Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases

Tarun Arya, Ravikumar Reddi, Chandan Kishor, Roopa Jones Ganji, Supriya Bhukya, Rajesh Gumpena, Sheena McGowan, Marcin Drag, Anthony Addlagatta

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12 Citations (Scopus)

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 alpha-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.
Original languageEnglish
Pages (from-to)2350 - 2357
Number of pages8
JournalJournal of Medicinal Chemistry
Volume58
Issue number5
DOIs
Publication statusPublished - 2015

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