Discovery of varlaxins, new aeruginosin-type inhibitors of human trypsins
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
Published inOrganic and Biomolecular Chemistry
DisciplineNanoscience CenterNanoscience Center
© The Royal Society of Chemistry 2022
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. ...
PublisherRoyal Society of Chemistry
ISSN Search the Publication Forum1477-0520
Publication in research information system
MetadataShow full item record
Additional information about fundingWe 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.
Showing items with similar title or keywords.
Structure-Activity Relationship Analysis of 3-phenylcoumarin-Based Monoamine Oxidase B Inhibitors Rauhamäki, Sanna; Postila, Pekka; Niinivehmas, Sanna; Kortet, Sami; Schildt, Emmi; Pasanen, Mira; Manivannan, Elangovan; Ahinko, Mira; Koskimies, Pasi; Nyberg, Niina; Huuskonen, Pasi; Multamäki, Elina; Pasanen, Markku; Juvonen, Risto O.; Raunio, Hannu; Huuskonen, Juhani; Pentikäinen, Olli (Frontiers Media S.A., 2018)Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked ...
Psychrophiles : a source of cold-adapted enzymes for energy efficient biotechnological industrial processes Bhatia, Ravi Kant; Ullah, Saleem; Hoque, Mubasher Zahir; Ahmad, Irshad; Yang, Yung-Hun; Bhatt, Arvind Kumar; Bhatia, Shashi Kant (Elsevier BV, 2021)Biocatalysts are the backbone of bioprocessing industries that are going through a phase of transition with reference to the requirement of extraordinary enzymes for various biochemical processes. This transition is well ...
Interactions of PP2A inhibitor proteins with PP2A regulatory subunits Roivas, Pekka (2020)Fosfataasit ovat tärkeitä solun sisällä tapahtuvan säätelyn kannalta. Proteiinifosfataasi 2A (PP2A) on yksi näistä säätelijöistä ja sen normaali toiminta liittyy solusyklin aktivointiin. Kun PP2A:n normaalia toimintaa ...
The effect of PLC-inhibitor on echovirus 1 internalization probed with fluorescently labeled echovirus 1 Myllynen, Mira (2014)Echovirus 1 (EV1) kuuluu Pikornavirusperheeseen ja tarkemmin luokiteltuna Enterovirusten sukuun. EV1 on pieni ja vaipaton RNA-virus, jonka proteiinikuori koostuu neljästä proteiinista VP1-VP4. Infektion on osoitettu alkavan, ...
Interaction mechanism of endogenous PP2A inhibitor protein ENSA with PP2A Thapa, Chandan; Roivas, Pekka; Haataja, Tatu; Permi, Perttu; Pentikäinen, Ulla (Wiley-Blackwell, 2022)The vast diversity of protein phosphatase 2A (PP2A) holoenzyme composition ensures its multi-faceted role in the regulation of cellular growth and signal transduction. In several pathological conditions, such as cancer, ...