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dc.contributor.authorHeinilä L. M., P.
dc.contributor.authorJokela, J.
dc.contributor.authorAhmed M., N.
dc.contributor.authorWahlsten, M.
dc.contributor.authorKumar, S.
dc.contributor.authorHrouzek, P.
dc.contributor.authorPermi, P.
dc.contributor.authorKoistinen, H.
dc.contributor.authorFewer D., P.
dc.contributor.authorSivonen, K.
dc.date.accessioned2022-03-17T12:15:22Z
dc.date.available2022-03-17T12:15:22Z
dc.date.issued2022
dc.identifier.citationHeinilä 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. <i>Organic and Biomolecular Chemistry</i>, <i>20</i>(13), 2681-2692. <a href="https://doi.org/10.1039/d1ob02454j" target="_blank">https://doi.org/10.1039/d1ob02454j</a>
dc.identifier.otherCONVID_104642289
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/80230
dc.description.abstractLow-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.en
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherRoyal Society of Chemistry
dc.relation.ispartofseriesOrganic and Biomolecular Chemistry
dc.relation.urihttp://dx.doi.org/10.1039/d1ob02454j
dc.rightsCC BY 3.0
dc.subject.otherseriiniproteaasi
dc.subject.othertrypsiinit
dc.titleDiscovery of varlaxins, new aeruginosin-type inhibitors of human trypsins
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-202203171929
dc.contributor.laitosBio- ja ympäristötieteiden laitosfi
dc.contributor.laitosDepartment of Biological and Environmental Scienceen
dc.contributor.oppiaineNanoscience Centerfi
dc.contributor.oppiaineNanoscience Centeren
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.type.coarhttp://purl.org/coar/resource_type/c_2df8fbb1
dc.description.reviewstatuspeerReviewed
dc.format.pagerange2681-2692
dc.relation.issn1477-0520
dc.relation.numberinseries13
dc.relation.volume20
dc.type.versionpublishedVersion
dc.rights.copyright© The Royal Society of Chemistry 2022
dc.rights.accesslevelopenAccessfi
dc.subject.ysobiotekniikka
dc.subject.ysosyanobakteerit
dc.subject.ysoentsyymit
dc.subject.ysoluonnonaineet
dc.subject.ysoinhibiittorit
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p2348
jyx.subject.urihttp://www.yso.fi/onto/yso/p3324
jyx.subject.urihttp://www.yso.fi/onto/yso/p4769
jyx.subject.urihttp://www.yso.fi/onto/yso/p6956
jyx.subject.urihttp://www.yso.fi/onto/yso/p24325
dc.rights.urlhttps://creativecommons.org/licenses/by/3.0/
dc.relation.doi10.1039/d1ob02454j
jyx.fundinginformationWe would also like to acknowledge support from the Sigrid Jusélius Foundation, the Magnus Ehrnrooth Foundation, the Jane and Aatos Erkko Foundation, the Nordforsk Nordic centre of Excellency NordAqua (project number #82845), and the University of Helsinki’s Doctoral Programme in Microbiology and Biotechnology funding to L. P. H. and M. N. A.
dc.type.okmA1


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