A1 Journal article (refereed)
Discovery of varlaxins, new aeruginosin-type inhibitors of human trypsins (2022)

Heinilä L. M., P., Jokela, J., Ahmed M., N., Wahlsten, M., Kumar, S., Hrouzek, P., Permi, P., Koistinen, H., Fewer D., P., & Sivonen, K. (2022). Discovery of varlaxins, new aeruginosin-type inhibitors of human trypsins. Organic and Biomolecular Chemistry, 20(13), 2681-2692. https://doi.org/10.1039/d1ob02454j

JYU authors or editors

Permi, Perttu

Publication details

All authors or editors: Heinilä L. M., P.; Jokela, J.; Ahmed M., N.; Wahlsten, M.; Kumar, S.; Hrouzek, P.; Permi, P.; Koistinen, H.; Fewer D., P.; Sivonen, K.

Journal or series: Organic and Biomolecular Chemistry

ISSN: 1477-0520

eISSN: 1477-0539

Publication year: 2022

Volume: 20

Issue number: 13

Pages range: 2681-2692

Publisher: Royal Society of Chemistry

Publication country: United Kingdom

Publication language: English

DOI: https://doi.org/10.1039/d1ob02454j

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/80230

Abstract

Low-molecular weight natural products display vast structural diversity and have played a key role in the development of novel therapeutics. Here we report the discovery of novel members of the aeruginosin family of natural products, which we named varlaxins. The chemical structures of varlaxins 1046A and 1022A were determined using a combination of mass spectrometry, analysis of one- and two-dimensional NMR spectra, and HPLC analysis of Marfey’s derivatives. These analyses revealed that varlaxins 1046A and 1022A are composed of the following moieties: 2-O-methylglyceric acid 3-O-sulfate, isoleucine, 2-carboxy-6-hydroxyoctahydroindole (Choi), and a terminal arginine derivative. Varlaxins 1046A and 1022A differ in the cyclization of this arginine moiety. Interestingly, an unusual α-D-glucopyranose moiety derivatized with two 4-hydroxyphenylacetic acid residues was bound to Choi, a structure not previously reported for other members of the aeruginosin family. We sequenced the complete genome of Nostoc sp. UHCC 0870andidentified the putative 36 kb varlaxin biosynthetic gene cluster. Bioinformatics analysis confirmed that varlaxins belong to the aeruginosin family of natural products. Varlaxins 1046A and 1022A strongly inhibited the three human trypsin isoenzymes with IC50 of 0.62–3.6 nM and 97–230 nM, respectively, including a prometastatic trypsin-3, which is a therapeutically relevant target in several types of cancer. These results substantially broaden the genetic and chemical diversity of the aeruginosin family and provide evidence that the aeruginosin family is a source of strong inhibitors of human serine proteases.

Keywords: naturally occurring substances; inhibitors; enzymes; cyanobacteria; biotechnology

Free keywords: seriiniproteaasi; trypsiinit

Fields of science: