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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

Arya, Tarun ; Reddi, Ravikumar ; Kishor, Chandan ; Ganji, Roopa Jones ; Bhukya, Supriya ; Gumpena, Rajesh ; McGowan, Sheena ; Drag, Marcin ; Addlagatta, Anthony. / Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 5. pp. 2350 - 2357.
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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 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.",
author = "Tarun Arya and Ravikumar Reddi and Chandan Kishor and Ganji, {Roopa Jones} and Supriya Bhukya and Rajesh Gumpena and Sheena McGowan and Marcin Drag and Anthony Addlagatta",
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Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases. / Arya, Tarun; Reddi, Ravikumar; Kishor, Chandan; Ganji, Roopa Jones; Bhukya, Supriya; Gumpena, Rajesh; McGowan, Sheena; Drag, Marcin; Addlagatta, Anthony.

In: Journal of Medicinal Chemistry, Vol. 58, No. 5, 2015, p. 2350 - 2357.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases

AU - Arya, Tarun

AU - Reddi, Ravikumar

AU - Kishor, Chandan

AU - Ganji, Roopa Jones

AU - Bhukya, Supriya

AU - Gumpena, Rajesh

AU - McGowan, Sheena

AU - Drag, Marcin

AU - Addlagatta, Anthony

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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