Metalloform-selective inhibitors of escherichia coli methionine aminopeptidase and X-ray structure of a Mn(II)-form enzyme complexed with an inhibitor.
Methionine aminopeptidase (MetAP) enzymes require a divalent metal ion such as Mn(II), Fe(II), Co(II), Ni(II), or Zn(II) for its removal of the N-terminal methionine from newly synthesized proteins, but it is not certain which of these ions is most important in vivo. Metalloform-selective MetAP inhibitors could be valuable for defining which metals are physiologically relevant for MetAP activation and could serve as leads for development of new therapeutic agents. We have screened a library of 43 736 small drug-like molecules against Escherichia coli MetAP and identified two groups of potent and highly metalloform-selective inhibitors of the Co(II)-form, and of the Mn(II)-form, of this enzyme. Compound 1 is 790-fold more selective for the Co(II)-form, while compound 4 is over 640-fold more potent toward the Mn(II)-form. The X-ray structure of a di-Mn(II) form of E. coli MetAP complexed with the Mn(II)-form-selective compound 4 was obtained, and it shows that the inhibitor interacts with both Mn(II) ions through the two oxygen atoms of its free carboxylate group. The preferential coordination of the hard (oxygen) donors to Mn(II) may contribute to its superb selectivity toward the Mn(II)-form.
Ye
Qi-Zhuang
QZ
High Throughput Screening Laboratory and Protein Structure Laboratory, University of Kansas, Lawrence, Kansas 66045, USA. qye@ku.edu
Xie
Sheng-Xue
SX
Huang
Min
M
Huang
Wei-Jun
WJ
Lu
Jing-Ping
JP
Ma
Ze-Qiang
ZQ
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D003035:Cobalt / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors; D008345:Manganese / Q000737:chemistry* / Q000494:pharmacology; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D029968:Escherichia coli Proteins; D009942:Organometallic Compounds; D011480:Protease Inhibitors; D003035:Cobalt; D008345:Manganese; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases