Search Results (4)

Natural products produced by microorganisms are considered an important resource of bioactive secondary metabolites, such as anticancer, antifungal, antibiotic, and immunosuppressive molecules. Streptomyces are the richest source of bioactive natural products via possessing a wide number of secondary metabolite biosynthetic gene clusters (SM-BGCs). Based on rapid development in sequencing technologies with advances in genome mining, exploring the newly isolated Streptomyces species for possible new secondary metabolites is mandatory to find novel natural products. The isolated Streptomyces thinghirensis strain HM3 from arid and sandy texture soil in Qassim, SA, exerted inhibition activity against tested animal pathogenic Gram-positive bacteria and pathogenic fungal species. In this study, we report the draft genome of S. thinghirensis strain HM3, which consists of 7,139,324 base pairs (bp), with an average G+C content of 71.49%, predicting 7949 open reading frames, 12 rRNA operons (5S, 16S, 23S) and 60 tRNAs. An in silico analysis of strain HM3 genome by the antiSMASH and PRISM 4 online software for SM-BGCs predicted 16 clusters, including four terpene, one lantipeptide, one siderophore, two polyketide synthase (PKS), two non-ribosomal peptide synthetase (NRPS) cluster)/NRPS-like fragment, two RiPP/RiPP-like (ribosomally synthesised and post-translationally modified peptide product), two butyrolactone, one CDPS (tRNA-dependent cyclodipeptide synthases), and one other (cluster containing a secondary metabolite-related protein that does not fit into any other category) BGC. The presented BGCs inside the genome, along with antibacterial and antifungal activity, indicate that HM3 may represent an invaluable source for new secondary metabolites. Full article

Previous studies revealed the potential of Labrenzia aggregata USBA 371 to produce cytotoxic metabolites. This study explores its metabolic diversity and compounds involved in its cytotoxic activity. Extracts from the extracellular fraction of strain USBA 371 showed high levels of cytotoxic activity associated with the production of diketopiperazines (DKPs). We purified two compounds and a mixture of two other compounds from this fraction. Their structures were characterized by 1D and 2D nuclear magnetic resonance (NMR). The purified compounds were evaluated for additional cytotoxic activities. Compound 1 (cyclo (l-Pro-l-Tyr)) showed cytotoxicity to the following cancer cell lines: breast cancer 4T1 (IC₅₀ 57.09 ± 2.11 µM), 4T1H17 (IC₅₀ 40.38 ± 1.94), MCF-7 (IC₅₀ 87.74 ± 2.32 µM), murine melanoma B16 (IC₅₀ 80.87 ± 3.67), human uterus sarcoma MES-SA/Dx5 P-pg (−) (IC₅₀ 291.32 ± 5.64) and MES-SA/Dx5 P-pg (+) (IC₅₀ 225.28 ± 1.23), and murine colon MCA 38 (IC₅₀ 29.85 ± 1.55). In order to elucidate the biosynthetic route of the production of DKPs and other secondary metabolites, we sequenced the genome of L. aggregata USBA 371. We found no evidence for biosynthetic pathways associated with cyclodipeptide synthases (CDPSs) or non-ribosomal peptides (NRPS), but based on proteogenomic analysis we suggest that they are produced by proteolytic enzymes. This is the first report in which the cytotoxic effect of cyclo (l-Pro-l-Tyr) produced by an organism of the genus Labrenzia has been evaluated against several cancer cell lines. Full article

Cyclodipeptides (CDP) represent a diverse family of small, highly stable, cyclic peptides that are produced as secondary functional metabolites or side products of protein metabolism by bacteria, fungi, and animals. They are widespread in nature, and exhibit a broad variety of biological and pharmacological activities. CDP synthases (CDPSs) and non-ribosomal peptide synthetases (NRPSs) catalyze the biosynthesis of the CDP core structure, which is further modified by tailoring enzymes often associated with CDP biosynthetic gene clusters. In this review, we provide a comprehensive summary of CDP biosynthetic pathways and modifying enzymes. We also discuss the biological properties of some known CDPs and their possible applications in metabolic engineering. Full article

In recent years it has become apparent that aminoacyl-tRNAs are not only crucial components involved in protein biosynthesis, but are also used as substrates and amino acid donors in a variety of other important cellular processes, ranging from bacterial cell wall biosynthesis and lipid modification to protein turnover and secondary metabolite assembly. In this review, we focus on tRNA-dependent biosynthetic pathways that generate modified cyclic dipeptides (CDPs). The essential peptide bond-forming catalysts responsible for the initial generation of a CDP-scaffold are referred to as cyclodipeptide synthases (CDPSs) and use loaded tRNAs as their substrates. After initially discussing the phylogenetic distribution and organization of CDPS gene clusters, we will focus on structural and catalytic properties of CDPSs before turning to two recently characterized CDPS-dependent pathways that assemble modified CDPs. Finally, possible applications of CDPSs in the rational design of structural diversity using combinatorial biosynthesis will be discussed before concluding with a short outlook. Full article