Journal
BIOCHIMIE
Volume 94, Issue 3, Pages 704-710Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2011.10.014
Keywords
Aminopeptidase; Substrate library; Protease; Enzyme; Inhibitor; Substrate specificity
Categories
Funding
- Foundation for Polish Science
- State for Scientific Research Grant in Poland [N N401 042838]
- Chemical Genetics Consortium of the Ministry of Education, Youth and Sports of the Czech Republic [LC060777]
- Academy of Sciences of the Czech Republic [Z4 055 0506]
- Deutsche Krebshilfe
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Methionyl aminopeptidases (MetAPs) are metallo-dependent proteases responsible for removing of N-terminal methionine residue of peptides and proteins during protein maturation and activation. In this report we use a comprehensive strategy to screen the substrate specificity of three methionyl aminopeptidases: Homo sapiens MetAP-1, Homo sapiens MetAP-2 and Escherichia coli MetAP-1. By utilizing a 65-membered fluorogenic substrate library consisting of natural and unnatural amino acids we established detailed substrate preferences of each enzyme in the Si pocket. Our results show that this pocket is highly conserved for all investigated MetAPs, very stringent for methionine, and that several unnatural amino acids with methionine-like characteristics were also well hydrolyzed by MetAPs. The substrate-derived results were verified using several phosphonate and phosphinate-based inhibitors. (C) 2011 Elsevier Masson SAS. All rights reserved.
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