Research >> Anti-cancer,
Bacterial
smitra@bu.edu
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Sangha Mitra, Ph.D. Senior Research Associate, Dept of Molecular and Cell biology 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 an
emerging therapy for the 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. 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 to elucidate their role in
catalysis. I also identified a distant Histidine 63 amino acid residue
pariticipating in providing substrate specificity to MetAP. I also
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, Feb 6 (In press, Read abstract here) 2.
Mitra, S.,
Dygas-Holz, A. M., Jiracek J., Zertova M., Zakova, L. and Holz, R.C. “A New
Colorimetric Assay for Methionyl Aminopeptidases: Examination of the Binding
of a New Class of Pseudopeptide Analog Inhibitors.”Analytical Biochemistry, 2006 Oct 1; 357(1):43-9. [Read abstract here] 3.
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] 4.
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] 5.
Watterson,
S. J., Mitra, S., Swierczek, 6. Frottin, F.1, |
