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Sangha Mitra Biotechnology Professional and Consultant MBA candidate, December 2012 Health Sector Management Boston University School of Management Methionine aminopeptidases (MetAPs) are ubiquitous enzymes responsible for the cleavage of N-terminal methionine residues from polypeptide chains. Methionine is the universal initiator of protein synthesis, and the removal of methionine is critical in protein maturation processes. A MetAP from eukaryote has been identified as the molecular target for the antiangiogenesis drugs ovalicin and fumagillin, among others. Inhibition of MetAP activity in tumors is a therapy for prevention of tumor vascularization, which often leads to tumor regression due to oxygen and nutrient deprivation. Used in conjunction with standard cancer therapies, including surgery, radiation, and/ or chemotherapy, antiangiogenic drugs are used to shrink localized tumors and protect against metastasis. Bacteria express only type-I MetAPs while archaea contain only the type-II enzyme. Eukaryotic cells, in contrast, have both enzymes. It has been shown that yeast is viable if the gene encoding for the type-I MetAP is deleted but the type-II gene is present. Since bacteria contain only type-I MetAPs, compounds with selective inhibition for type-I MetAPs can function as potential anti-bacterial drugs. The catalytic roles of both the active site metal ions as well as active site residues have been proposed. However, the proposed catalytic mechanism for MetAP assigned no definitive role to the conserved histidine 79 and aspartate 97, two active site amino acid residues that I investigated and elucidated their role in catalysis. I also identified a distant Histidine 63 amino acid residue participating in providing substrate specificity to MetAP. In addition, I investigated the interaction of potential inhibitor with MetAP and found that some inhibitors interact differently with the two types of MetAP. Related Publications: 1. Mitra, S., Sheppard, G., Wang J., Bennett, B. and Holz, R. C. “Analyzing the binding of Co(II)-specific inhibitors to the methionyl aminopeptidases from Escherichia coli and Pyrococcus furiosus.” Journal of Biological Inorganic Chemistry, 2009, May; 14(4):573-85. [Read abstract here] 2. Mitra, S., Job, K. M., Meng, L., Bennett, B. and Holz, R.C. “Analyzing the catalytic role of Asp97 in the methionine aminopeptidase from Escherichia coli.” FEBS J., 2008 Dec; 275(24):6248-59. [Read abstract here] 3. Mitra, S., Bennett, B. and Holz, R. C. “Mutation of H63 and its catalytic affect on the methionine aminopeptidase from Escherichia coli.” Biochim Biophys Acta, 2009 Jan;1794(1):137-43. [Read abstract here] 4. Watterson, S. J., Mitra, S., Swierczek, S. I., Bennett, B. and Holz, R. C. “Kinetic and spectroscopic analysis of the catalytic role of H79 in the methionine aminopeptidase from Escherichia coli.” Biochemistry, 2008 Nov 11; 47(45):11885-93. [Read abstract here] Back to R&D