Identification of the Molecular
Basis of Inhibitor
Selectivity between the Human and Streptococcal Type I Methionine
Aminopeptidases
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Abstract
The methionine aminopeptidase (MetAP)
family is responsible for
the cleavage of the initiator methionine from newly synthesized proteins.
Currently, there are no small molecule inhibitors that show selectivity
toward the bacterial MetAPs compared to the human enzyme. In our current
study, we have screened 20 α-aminophosphonate derivatives and
identified a molecule (compound <b>15</b>) that selectively
inhibits the <i>S. pneumonia</i> MetAP in low micromolar
range but not the human enzyme. Further bioinformatics, biochemical,
and structural analyses suggested that phenylalanine (F309) in the
human enzyme and methionine (M205) in the <i>S. pneumonia</i> MetAP at the analogous position render them with different susceptibilities
against the identified inhibitor. X-ray crystal structures of various
inhibitors in complex with wild type and F309M enzyme further established
the molecular basis for the inhibitor selectivity