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Discovery of varlaxins, new aeruginosin-type inhibitors of human trypsins
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SYSNO ASEP 0556382 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of varlaxins, new aeruginosin-type inhibitors of human trypsins Author(s) Heinila, L. (FI)
Jokela, J. (FI)
Ahmed, M. (FI)
Wahlsten, M. (FI)
Saurav, Kumar (MBU-M) ORCID
Hrouzek, Pavel (MBU-M) ORCID
Permi, P. (FI)
Koistinen, H. (FI)
Fewer, D. (FI)
Sivonen, K. (FI)Source Title Organic & Biomolecular Chemistry. - : Royal Society of Chemistry - ISSN 1477-0520
Roč. 20, č. 13 (2022), s. 2681-2692Number of pages 12 s. Language eng - English Country GB - United Kingdom Keywords biosynthetic gene-cluster ; nostoc sp ; identification ; evolution ; 298-a ; prss3/mesotrypsin ; microcystis ; expression ; resistance ; peptides Subject RIV CC - Organic Chemistry OECD category Organic chemistry Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 000769605700001 EID SCOPUS 85127631800 DOI 10.1039/d1ob02454j Annotation 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 alpha-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 0870 and identified 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. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2023 Electronic address https://pubs.rsc.org/en/content/articlelanding/2022/OB/D1OB02454J
Number of the records: 1