosine nitration in hypercholesterolemia and improves nitric oxide-induced relaxation," Circ. Res., 90: 1114–1121 (2002).