Year: 2014
Type: dissertation
Abstract: Cyanobacteria are one of the most widespread microorganisms on earth, and they are found in almost all ecosystems, from fresh and marine water to terrestrial environments. Cyanobacteria received a great deal of attention as prolific producers of bioactive secondary metabolites. The aim of this study was to screen and characterize novel bioactive natural products, which present biological activity against acute myeloid leukemia (AML) cells, trypsin, and hepatotoxin microcystin/nodularin, from cyanobacteria isolated from different habitats. Of 40 cyanobacteria strains isolated from the Baltic Sea shore and lichen symbiosis were used to look for anti-cancer compounds which could induce apoptosis of AML cells. Half of these cyanobacteria strains contain apoptosis-inducing anti-AML activity, and seven cell extracts contain potent apoptosis-induced activities against AML. Two of apoptogens were confirmed to be new variants of hassallidin and scytophycin. Cyanobacteria produce a plethora of serine protease inhibitors with a broad range of chemical structures. Nostosins, new trypsin inhibitors, were discovered through the analysis of secondary metabolites in methanol extracts of Nostoc sp. FSN. The data showed that they were linear peptides with three residues: Hhpba, L-Ile and L-argininal/argininol. Nostosin A and B inhibited trypsin with IC50 values of 0.35 μM and 55 μM, respectively. Computer docking data indicated that the argininal aldehyde and guanidino groups played the most crucial role in the efficient inhibition of trypsin. The bloom-forming cyanobacterium Nodularia spumigena has been reported to produce several bioactive peptides. In this study, Nodularia spumigena strains from the Baltic Sea were discovered to produce new hybrid peptides named as pseudoaeruginosins. Because of the low abundance in cyanobacteria strains, pseudoaeruginosins were chemically synthesized and the structure was confirmed with LC-MS and NMR. Pseudoaeruginosins contained all the structure blocks of aeruginosin NAL2 except that the Choi was replaced by 4-methylproline (4-mPro), which is a specific subunit of spumigins in N. spumigena. The aldehyde group containing pseudoaeruginosin NS1 exhibited IC50 of 0.19 μM against porcine trypsin. The biosynthesis of pseudoaerugnosins was proposed to be a joint action of aeruginosin and spumigin biosynthesis pathways in N. spumigena. 4-mPro is a rare non-proteinogenic amino acid, which has been found in a small number of bioactive compounds identified from cyanobacteria. A combination of PCR and LC-MS were used to screen 116 cyanobacteria strains for the production of 4-mPro. A total of 12 strains were confirmed to produce 4-mPro, and eleven new cyclic peptides belonging to two groups were identified from two Nostoc spp. XPORK 5A and UK2aImI strains, respectively. Among 11 peptides, the tested five could inhibit the organic anion transporters OATP1B1/B3 to block the induction of apoptosis of hepatocytes by microcystin/nodularin. In this research, a total of two new trypsin inhibitors and five new cyclic peptides with the antitoxic bioactivity against microcystin/nodularin were identified. It was shown that cyanobacteria from both marine and terrestrial environments are a good resource for discovering new bioactive compounds. These findings increased the diversity of bioactive secondary metabolites characterized from cyanobacteria and provide new leads for drug research.
Source: Työväentutkimus Vuosikirja
Author: Liwei Liu
Language: English
Subfield: Applied Microbiology and Biotechnology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1492660309