Browsing by Subject "PEPTIDES"

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  • Nionelli, Luana; Wang, Yaqin; Pontonio, Erica; Immonen, Mikko; Rizzello, Carlo; Maina, Ndegwa; Katina, Kati; Coda, Rossana (2020)
    Bread is one of the most consumed food products in the world and one of the most discarded, due to its intrinsic short shelf-life and susceptibility to mold spoilage. Additionally, bread waste is generated during production and distribution, leading to the disposal of bread otherwise still fit for consumption. To avoid generating huge amount of bread waste, strategies to enable its reutilization should be sought. In this study, surplus bread, still suitable for consumption, was bioprocessed with enzymes and fermented by selected lactic acid bacteria generating an ingredient with antifungal properties. Bread hydrolysate fermented by Lactobacillus brevis AM7 showed broad inhibitory spectrum against the fungal species tested and antifungal activity ranging from 20 to 70%. Nine antifungal peptides were identified via Liquid Chromatography-Electrospray Ionisation-Mass Spectra/ Mass Spectra (nano-LC-ESI-MS/MS), having 10-17 amino acid residues and mass ranging from 1083.6 to 1980.7 Da, all of them encrypted in wheat proteins sequences. Bread hydrolysate fermented by Lb. brevis AM7, non fermented bread hydrolysate and a slurry consisting of water-bread mixture were used as ingredients in bread making and compared to regular wheat bread. Breads containing the fermented hydrolysate (18 and 22% of the dough weight) showed the longest mold-free shelf-life compared to the other breads, lasting up to 10 days before mold appearance. Additionally, the fermented hydrolysate was the least detrimental on bread quality, emphasizing the positive impact and potential of the studied biotechnology.
  • Leino, Teppo O.; Turku, Ainoleena; Yli-Kauhaluoma, Jari Tapani; Kukkonen, Jyrki P.; Xhaard, Henri; Wallén, Erik A. A. (2018)
    A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX2 receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 mu M range and two other compounds showed weak OX2 receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX1 but not the OX2 receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold. (C) 2018 Elsevier Masson SAS. All rights reserved.
  • Tienaho, Jenni; Karonen, Maarit; Muilu-Mäkelä, Riina; Kaseva, Janne; de Pedro, Nuria; Vicente, Francisca; Genilloud, Olga; Aapola, Ulla; Uusitalo, Hannu; Vuolteenaho, Katriina; Franzen, Robert; Wähälä, Kristiina; Karp, Matti; Santala, Ville; Sarjala, Tytti (2020)
    Despite the continuing interest in various plant and natural products, only a small portion of the biologically active compounds from nature has been discovered and exploited. In this study, antioxidant and antibacterial properties of aqueous fractions of three endophytic fungi isolated from the roots of 8-year-old Scots pines (Pinus sylvestris) growing on a drained peatland were investigated. The endophytic fungi species were Acephala applanata, Phialocephala fortinii, and Humicolopsis cephalosporioides/Coniochaeta mutabilis. The bioactivities were examined using hydrogen peroxide scavenging and oxygen radical absorbance capacity tests as well as sensitive Escherichia coli-based biosensors, which produce a luminescent signal in the presence of substances with oxidative or genotoxic properties. In addition, cell models for Parkinson's disease, age-related macular degeneration, and osteoarthritis were used to evaluate the potential for pharmaceutical applications. The aqueous extracts of fungi and 19 out of 42 fractions were found to be active in one or more of the tests used. However, no activity was found in the age-related macular degeneration and osteoarthritis cell model tests. Additionally, bioactivity data was connected with metabolites putatively annotated, and out of 330 metabolites, 177 were interesting in view of the bioactivities investigated. A majority of these were peptides and all three fungal species shared a highly similar metabolome. We propose that Scots pine endophytic fungi are a rich source of interesting metabolites, and synergistic effects may cause the bioactivities, as they were found to vary after the fractionation process.
  • Pahr, Sandra; Selb, Regina; Weber, Milena; Focke-Tejkl, Margarete; Hofer, Gerhard; Dordic, Andela; Keller, Walter; Papadopoulos, Nikolaos G.; Giavi, Stavroula; Makela, Mika; Pelkonen, Anna; Niederberger, Verena; Vrtala, Susanne; Valenta, Rudolf (2014)
  • Mattila, Antti; Andsten, Rose-Marie; Jumppanen, Mikael; Assante, Michele; Jokela, Jouni; Wahlsten, Matti; Mikula, Kornelia M; Sigindere, Cihad; Kwak, Daniel H.; Gugger, Muriel; Koskela, Harri; Sivonen, Kaarina; Liu, Xinyu; Yli-Kauhaluoma, Jari; Iwaï, Hideo; Fewer, David (2019)
    Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino- and carboxy-termini. Here we identified the 12.7 kb muscoride (mus) biosynthetic gene clusters from Nostoc spp. PCC 7906 and UHCC 0398. The mus biosynthetic gene clusters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The mus biosynthetic gene clusters encode two copies of the cyanobactin prenyltransferase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide substrate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from Nostoc spp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyltransferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxazole linear peptides.
  • Rizzello, Carlo G.; Coda, Rossana; Wang, Yaqin; Verni, Michela; Kajala, Ilkka; Katina, Kati; Laitila, Arja (2019)
    The interest towards legumes in food applications has risen over the past decades. However, the presence of antinutritional factors (ANF) and the poor technological performances still restricts their application in food fortification. In this study, four lactic acid bacteria (LAB) isolated from faba bean were applied as starter cultures for faba bean bioprocessing. None of the strains employed produced exopolysaccharides from raffinose, on the contrary, they did with sucrose as substrate. The fermented doughs were characterized and the strains were compared for their adaptation capacity and metabolic performance including the formation of dextrans, the degradation of ANF and the ability to improve antioxidant activity and in vitro protein digestibility (IVPD). A contribution to the proteolysis was given by the presence of endogenous enzymes, responsible for the increase of peptides and amino acids in dough from irradiated flour. However, the LAB strains further enhanced proteolysis. Weissella cibaria VTT E-153485 led to the highest peptide release and consequentially to the highest IVPD. In doughs fermented with Pediococcus pentosaceus VTT E-153483 and Leuconostoc kimchi VTT E-153484, phytic acid was reduced to more than half the initial concentration. Inoculated doughs had significantly lower content of oligosaccharides after 24 h of incubation compared to the controls. The most efficient raffinose consumption was found for Leuc. kimchi and W. cibaria. Doughs inoculated with weissellas contained > 1% of dextrans. Weissella confusa VTT E-143403 induced a significant increment in viscosity (ca. 7 times higher than the controls). This study revealed that well-characterized, indigenous LAB provided beneficial biotechnological features in faba bean dough processing and contributed to its implementation in the food production.
  • Fewer, David P.; Jokela, Jouni; Heinila, Lassi; Aesoy, Reidun; Sivonen, Kaarina; Galica, Tomas; Hrouzek, Pavel; Herfindal, Lars (2021)
    Cyanobacteria produce a variety of chemically diverse cyclic lipopeptides with potent antifungal activities. These cyclic lipopeptides have an amphipathic structure comprised of a polar peptide cycle and hydrophobic fatty acid side chain. Many have antibiotic activity against a range of human and plant fungal pathogens. This review article aims to summarize the present knowledge on the chemical diversity and cellular effects of cyanobacterial cyclic lipopeptides that display antifungal activity. Cyclic antifungal lipopeptides from cyanobacteria commonly fall into four structural classes; hassallidins, puwainaphycins, laxaphycins, and anabaenolysins. Many of these antifungal cyclic lipopeptides act through cholesterol and ergosterol-dependent disruption of membranes. In many cases, the cyclic lipopeptides also exert cytotoxicity in human cells, and a more extensive examination of their biological activity and structure-activity relationship is warranted. The hassallidin, puwainaphycin, laxaphycin, and anabaenolysin structural classes are unified through shared complex biosynthetic pathways that encode a variety of unusual lipoinitiation mechanisms and branched biosynthesis that promote their chemical diversity. However, the biosynthetic origins of some cyanobacterial cyclic lipopeptides and the mechanisms, which drive their structural diversification in general, remain poorly understood. The strong functional convergence of differently organized chemical structures suggests that the production of lipopeptide confers benefits for their producer. Whether these benefits originate from their antifungal activity or some other physiological function remains to be answered in the future. However, it is clear that cyanobacteria encode a wealth of new cyclic lipopeptides with novel biotechnological and therapeutic applications.
  • Jones, Martin R.; Pinto, Ernani; Torres, Mariana A.; Dörr, Fabiane; Mazur-Marzec, Hanna; Szubert, Karolina; Tartaglione, Luciana; Dell'Aversano, Carmela; Miles, Christopher O.; Beach, Daniel G.; McCarron, Pearse; Sivonen, Kaarina; Fewer, David P.; Jokela, Jouni; Janssen, Elisabeth M.-L. (2021)
    Harmful cyanobacterial blooms, which frequently contain toxic secondary metabolites, are reported in aquatic environments around the world. More than two thousand cyanobacterial secondary metabolites have been reported from diverse sources over the past fifty years. A comprehensive, publically-accessible database detailing these secondary metabolites would facilitate research into their occurrence, functions and toxicological risks. To address this need we created CyanoMetDB, a highly curated, flat-file, openly-accessible database of cyanobacterial secondary metabolites collated from 850 peer-reviewed articles published between 1967 and 2020. CyanoMetDB contains 2010 cyanobacterial metabolites and 99 structurally related compounds. This has nearly doubled the number of entries with complete literature metadata and structural composition information compared to previously available open access databases. The dataset includes microcytsins, cyanopeptolins, other depsipeptides, anabaenopeptins, microginins, aeruginosins, cyclamides, cryptophycins, saxitoxins, spumigins, microviridins, and anatoxins among other metabolite classes. A comprehensive database dedicated to cyanobacterial secondary metabolites facilitates: (1) the detection and dereplication of known cyanobacterial toxins and secondary metabolites; (2) the identification of novel natural products from cyanobacteria; (3) research on biosynthesis of cyanobacterial secondary metabolites, including substructure searches; and (4) the investigation of their abundance, persistence, and toxicity in natural environments.
  • Reinert, Jochim; Richard, Bernhard C.; Klafki, Hans W.; Friedrich, Beate; Bayer, Thomas A.; Wiltfang, Jens; Kovacs, Gabor G.; Ingelsson, Martin; Lannfelt, Lars; Paetau, Anders; Bergquist, Jonas; Wirths, Oliver (2016)
    In Alzheimer's disease (AD) a variety of amyloid beta-peptides (A beta) are deposited in the form of extracellular diffuse and neuritic plaques (NP), as well as within the vasculature. The generation of A beta from its precursor, the amyloid precursor protein (APP), is a highly complex procedure that involves subsequent proteolysis of APP by beta-and gamma-secretases. Brain accumulation of A beta due to impaired A beta degradation and/or altered ratios between the different A beta species produced is believed to play a pivotal role in AD pathogenesis. While the presence of A beta 40 and A beta 42 in vascular and parenchymal amyloid have been subject of extensive studies, the deposition of carboxyterminal truncated A beta peptides in AD has not received comparable attention. In the current study, we for the first time demonstrate the immunohistochemical localization of A beta 37 and A beta 39 in human sporadic AD (SAD). Our study further included the analysis of familial AD (FAD) cases carrying the APP mutations KM670/671NL, E693G and I716F, as well as a case of the PSEN1 Delta Exon9 mutation. A beta 37 and A beta 39 were found to be widely distributed within the vasculature in the brains of the majority of studied SAD and FAD cases, the latter also presenting considerable amounts of A beta 37 containing NPs. In addition, both peptides were found to be present in extracellular plaques but only scarce within the vasculature in brains of a variety of transgenic AD mouse models. Taken together, our study indicates the importance of C-terminally truncated A beta in sporadic and familial AD and raises questions about how these species are generated and regulated.
  • Karhu, Lasse; Magarkar, Aniket; Bunker, Alex; Xhaard, Henri (2019)
    We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX2 receptor through extensive molecular dynamics simulations. As the activation determinants of the receptor remain unknown, we simulated an unliganded receptor and two small-molecular ligands, the antagonist suvorexant and the agonist Nag26 for comparison. Each system was simulated in pure POPC membrane as well as in the 25% cholesterol–POPC membrane. In total, we carried out 36 μs of simulations. Through this set of simulations, we report a stable binding mode for the C-terminus of orexin-A. In addition, we suggest interactions that would promote orexin receptor activation, as well as others that would stabilize the inactive state.
  • Parmar, Amarjit; Greco, Dario; Venalainen, Jarkko; Gentile, Massimiliano; Dukes, Emma; Saavalainen, Päivi (2013)
  • Konstantinou, Despoina; Popin, Rafael; Fewer, David P.; Sivonen, Kaarina; Gkelis, Spyros (2021)
    Sponges form symbiotic relationships with diverse and abundant microbial communities. Cyanobacteria are among the most important members of the microbial communities that are associated with sponges. Here, we performed a genus-wide comparative genomic analysis of the newly described marine benthic cyanobacterial genus Leptothoe (Synechococcales). We obtained draft genomes from Le. kymatousa TAU-MAC 1615 and Le. spongobia TAU-MAC 1115, isolated from marine sponges. We identified five additional Leptothoe genomes, host-associated or free-living, using a phylogenomic approach, and the comparison of all genomes showed that the sponge-associated strains display features of a symbiotic lifestyle. Le. kymatousa and Le. spongobia have undergone genome reduction; they harbored considerably fewer genes encoding for (i) cofactors, vitamins, prosthetic groups, pigments, proteins, and amino acid biosynthesis; (ii) DNA repair; (iii) antioxidant enzymes; and (iv) biosynthesis of capsular and extracellular polysaccharides. They have also lost several genes related to chemotaxis and motility. Eukaryotic-like proteins, such as ankyrin repeats, playing important roles in sponge-symbiont interactions, were identified in sponge-associated Leptothoe genomes. The sponge-associated Leptothoe stains harbored biosynthetic gene clusters encoding novel natural products despite genome reduction. Comparisons of the biosynthetic capacities of Leptothoe with chemically rich cyanobacteria revealed that Leptothoe is another promising marine cyanobacterium for the biosynthesis of novel natural products.
  • Freitag, Tobias L.; Podojil, Joseph R.; Pearson, Ryan M.; Fokta, Frank J.; Sahl, Cecilia; Messing, Marcel; Andersson, Leif C.; Leskinen, Katarzyna; Saavalainen, Päivi; Hoover, Lisa I.; Huang, Kelly; Phippard, Deborah; Maleki, Sanaz; King, Nicholas J. C.; Shea, Lonnie D.; Miller, Stephen D.; Meri, Seppo K.; Getts, Daniel R. (2020)
  • Wang, Shiqi; Wannasarit, Saowanee; Figueiredo, Patricia; Molinaro, Giuseppina; Ding, Yaping; Correia, Alexandra; Casettari, Luca; Wiwattanapatapee, Ruedeekorn; Hirvonen, Jouni; Liu, Dongfei; Li, Wei; Santos, Hélder A. (2021)
    In this study, a rationally designed nanocomposite (BUDPDA@MAP) composed of polydopamine (PDA) nanoparticle and anti‐inflammatory drug budesonide (BUD) encapsulated in a pH‐responsive endosomolytic polymer (poly(butyl methacrylate‐co‐methacrylic acid) grafted acetalated dextran, denoted by MAP), is proposed. The uniform nanocomposite is prepared using a microfluidic device. At low endosomal pH (5.5), MAP destabilizes the endosomal membranes for the cytoplasmic delivery of PDA, and releases BUD simultaneously, resulting in a greater reactive oxygen species scavenging capability than both the free drug and PDA alone. The combined therapeutic efficacy from PDA and BUD also leads to a successful macrophage phenotype switch from pro‐inflammatory M1 to anti‐inflammatory M2.
  • Fewer, David P.; Jokela, Jouni; Paukku, Eeva; Osterholm, Julia; Wahlsten, Matti; Permi, Perttu; Aitio, Olli; Rouhiainen, Leo; Gomez-Saez, Gonzalo V.; Sivonen, Kaarina (2013)
  • Hoever, P.; Dorffner, G.; Benes, H.; Penzel, T.; Danker-Hopfe, H.; Barbanoj, M. J.; Pillar, G.; Saletu, B.; Polo, O.; Kunz, D.; Zeitlhofer, J.; Berg, S.; Partinen, M.; Bassetti, C. L.; Hoegl, B.; Ebrahim, I. O.; Holsboer-Trachsler, E.; Bengtsson, H.; Peker, Y.; Hemmeter, U-M; Chiossi, E.; Hajak, G.; Dingemanse, J. (2012)
  • Ruokolainen, Miina; Ollikainen, Elisa; Sikanen, Tiina; Kotiaho, Tapio; Kostiainen, Risto (2016)
    Protein phosphorylation has a key role in cell regulation. Oxidation of proteins, in turn, is related to many diseases and to aging, but the effects of phosphorylation on the oxidation of proteins and peptides have been rarely studied. The aim of this study was to examine the mechanistic effect of phosphorylation on peptide oxidation induced by titanium dioxide photo catalysis. The effect of phosphorylation was compared between nonphosphorylated and tyrosine phosphorylated peptides using electrospray tandem mass spectrometry. We observed that tyrosine was the most preferentially oxidized amino acid, but the oxidation reaction was significantly inhibited by its phosphorylation. The study also shows that titanium dioxide photocatalysis provides a fast and easy method to study oxidation reactions of biomolecules, such as peptides.
  • Jokela, Jouni; Heinilä, Lassi M. P.; Shishido, Tania K.; Wahlsten, Matti; Fewer, David P.; Fiore, Marli F.; Wang, Hao; Haapaniemi, Esa; Permi, Perttu; Sivonen, Kaarina (2017)
    Nostoc is a cyanobacterial genus, common in soils and a prolific producer of natural products. This research project aimed to explore and characterize Brazilian cyanobacteria for new bioactive compounds. Here we report the production of hepatotoxins and new protease inhibitors from benthic Nostoc sp. CENA543 isolated from a small, shallow, saline-alkaline lake in the Nhecolandia, Pantanal wetland area in Brazil. Nostoc sp. CENA543 produces exceptionally high amounts of nodularin-R. This is the first free-living Nostoc that produces nodularin at comparable levels as the toxic, bloom-forming, Nodularia spumigena. We also characterized pseudospumigins A-F, which are a novel family of linear tetrapeptides. Pseudospumigins are structurally related to linear tetrapeptide spumigins and aeruginosins both present in N. spumigena but differ in respect to their diagnostic amino acid, which is Ile/Leu/Val in pseudospumigins, Pro/mPro in spumigins, and Choi in aeruginosins. The pseudospumigin gene cluster is more similar to the spumigin biosynthetic gene cluster than the aeruginosin gene cluster. Pseudospumigin A inhibited trypsin (IC50 4.5 mu M after 1 h) in a similar manner as spumigin E from N. spumigena but was almost two orders of magnitude less potent. This study identifies another location and environment where the hepatotoxic nodularin has the potential to cause the death of eukaryotic organisms.
  • Merezhko, Maria; Brunello, Cecilia A.; Yan, Xu; Vihinen, Helena; Jokitalo, Eija; Uronen, Riikka-Liisa; Huttunen, Henri J. (2018)
    Tauopathies are characterized by cerebral accumulation of Tau protein aggregates that appear to spread throughout the brain via a cell-to-cell transmission process that includes secretion and uptake of pathological Tau, followed by templated misfolding of normal Tau in recipient cells. Here, we show that phosphorylated, oligomeric Tau clusters at the plasma membrane in N2A cells and is secreted in vesicle-free form in an unconventional process sensitive to changes in membrane properties, particularly cholesterol and sphingomyelin content. Cell surface heparan sulfate proteoglycans support Tau secretion, possibly by facilitating its release after membrane penetration. Notably, secretion of endogenous Tau from primary cortical neurons is mediated, at least partially, by a similar mechanism. We suggest that Tau is released from cells by an unconventional secretory mechanism that involves its phosphorylation and oligomerization and that membrane interaction may help Tau to acquire properties that allow its escape from cells directly through the plasma membrane.
  • Martins, Joana; Leikoski, Niina; Wahlsten, Matti; Azevedo, Joana; Antunes, Jorge; Jokela, Jouni; Sivonen, Kaarina; Vasconcelos, Vitor; Fewer, David P.; Leão, Pedro N. (2018)
    Cyanobactins are a family of linear and cyclic peptides produced through the post-translational modification of short precursor peptides. A mass spectrometry-based screening of potential cyanobactin producers led to the discovery of a new prenylated member of this family of compounds, sphaerocyclamide (1), from Sphaerospermopsis sp. LEGE 00249. The sphaerocyclamide biosynthetic gene cluster (sph) encoding the novel macrocyclic prenylated cyanobactin, was sequenced. Heterologous expression of the sph gene cluster in Escherichia coli confirmed the connection between genomic and mass spectrometric data. Unambiguous establishment of the orientation and site of prenylation required the full structural elucidation of 1 using Nuclear Magnetic Resonance (NMR), which demonstrated that a forward prenylation occurred on the tyrosine residue. Compound 1 was tested in pharmacologically or ecologically relevant biological assays and revealed moderate antimicrobial activity towards the fouling bacterium Halomonas aquamarina CECT 5000.