title: Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases.
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 15) that selectively inhibits the S. pneumonia 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 S. pneumonia 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.
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology , Hyderabad 500 007, India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Arya
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Reddi
authors.forename: Chandan
authors.initials: C
authors.lastname: Kishor
authors.forename: Roopa Jones
authors.initials: RJ
authors.lastname: Ganji
authors.forename: Supriya
authors.initials: S
authors.lastname: Bhukya
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gumpena
authors.forename: Sheena
authors.initials: S
authors.lastname: McGowan
authors.forename: Marcin
authors.initials: M
authors.lastname: Drag
authors.forename: Anthony
authors.initials: A
authors.lastname: Addlagatta
mesh_terms: D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008715:Methionine / Q000737:chemistry*; D063208:Methionyl Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010649:Phenylalanine / Q000737:chemistry*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013291:Streptococcus / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D010649:Phenylalanine; D008715:Methionine; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases