Design and synthesis of new substrates of HtrA2 protease.

Magdalena Wysocka, Anna Wojtysiak, Małgorzata Okońska, Natalia Gruba, Mirosław Jarząb, Tomasz Wenta, Barbara Lipińska, Reneta Grzywa, Marcin Sieńczyk, Krzysztof Rolka, Adam Lesner

Analytical biochemistry 2015 Apr 15

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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 14,535M(-1)s(-1). Copyright © 2015 Elsevier Inc. All rights reserved.

Citation

Magdalena Wysocka, Anna Wojtysiak, Małgorzata Okońska, Natalia Gruba, Mirosław Jarząb, Tomasz Wenta, Barbara Lipińska, Reneta Grzywa, Marcin Sieńczyk, Krzysztof Rolka, Adam Lesner. Design and synthesis of new substrates of HtrA2 protease. Analytical biochemistry. 2015 Apr 15;475:44-52