TY - JOUR
T1 - Synthesis and inhibition properties of a series of pyranose derivatives towards a Zn-metalloproteinase from Saccharomonospora canescens
AU - Dolashka-Angelova, Pavlina
AU - Abdel-Jalil, Raid J.
AU - Al-Qawasmeh, Raed A.
AU - Stambolieva, Nicolina
AU - Voelter, Wolfgang
N1 - Funding Information:
Dr. Pavlina Dolashka thanks DFG (Deutsche Forschungsgemeinschaft) for granting a scholarship and Professor I. Pojarlieff for discussion of the results.
PY - 2010/11/2
Y1 - 2010/11/2
N2 - The Zn-proteinase, isolated from Saccharomonospora canescens (NPS), shares many common features with thermolysin, but considerable differences are also evident, as far as the substrate recognition site is concerned. In substrates of general structure AcylAlaAlaPhe 4NA, this neutral proteinase cleaves only the arylamide bond (non-typical activity of Zn-proteinases), while thermolysin attacks the peptide bond Ala-Phe. Phosphoramidon is a powerful tight binding inhibitor for thermolysin and significantly less specific towards NPS. The Ki-values (65 μM for NPS vs 0.034 μM for thermolysin) differ nearly 2000-folds. This implies significant differences in the specificity of the corresponding subsites. The carbohydrate moiety is supposed to accommodate in the S1-subsite and the series of arabinopyranosides and glucopyranosides (12 compounds), which are assayed as inhibitors in a model system: NPS with SucAlaAlaPhe4NA as a substrate could be considered as mapping the S1-subsite of NPS. Members of the series with an additional ring (3,4-epithio, 3,4-anhydro-derivatives) turned out to be reasonably good competitive inhibitors (Ki ≈ 0.1-0.2 mM are of the same order as the Ki value for phosphoramidon). The structure of these compounds (8, 9, 11 and 12) seems to fit the size of the S1-subsite and due to an appropriately oriented OH-group in addition, to protect the active site Zn2+.
AB - The Zn-proteinase, isolated from Saccharomonospora canescens (NPS), shares many common features with thermolysin, but considerable differences are also evident, as far as the substrate recognition site is concerned. In substrates of general structure AcylAlaAlaPhe 4NA, this neutral proteinase cleaves only the arylamide bond (non-typical activity of Zn-proteinases), while thermolysin attacks the peptide bond Ala-Phe. Phosphoramidon is a powerful tight binding inhibitor for thermolysin and significantly less specific towards NPS. The Ki-values (65 μM for NPS vs 0.034 μM for thermolysin) differ nearly 2000-folds. This implies significant differences in the specificity of the corresponding subsites. The carbohydrate moiety is supposed to accommodate in the S1-subsite and the series of arabinopyranosides and glucopyranosides (12 compounds), which are assayed as inhibitors in a model system: NPS with SucAlaAlaPhe4NA as a substrate could be considered as mapping the S1-subsite of NPS. Members of the series with an additional ring (3,4-epithio, 3,4-anhydro-derivatives) turned out to be reasonably good competitive inhibitors (Ki ≈ 0.1-0.2 mM are of the same order as the Ki value for phosphoramidon). The structure of these compounds (8, 9, 11 and 12) seems to fit the size of the S1-subsite and due to an appropriately oriented OH-group in addition, to protect the active site Zn2+.
KW - Carbohydrate inhibitors
KW - Neutral Zn-proteinase
KW - S-Subsite
UR - http://www.scopus.com/inward/record.url?scp=77958102048&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77958102048&partnerID=8YFLogxK
U2 - 10.1016/j.carres.2010.07.038
DO - 10.1016/j.carres.2010.07.038
M3 - Article
C2 - 20801431
AN - SCOPUS:77958102048
SN - 0008-6215
VL - 345
SP - 2343
EP - 2347
JO - Carbohydrate Research
JF - Carbohydrate Research
IS - 16
ER -