Analyzing the binding of Co(II)-specific inhibitors to the methionyl aminopeptidases from Escherichia coli and Pyrococcus furiosus.
Methionine aminopeptidases (MetAPs) represent a unique class of protease that is capable of the hydrolytic removal of an N-terminal methionine residue from nascent polypeptide chains. MetAPs are physiologically important enzymes; hence, there is considerable interest in developing inhibitors that can be used as antiangiogenic and antimicrobial agents. A detailed kinetic and spectroscopic study has been performed to probe the binding of a triazole-based inhibitor and a bestatin-based inhibitor to both Mn(II)- and Co(II)-loaded type-I (Escherichia coli) and type-II (Pyrococcus furiosus) MetAPs. Both inhibitors were found to be moderate competitive inhibitors. The triazole-type inhibitor was found to interact with both active-site metal ions, while the bestatin-type inhibitor was capable of switching its mode of binding depending on the metal in the active site and the type of MetAP enzyme.
Mitra
Sanghamitra
S
Department of Chemistry, Loyola University-Chicago, Chicago, IL 60626, USA.
Sheppard
George
G
Wang
Jieyi
J
Bennett
Brian
B
Holz
Richard C
RC
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D020134:Catalytic Domain; D003035:Cobalt / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D008345:Manganese / Q000737:chemistry* / Q000378:metabolism; D063208:Methionyl Aminopeptidases; D015394:Molecular Structure; D011485:Protein Binding; D020027:Pyrococcus furiosus / Q000201:enzymology*; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D014230:Triazoles; D003035:Cobalt; D008345:Manganese; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases; D007930:Leucine; C012211:ubenimex