The mammalian neuraminidase enzyme, Neu3, is known to act on plasma membrane glycolipid substrates. The enzyme appears to play a role in cancer progression, likely through glycolipid remodeling of the membrane. Specific inhibitors of the enzyme could be valuable tools for evaluating the enzyme's biological function. However, few potent, specific inhibitors of Neu3 are currently known. We propose that improved models of the Neu3 active site will be a useful tool for designing inhibitors. Towards this end, we have generated a series of site-directed mutants based on a revised homology model of Neu3, and tested the resulting mutants for activity. Several arginine-to-alanine point mutations have confirmed the expected catalytic residues of the active site. Also, the pH optimum, kinetics and inhibition of active enzymes by transition-state mimics will be reported. Together, these data will be used to refine our model and guide inhibitor design.

Insights into the structure and specificity of the mammalian neuraminidase 3 (Neu3) through site directed mutagenesis and kinetic studies

239th National Meeting (2010)

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