Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-65045
Petrera, Agnese; Amstutz, Beat; Gioia, Magda; Hähnlein, Janine; Baici, Antonio; Selchow, Petra; Ferraris, Davide M; Rizzi, Menico; Sbardella, Diego; Marini, Stefano; Coletta, Massimo; Sander, Peter (2012). Functional characterization of the Mycobacterium tuberculosis zinc metallopeptidase Zmp1 and identification of potential substrates. Biological Chemistry, 393(7):631-640.
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Zinc metallopeptidases of bacterial pathogens are widely distributed virulence factors and represent promising pharmacological targets. In this work, we have characterized Zmp1, a zinc metallopeptidase identified as a virulence factor of Mycobacterium tuberculosis and belonging to the neprilysin (NEP; M13) family, whose X-ray structure has been recently solved. Interestingly, this enzyme shows an optimum activity toward a fluorogenic substrate at moderately acidic pH values (i.e., 6.3), which corresponds to those reported for the Mtb phagosome where this enzyme should exert its pathological activity. Substrate specificity of Zmp1 was investigated by screening a peptide library. Several sequences derived from biologically relevant proteins were identified as possible substrates, including the neuropeptides bradykinin, neurotensin, and neuropeptide FF. Further, subsequences of other small bioactive peptides were found among most frequently cleaved sites, e.g., apelin-13 and substance P. We determined the specific cleavage site within neuropeptides by mass spectrometry, observing that hydrophobic amino acids, mainly phenylalanine and isoleucine, are overrepresented at position P1'. In addition, the enzymatic mechanism of Zmp1 toward these neuropeptides has been characterized, displaying some differences with respect to the synthetic fluorogenic substrate and indicating that the enzyme adapts its enzymatic action to different substrates.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Biochemistry|
07 Faculty of Science > Institute of Biochemistry
04 Faculty of Medicine > Institute of Medical Microbiology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||09 Oct 2012 17:36|
|Last Modified:||04 Feb 2013 00:12|
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