College of Pharmacy

Pharmaceutical Sciences

Margaret Black picture

 

Margaret E. Black, Ph.D.
Associate Professor
J. Roberts and Marcia Fosberg Distinguished Professor
Director, Pharmacology and Toxicology Graduate Program
Department of Pharmaceutical Sciences
P.O. Box 646534
Washington State University
Pullman, WA 99164-6534
(509) 335-6265 (phone)
(509) 335-5902 (fax)
blackm@mail.wsu.edu


 

Other Affiliations:
School of Molecular Biosciences
Center for Integrated Biotechnology
NIH Protein Biotechnology Training Grant
NSF Undergraduates in Biological and Mathematical Sciences Training Grant

Research Interests: Enzymes involved in nucleic acid biosynthesis are a major focus of my lab's research. We are primarily interested in the structure to function relationship of enzymes that catalyze the formation of precursors for DNA and RNA and, most notably, also convert nucleoside analogs or prodrugs to cytotoxic compounds. Using several mutagenesis and molecular strategies we target these enzymes and select for variants with altered activities towards the nontoxic prodrugs. Biochemical evaluation along with in vitro and in vivo analysis of derived mutants that display enhanced prodrug activation allows the identification of mutants for use in gene therapy for the treatment of cancer. In a process known as suicide gene therapy, a nucleoside metabolizing gene is delivered to a cancer cell followed by administration of the nontoxic prodrug. The gene product (enzyme) converts the prodrug to a cytotoxin, thereby leading to death of the cancer cell. Molecular modeling of the active site of enzymes and their variants has provided further insights on how the enzyme might be altered to improve prodrug activation and therefore enhance tumor ablation for a safer and more effective cancer cure. Key words: suicide gene therapy, molecular evolution, thymidine kinase, nucleotide metabolizing enzymes.

Teaching Expertise: My primary teaching responsibility is Pharmaceutical Biotechnology (PharmSci 534) with additional graduate level teaching to students in the Pharmacology/Toxicology Graduate Program.

Employment Opportunities: I am currently seeking applications for the following position.

Postdoctoral Fellow (Ph.D. in Biochemistry, Microbiology or Molecular Biology) to work on an NIH funded research project involving creation of novel enzymes using random mutagenesis techniques.

Recent Publications (2002-2008):

C. L. Willmon, D. Sussman and M. E. Black. (2008) The Role of Herpes Simplex Virus-1 Thymidine Kinase Alanine 168 in Substrate Specificity. Open Biochem. J., 2:54-60.

T. S. Stolworthy*, A. Korkegian*, C. L. Willmon, A. Ardiani, J. Cundiff, B. L. Stoddard and M. E. Black. (2008) Yeast Cytosine Deaminase Mutants with Increased Thermostability Impart Sensitivity to 5-Fluorocytosine. J. Mol. Biol., 377:854-869.
* -joint first authors.

S. A. Kaliberov, J. M. Markert, V. Krendelchtchikova, D. D. Manna, J. C. Sellers, L. N. Kaliberova, M. E. Black and D. J. Buchsbaum. (2007) Gene Directed/Enzyme Prodrug Therapy of Human Glioma Using Mutant Escherichia coli Cytosine Deaminase. Gene Therapy, 14:1111-1119.

C. L. Willmon, E. Krabbenhoft and M. E. Black. (2006) A Guanylate Kinase/HSV-1 Thymidine Kinase Fusion Protein Enhances Prodrug Mediated Cell Killing. Gene Therapy, 13:1309-1312.

A. Korkegian, M. E. Black, D. Baker and B. L. Stoddard. (2005) Computational Thermostabilization of an Enzyme. Science, 308:857-860.

S. D. Mahan, G. C. Ireton, C. Knoeber, B. L. Stoddard and M. E. Black. (2004) Random Mutagenesis and Selection of E. coli Cytosine Deaminase for Cancer Gene Therapy. Protein Engineering, Design and Selection, 17:625-633.

S. D. Mahan, G. C. Ireton, B. L. Stoddard and M. E. Black. (2004) Alanine Scanning Mutagenesis Reveals a Cytosine Deaminase Mutant with Altered Substrate Preference. Biochemistry, 43:8957-8964.

J.-E. Kurtz and M. E. Black. (2003) Enhancement of Suicide Gene Prodrug Activation by Random Mutagenesis. Suicide Gene Therapy: Methods and Reviews. C. J. Springer, Ed. Methods in Molecular Medicine Series, Humana Press, New Jersey, 90:331-344.

T. S. Stolwothy, E. Krabbenhoft and M. E. Black. (2003) A Novel Escherichia coli Strain Allows Functional Analysis of Guanylate Kinase Drug Resistance and Sensitivity. Analytical Biochem., 322:40-47.

G. C. Ireton, M. E. Black and B. L. Stoddard. (2003) The 1.14Å Resolution of Yeast Cytosine Deaminase: Parallel Divergent Evolution of Nucleotide Salvage Enzymes and Implications for Anticancer Gene Therapy. Structure, 11:961-972.

R. Wiewrodt, K. Amin, M. Kiefer, V. P. Jovanovic, V. Kapoor, S. Force, M. Chang, M. Lanuti, M. E. Black, L. R. Kaiser and S. M. Albelda. (2003) Adenovirus-Mediated Gene Transfer of Enhance Herpes Simplex Virus Thymidine Kinase Mutants Improves Prodrug-Mediated Tumor Cell Killing. Cancer Gene Therapy, 10:353-364.

H. Kubo, T. A. Gardner, Y. Wada, K. S. Koeneman, A. Gotoh, L. Yang, C. Kao, S. D. Lim, M. B. Amin, H. Yang, M. E. Black, S. Matsubara, M. Nakagawa, J. Y. Gillenwater, H. E. Zhau and L. W. K. Chung. (2003) Phase I Dose Escalation Clinical Trial of Adenovirus Vector Carrying Osteocalcin Promoter-Driven Herpes Simplex Virus Thymidine Kinase in Localized and Metastatic Hormone-Refractory Prostate Cancer. Human Gene Therapy, 14:227-241.

M. S. Kokoris and M. E. Black. (2002) Characterization of Herpes Simplex Virus Type 1 Thymidine Kinase Mutants Engineered for Improved Ganciclovir or Acyclovir Activity. Protein Science, 11:2267-2272.

W. Qasim, A. J. Thrasher, J. Buddle, C. Kinnon, M. E. Black and H. B. Gaspar. (2002) T-Cell Transduction and Suicide With an Enhanced Mutant Thymidine Kinase. Gene Therapy, 9(12):824-827.

A. J. Pantuck, J. Matherly, A. Zisman, D. Nyugen, F. Berger, S. S. Gambhir, M. E. Black, A. Belldegrun and L. Wu. (2002) Optimizing Prostate Cancer Suicide Gene Therapy Using Herpes Simplex Virus Thymidine Kinase Active Site Variants. Human Gene Therapy, 13(7):777-790.

G. C. Ireton, G. McDermitt, M. E. Black and B. L. Stoddard. (2002) The Structure of Escherichia coli Cytosine Deaminase. J. Mol. Biol., 315:687-697.

 

 

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