2 research outputs found
Identification of the Molecular Basis of Inhibitor Selectivity between the Human and Streptococcal Type I Methionine Aminopeptidases
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
Identification, Biochemical and Structural Evaluation of Species-Specific Inhibitors against Type I Methionine Aminopeptidases
Methionine
aminopeptidases (MetAPs) are essential enzymes that
make them good drug targets in cancer and microbial infections. MetAPs
remove the initiator methionine from newly synthesized peptides in
every living cell. MetAPs are broadly divided into type I and type
II classes. Both prokaryotes and eukaryotes contain type I MetAPs,
while eukaryotes have additional type II MetAP enzyme. Although several
inhibitors have been reported against type I enzymes, subclass specificity
is scarce. Here, using the fine differences in the entrance of the
active sites of MetAPs from Mycobacterium tuberculosis, Enterococcus faecalis, and human,
three hotspots have been identified and pyridinylpyrimidine-based
molecules were selected from a commercial source to target these hotspots.
In the biochemical evaluation, many of the 38 compounds displayed
differential behavior against these three enzymes. Crystal structures
of four selected inhibitors in complex with human MetAP1b and molecular
modeling studies provided the basis for the binding specificity