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Nienaturalne aminokwasy jako strategia do otrzymywania substratów, inhibitorów i niskocząsteczkowych sond aktywności dla enzymów proteolitycznych

Poręba Marcin, Kasperkiewicz-Wasilewska Paulina, Rut Wioletta, Drąg Marcin

Wiadomości Chemiczne

2022

[Z] 76, 5-6

433--454

Proteolytic enzymes are molecular scissors that are responsible for the amide bond breakdown in peptide and protein substrates. Over the years, the view on proteases has been considerably changed from non-specific digestive enzymes to sophisticated biocatalysts, which by performing limited proteolysis control virtually all biological processes. In order to better understand how proteases work and what are their biologically relevant target substrates, it is indispensable to determine their catalytic preferences. This knowledge can be further utilized to develop selective substrates, inhibitors and activity-based probes (ABPs) enabling the monitoring of proteases activity in various settings, from in vitro analysis on recombinant enzymes or cell lysates to ex vivo and in vivo imaging at the single cell level. Among many chemical-based approaches that have been developed and applied over the years, the Hybrid Combinatorial Substrate Library (HyCoSuL) technology has emerged as one of the most powerful one. HyCoSuL is a combinatorial peptide-based library of fluorogenic substrates, that comprise natural and unnatural amino acids, that can deeply explore the chemical space in proteases active site, providing a structural framework for the development of highly-selective chemical tools. In this review we present the most prominent examples of proteolytic enzymes that have been profiled with HyCoSuL approach yielding selective substrates, potent inhibitors, and very sensitive activity-based probes.

Extremophilic and modified aminotransferases as a versatile tool for the synthesis of optically pure building blocks for pharmaceutical industry

Szmejda K., Florczak T., Jodłowska I., Turkiewicz M.

Biotechnology and Food Science

2017

Vol. 81, nr 1

23--34

Considerable progress has been made in the past few years with industrial use of essential key intermediates for chemical and pharmaceutical industry. The increasing demand for obtaining chiral drugs in enantiomerically pure form makes it necessary to search for novel biocatalysts useful in the synthesis of amino acids, chiral amines, amino sugars and alcohols. According to the reaction mechanism, aminotransferases (ATs) have useful applications because of their capability of transfer of an amino group from a donor substrate to an acceptor, thus resulting in the synthesis of a wide variety of building blocks. This article reviews current biocatalytic approaches using microbial ATs in the synthesis of optically active products. Focus is also put on the engineering of ATs and their limitations in the industrial applications. Moreover this review covers biocatalytic approaches using ATs isolated from extreme environments.

Structural Studies of Position 2 Modified Endomorphin-2 Analogs by NMR Spectroscopy and Molecular Modeling

Janecka A., Perlikowska R., Gach K., Fichna J., Mazur A., Kruszyński R., Janecki T., Jankowski S.

Polish Journal of Chemistry

2009

Vol. 83, nr 7

1293-1307

Endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) is an endogenous ligand for the mi-opioid receptor. To examine the importance of Pro2 in EM-2 structure, we synthesized a series of analogs in corporating piperidine-2-, 3- and 4-carboxylic acids (Pip, Nip and Inp, respectively) in position 2. Pip, Nip and Inp are six-membered mimics of Pro and can be considered as alfa-, beta- and gamma-amino acids, respectively. Receptor binding studies revealed that [(R)-Nip2]EM-2 had greatly in creased mi-opioid receptor affinity compared with the parent peptide, while two other analogs were in active. In order to determine which structural elements of [(R)-Nip2]EM-2 could be responsible for the out standing affinity of this analog, the solution conformations of EM-2 analogs in corporating Promimics were investigated by the combination of 2D 1H NMR measurements and molecular modeling calculations. Evaluating the ratios of cis/trans rotamers, aromatic inter actions and dihedral angles we have found that all three analogs exist as a mixture of cis/trans rotamers of the Tyr–Xaa peptide bond and have flexible, extended conformations, with no intramolecular hydrogen bonds or aromatic ring inter actions observed for EM-2. The obtained results do not allow to draw conclusions on the bioactive conformation of the most active analog. We can suggest that a well known preference of the substituents to occupy equatorial positions in six-membered rings, to gether with a greater distance between Tyr1 and Phe3 aromatic rings, in Nip, which is a beta-amino acid, as compared with EM-2, are the main differentiating factors which are responsible for the exceptional affinity of [(R)-Nip2]EM-2.