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Abstract
Understanding the reaction mechanism of co-catalytic metallopeptidases provides a
starting point for the design and synthesis of new molecules that can be screened
as potential pharmaceuticals. Many of the enzymes that contain co-catalytic metallo-active
sites play important roles in cellular processes such as tissue repair, protein maturation,
hormone level regulation, cell-cycle control and protein degradation. Therefore, these
enzymes play central roles in several disease states including cancer, HIV, stroke,
diabetes, bacterial infections, neurological processes, schizophrenia, seizure disorders,
and amyotrophic lateral sclerosis. The mechanism of AAP, an aminopeptidase from Aeromonas
proteolytica, is one of the best-characterized examples of a metallopeptidase containing
a co-catalytic metallo-active site, although this enzyme is not a specific pharmaceutical
target at this time. As a large majority of co-catalytic metallopeptidases contain
active sites that are nearly identical to the one observed in AAP, the major steps
of their catalytic mechanisms are likely to be very similar. With this in mind, it
is possible to propose a general catalytic mechanism for the hydrolysis of amino acid
substrates.