George Peter Beardsley MD, PhD

Professor of Pediatrics

Research Interests

Biology of Osteosarcoma; Molecular enzymology of purine biosynthesis indicators for osteosarcoma; Molecular Pharmacology of anticancer and antiviral drugs which alter DNA structure; Biochemical Pharmacology of antifolate drugs; Development of novel antifolates


Research Summary

The Beardsley laboratory is involved in what may be termed molecular pharmacology. We are interested in how drugs work at the most basic level, largely structurally and chemically oriented. We have two major themes: 1. The structure and function of folate-metabolizing enzymes and their role as targets for antifolate drug development. This has involved cloning, sequence determination, and expression of these proteins followed by functional and structural studies using site directed mutagenesis, irreversible active site directed inhibitors, transient phase kinetics, NMR spectroscopy, molecular modeling, and x-ray crystallography. The goal of these investigations is to understand the details of how these enzymes work, and to be able to design and test inhibitors as potential therapeutic agents. 2. Functional consequences of DNA structural lesions. Abnormalities in the structure of DNA have potentially very profound biological consequences. We have been exploring the nature of many DNA structural anomalies, focusing on those which are produced by misincorporation of nucleoside analog anti-cancer or anti-viral agents. The methodology generally involves chemical synthesis of DNA oligomers containing the lesion at specific sites, followed by structural studies done by NMR and x-ray crystallography and biochemical studies of the functional consequences.


Selected Publications

  • Foti, M., Marshalko, S.J., Schurter, E., Kumar, S., Beardsley G.P., and Schweitzer, B.I. (1997). Solution Structure of a DNA Dodecamer Containing the Antiviral Drug Ganciclovir: Combined use of NMR, Restrained Molecular Dynamics, and Full Relaxation Matrix Refinement. Biochemistry.
  • Rayl, E., Moroson, B.A., and Beardsley, G.P. (1996). The human pur H gene product, 5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase / IMP cyclohydrolase. J. Biol. Chem. 271:2225-33.
  • Marshalko SJ, Schweitzer BI, Beardsley GP, Chiral chemical synthesis of DNA containing \(S\)-9-\(1,3-dihydroxy-2-propoxymethyl\)guanine \(DHPG\) and effects on thermal stability, duplex structure, and thermodynamics of duplex formation., Biochemistry, 34(28):9235-48, 18 1995 Abstract
  • Mikita, T. and Beardsley, G.P., Effects of Arabinosylcytosine Substituted DNA on DNA/RNA Hybrid Stability and Transcription by T7 RNA Polymerase. Biochemistry, 1994, 33:9195-92
  • Greasley SE, Horton P, Ramcharan J, Beardsley GP, Benkovic SJ, Wilson IA. Crystal structure of a bifunctional transformylase and cyclohydrolase enzyme in purine biosynthesis. Nature: Struct Biol. 2001 May;8(5):402-6.
  • Bulock KG, Beardsley GP, Anderson KS. The kinetic mechanism of the human bifunctional enzyme ATIC (5-amino-4-imidazolecarboxamide ribonucleotide transformylase/inosine 5'-monophosphate cyclohydrolase). A surprising lack of substrate channeling. J Biol Chem. 2002 Jun 21;277(25):22168-74.

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