TAYEBEH POURMOTABBED
ASSISTANT PROFESSOR

EDUCATION:
B.A., 1981, Chemistry, College of Notre Dame of Maryland
Ph.D., 1986, Biochemistry, University of Maryland, Baltimore County
Postdoctoral, 1986-88, Biochemistry/Molecular Biology, University of Maryland, College Park

RESEARCH INTERESTS: The primary focus in our laboratory is to elucidate the molecular organization of matrix metalloproteinases and to unravel their mechanism of actions in tumor cell invasion. This family of enzymes plays a central role in both normal connective tissue remodeling and the accelerated matrix breakdown associated with rheumatoid arthritis and tumor cell invasion. Using deletion mutagenesis and domain swapping techniques, we have identified several individual domains that are critical for enzymatic activity and substrate specificity of two of the members of the MMP family, MMP-1 and MMP-9. Consequently, one major focus of interest is to identify specific amino acid residues that are involved in substrate recognition and/or catalytic activity of these enzymes. In addition to the biosynthetic regulation of MMPs by transcriptional and post-transcriptional mechanisms, it is thought that the activation of the latent enzymes is an important regulatory step. We have demonstrated that Ca+2 plays a significant role in activation of pro-MMP-9 and a Ca+2-dependent mechanism of activation has been proposed for the enzyme. The role of Ca+2 in regulation of MMPs is further being investigated in our laboratory.
The secondary objective in the laboratory is to inhibit the invasion by competition gene therapy. To achieve this goal, we are investigating the role of these enzymes in the transformation of tumorogenic to metastatic phenotype in a series of tumor cells by transfecting the cells with the metalloproteinases cDNA. The effect of metalloproteinases mutants in preventing metastasis in vitro and in vivo is being determined. Overall, these studies are aimed at advancing our knowledge of the mechanism underlying connective tissue destruction in tumor cell invasion in order to be able to control and prevent the spread of cancer.

CURRENT RESEARCH SUPPORT:
American Cancer Society "Role of Matrix Metalloproteinases in Tumor Cell Invasion" January 1, 1995 - December 31, 1997; $239,180 TDC
NIH First Award "Type V Collagenase in Rheumatoid Arthritis" February 1, 1993 - January 31, 1997; $279,987 TDC

GRADUATE STUDENTS:
University of Maryland: Mark Dell'Acqua, Ph.D., 1988
University of Tennessee, Memphis: Chun Hui Bu (current student); Thomas O'Farrell (current student)

RESEARCH PUBLICATIONS:
Pourmotabbed, T. and Creighton, D.J. (1986) Substrate specificity of bovine liver formaldehyde dehydrogenase. J. Biol. Chem., 26, 14240-14244.
Creighton D.J. and Pourmotabbed, T. (1988) Glutathione-dependent aldehyde oxidation reaction. In J.F. Liebman and A. Greenberg (Eds.), Molecular Structure and Energetics: Principles of Enzyme Activity. Vol. 9. VCH Publishers.
Creighton, D.J., Migliorini, M., Pourmotabbed, T. and Guha, M. (1988) Optimization of efficiency in the glyoxalase pathway. Biochemistry, 27, 7376-7384.
Wilde, J.A., Bolton, P.H., Dell'Acqua, M., Hibler, D.W., Pourmotabbed, T., and Gerlt, J.A. (1988) Identification of residues involved in a conformational change accompanying substitutions for glutamate 43 in Staphylococcal nuclease. Biochemistry, 27, 4127-4132.
Stanczyk, S.M., Bolton, P.H., Dell'Acqua, M., Pourmotabbed, T., and Gerlt, J.A. (1988) Direct observation of multiple environment for the Hd but not the He proton of a histidine residue in Staphylococcal nuclease. J. Am. Chem. Soc. (JACS), 110, 313-316.
Hibler, D.W., Pourmotabbed, T., Harpold, L., Dell'Acqua, M., Gerlt, J.A., Wilde, J.A., and Bolton, P.H. (1989) The use of isotopic labeling with 2H and 13C to compare the conformations of proteins and mutants generated by site-directed mutagenesis I. Methods Enzymol., 177, 74-86.
Wilde, J.A., Bolton, P.H., Hibler, D.W., Pourmotabbed, T., Harpold, L., Dell'Acqua, M., and Gerlt, J.A. (1989) The use of isotopic labeling with 2H and 13C to compare the conformations of proteins and mutants generated by site-directed mutagenesis II. Methods Enzymol., 177, 282-292.
Pourmotabbed, T., Mei, J.S., and Creighton, D.J. (1989) Bovine liver formaldehyde dehydrogenase kinetic and molecular properties. J. Biol. Chem., 264, 17384-17388.
Pourmotabbed, T., Gerlt, J.A., Stanczyk, S.M., and Bolton, P.H. (1990) Kinetic and conformational effects of lysine substitutions for arginines 35 and 87 in the active site of Staphylococcal nuclease. Biochemistry, 29, 3677-3683.
Hasty, K.A., Pourmotabbed, T., Goldberg, G.I., Thompson, J.P., Nelson, R.L., and Mainardi, C.L. (1990) Human neutrophil collagenase: A distinct gene product with homology to other matrix metalloproteinases. J. Biol. Chem., 265, 11421-11424.
Mainardi, C.L., Hasty, K.A., and Pourmotabbed, T. (1991) The neutrophil in connective tissue destruction. Am. J. Med. Sci., 302, 171-176.
Hirose, T., Pourmotabbed, T., Patterson, C.E., Mainardi, C.L., and Hasty, K.A. (1993) Structure-function relationship of human neutrophil collagenase: Identification of region responsible for substrate specificity. Proc. Natl. Acad. Sci., 90, 2569-2573.
Pourmotabbed, T., Solomon, T.L., Hasty, K.A., and Mainardi, C.L. (1994) Characteristics of 92 kDa type IV collagenase/gelatinase produced by granulocytic leukemia cells: Structure, expression of cDNA in E.coli and enzymic properties. Biochem. Biophys. Acta, 1204, 79-107.
Pourmotabbed, T. (1994) The relationship between substrate specificity and domain structure of 92 kDa type IV collagenase. Ann. NY Acad. Sci., 732, 372-374.
Bu, C.H. and Pourmotabbed, T. (1995) Mechanism of activation of gelatinase B: Discriminating between the role of Ca2+ in activation and catalysis. J. Biol. Chem., 270, 18563-18569.
Pourmotabbed, T., Aelion, J.A., Tyrrell, D., Hasty, K.A., Bu, C.H., and Mainardi, C.L. (1995) Role of the conserved histidine and aspartic acid residues in activity and stabilization of human gelatinase B: An example of matrix metalloproteinases. J. Prot. Chem., 14, 735.
Pourmotabbed, T., Kaur, T., Whittemore, M.S., Peterson, R.L., Lichte, A., and Tschesche, H. Gelatinase B only requires 12% of the protein sequence for proteolytic activity and TIMP-1 binding. J. Biol. Chem., in press.