Konrad, Manfred, Dr.
Group Leader at the MPI for Biophysical Chemistry
- 1981: Dr. rer. nat., University of Heidelberg, Germany
- 1982: Postdoctoral Fellow at the University of Bristol, U.K.
- 1983: Head of Laboratory, Goedecke Pharmaceutical Company, Freiburg, Germany
- 1984-1986: Research Assistant, Institute for Pharmacology, U. of Marburg, Germany
- 1987-2004: Staff Scientist, MPI for Biophysical Chemistry, Göttingen
- since 2005: Research Group Leader, MPI for Biophysical Chemistry, Göttingen
Major Research Interests
Our research group studies several classes of enzymes which play critical roles in the therapy of various diseases:
Several enzymes of the family of nucleoside and nucleotide kinases play key roles not only in intracellular phosphorylation of the constituents of all nucleic acids, but also of structurally related nucleoside analog prodrugs used in chemotherapy. Upon ATP-dependent three-step phosphorylation, such prodrugs are converted from a physiologically inactive compound to an active one. If incorporated into newly synthesized DNA strands via polymerases, these analogs induce chain termination, or cause instability of DNA, thus blocking proliferation of tumor cells and viruses. Analyzing the specific interaction of these enzymes with prodrugs, structurally and kinetically, allows us to understand at the molecular level the reasons behind poor metabolic activation of certain therapeutic agents. We aim to design catalytically improved enzyme variants that can be delivered to target cells using antibodies and nanoparticles as vehicles.
Choline kinases are key enzymes in the synthesis of phospholipids that are essential constituents of cell membranes of all eukaryotic cells and are involved in the regulation of cell proliferation, oncogenic transformation, and carcinogenesis. Increase in choline kinase activity and elevated levels of its reaction product phosphocholine have been observed in different tumor-derived cell lines, and in several human cancers, notably in those transformed by the ras oncogene. Our goal is to develop novel inhibitors that selectively interfere with this enzyme and could thus function as anti-cancer drugs.
Our research interest in the enzyme asparaginase, which catalyzes the conversion of the natural amino acid L-asparagine to L-aspartic acid and ammonia, derives from the observation that alterations to cellular metabolism constitute a nearly universal property of various types of cancer. In particular, deficiencies in the biosynthesis of certain amino acids make cancer cells rely upon the extracellular pool of these protein building blocks. We pursue the molecular analysis and engineering of the human enzyme to generate catalytically improved variants and replace bacterial enzymes that have been used over decades as efficient agents in blood cancers, despite showing severe immunogenic and toxic side effects.
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Selected Recent Publications