Metal mediated inhibition of methionine aminopeptidase by quinolinyl sulfonamides

Min Huang, Sheng Xue Xie, Ze Qiang Ma, Robert P. Hanzlik, Qizhuang Ye

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Quinolinyl sulfonamides, such as N-(quinolin-8-yl)methanesulfonamide (10) and N-(5-chloroquinolin-8-yl)methanesulfonamide (11), were identified as potent methionine aminopeptidase (MetAP) inhibitors by high throughput screening of a diverse chemical library of small organic compounds. They showed different inhibitory potencies on Co(II)-, Ni(II)-, Fe(II)-, Mn(II)-, and Zn(II)-forms of Escherichia coli MetAP, and their inhibition is dependent on metal concentration. X-ray structures of E. coli MetAP complexed with 10 revealed that the inhibitor forms a metal complex with the residue H79 at the enzyme active site; the complex is further stabilized by an extended H-bond and metal interaction network. Analysis of the inhibition of MetAP by these inhibitors indicates that this is a typical mechanism of inhibition for many non-peptidic MetAP inhibitors and emphasizes the importance of defining in vitro conditions for identifying and evaluating MetAP inhibitors that will be capable of giving information relevant to the in vivo situation.

Original languageEnglish (US)
Pages (from-to)506-513
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume339
Issue number2
DOIs
StatePublished - Jan 13 2006
Externally publishedYes

Fingerprint

Aminopeptidases
Sulfonamides
Methionine
Metals
Escherichia coli
Small Molecule Libraries
Coordination Complexes
Organic compounds
Catalytic Domain
Screening
Throughput
X-Rays
X rays
Enzymes

Keywords

  • Enzyme inhibition
  • Metalloenzyme
  • Protein structure

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Metal mediated inhibition of methionine aminopeptidase by quinolinyl sulfonamides. / Huang, Min; Xie, Sheng Xue; Ma, Ze Qiang; Hanzlik, Robert P.; Ye, Qizhuang.

In: Biochemical and Biophysical Research Communications, Vol. 339, No. 2, 13.01.2006, p. 506-513.

Research output: Contribution to journalArticle

Huang, Min ; Xie, Sheng Xue ; Ma, Ze Qiang ; Hanzlik, Robert P. ; Ye, Qizhuang. / Metal mediated inhibition of methionine aminopeptidase by quinolinyl sulfonamides. In: Biochemical and Biophysical Research Communications. 2006 ; Vol. 339, No. 2. pp. 506-513.
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