Design and synthesis of new substrates of HtrA2 protease |
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| Authors: | Magdalena Wysocka Anna Wojtysiak Ma?gorzata Okońska Natalia Gruba Miros?aw Jarz?b Tomasz Wenta Barbara Lipińska Reneta Grzywa Marcin Sieńczyk Krzysztof Rolka Adam Lesner |
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| Institution: | 1. Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland;2. Faculty of Biology, University of Gdansk, 80-308 Gdansk, Poland;3. Faculty of Chemistry, Wroclaw Technical University, 50-370 Wroc?aw, Poland |
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| Abstract: | HtrA2 belongs to the HtrA (high temperature requirement A) family of ATP-independent serine proteases. The primary function of HtrA2 includes maintaining the mitochondria homeostasis, cell death (by apoptosis, necrosis, or anoikis), and contribution to the cell signaling. Several recent reports have shown involvement of HtrA2 in development of cancer and neurodegenerative disorders. Here, we describe the profiling of HtrA2 protease substrate specificity via the combinatorial chemistry approach that led to the selection of novel intramolecularly quenched substrates. For all synthesized compounds, the highest HtrA2-mediated hydrolysis efficiency and selectivity among tested HtrA family members was observed for ABZ-Ile-Met-Thr-Abu-Tyr-Met-Phe-Tyr(3-NO2)-NH2, which displayed a specificity constant kcat/KM value of 14,535 M−1 s−1. |
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| Keywords: | Proteolytic enzymes HtrA2 proteinase Fluorogenic substrates Peptide libraries |
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