Nucleoside antibiotics possess various biological activities such as antibacterial, antifungal, anticancer, and herbicidal activities. RIKEN scientists contributed to this area of research with two ...representative antifungal nucleoside antibiotics, blasticidin S and polyoxin. Blasticidin S was the first antibiotic exploited in agriculture worldwide. Meanwhile, the polyoxins discovered by Isono and Suzuki are still used globally as an agricultural antibiotic. In this review article, the research on nucleoside antibiotics mainly done by Isono and his collaborators is summarized from the discovery of polyoxin to subsequent investigations.
The research on antibiotics requires the integration of broad areas, such as microbiology, organic chemistry, biochemistry and pharmacology. It is similar to the field of chemical biology that is ...recently popular as an approach for drug discovery. When we isolate a new compound from a microorganism, we can pursue the interesting research on chemistry and biology. In this review, I would like to introduce our achievements in relation to reveromycin A.
The Warburg effect, a widely known characteristic of cancer cells, refers to the utilization of glycolysis under aerobic conditions for extended periods of time. Recent studies have revealed that ...cancer cells are capable of reprogramming their metabolic pathways to meet vigorous metabolic demands. New anticancer drugs that target the complicated metabolic systems of cancer cells are being developed. Identifying the potential targets of novel compounds that affect cancer metabolism may enable the discovery of new therapeutic targets for cancer treatment, and hasten the development of anticancer drugs. Historically, various drug screening techniques such as the analysis of a compound's antiproliferative effect on cancer cells and proteomic methods, that enable target identification have been used to obtain many useful drugs from natural products. Here, we review proteomics-based target identification methods applicable to natural products that affect cancer metabolism.
Tenuazonic acid (TeA) is a well-known mycotoxin produced by various plant pathogenic fungi. However, its biosynthetic gene has been unknown to date. Here we identify the TeA biosynthetic gene from ...Magnaporthe oryzae by finding two TeA-inducing conditions of a low-producing strain. We demonstrate that TeA is synthesized from isoleucine and acetoacetyl-coenzyme A by TeA synthetase 1 (TAS1). TAS1 is a unique non-ribosomal peptide synthetase and polyketide synthase (NRPS-PKS) hybrid enzyme that begins with an NRPS module. In contrast to other NRPS/PKS hybrid enzymes, the PKS portion of TAS1 has only a ketosynthase (KS) domain and this domain is indispensable for TAS1 activity. Phylogenetic analysis classifies this KS domain as an independent clade close to type I PKS KS domain. We demonstrate that the TAS1 KS domain conducts the final cyclization step for TeA release. These results indicate that TAS1 is a unique type of NRPS-PKS hybrid enzyme.
Recently, high-throughput screening (HTS) has become the mainstream technique for drug discovery. Compounds that are synthesized by combinatorial chemistry might be more suitable than natural ...products to apply to HTS, because the purification procedure is a drawback of using natural products. Nevertheless, natural products remain an extremely important source of drugs. To overcome the demerits of natural products, we are constructing the RIKEN Natural Products Depository (NPDepo) that is focused primarily on microbial metabolites. In this review, I describe (i) engineering pathways for biosynthetic gene clusters of microbial metabolites, (ii) construction of fraction libraries of microbial metabolites, and (iii) the development of a new screening system using a chemical array and a protein library produced by GLORIA.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including salicylic acid (SA), target mammalian cyclooxygenases. In plants, SA is a defense hormone that regulates NON-EXPRESSOR OF PATHOGENESIS RELATED ...GENES 1 (NPR1), the master transcriptional regulator of immunity-related genes. We identify that the oxicam-type NSAIDs tenoxicam (TNX), meloxicam, and piroxicam, but not other types of NSAIDs, exhibit an inhibitory effect on immunity to bacteria and SA-dependent plant immune response. TNX treatment decreases NPR1 levels, independently from the proposed SA receptors NPR3 and NPR4. Instead, TNX induces oxidation of cytosolic redox status, which is also affected by SA and regulates NPR1 homeostasis. A cysteine labeling assay reveals that cysteine residues in NPR1 can be oxidized in vitro, leading to disulfide-bridged oligomerization of NPR1, but not in vivo regardless of SA or TNX treatment. Therefore, this study indicates that oxicam inhibits NPR1-mediated SA signaling without affecting the redox status of NPR1.
Recent advances in genome sequencing have revealed a variety of secondary metabolite biosynthetic gene clusters in actinomycetes. Understanding the biosynthetic mechanism controlling secondary ...metabolite production is important for utilizing these gene clusters. In this study, we focused on the kinanthraquinone biosynthetic gene cluster, which has not been identified yet in Streptomyces sp. SN-593. Based on chemical structure, 5 type II polyketide synthase gene clusters were listed from the genome sequence of Streptomyces sp. SN-593. Among them, a candidate gene cluster was selected by comparing the gene organization with grincamycin, which is synthesized through an intermediate similar to kinanthraquinone. We initially utilized a BAC library for subcloning the kiq gene cluster, performed heterologous expression in Streptomyces lividans TK23, and identified the production of kinanthraquinone and kinanthraquinone B. We also found that heterologous expression of kiqA, which belongs to the DNA-binding response regulator OmpR family, dramatically enhanced the production of kinanthraquinones.
Filamentous fungi have many secondary metabolism genes and produce a wide variety of secondary metabolites with complex and unique structures. However, the role of most secondary metabolites remains ...unclear. Moreover, most fungal secondary metabolism genes are silent or poorly expressed under laboratory conditions and are difficult to utilize. Pyricularia oryzae, the causal pathogen of rice blast disease, is a well-characterized plant pathogenic fungus. P. oryzae also has a large number of secondary metabolism genes and appears to be a suitable organism for analyzing secondary metabolites. However, in case of this fungus, biosynthetic genes for only four groups of secondary metabolites have been well characterized. Among two of the four groups of secondary metabolites, biosynthetic genes were identified by activating secondary metabolism. These secondary metabolites include melanin, a polyketide compound required for rice infection; tenuazonic acid, a well-known mycotoxin produced by various plant pathogenic fungi and biosynthesized by a unique nonribosomal peptide synthetase-polyketide synthase hybrid enzyme; nectriapyrones, antibacterial polyketide compounds produced mainly by symbiotic fungi, including plant pathogens and endophytes, and pyriculols, phytotoxic polyketide compounds. This review mainly focuses on the biosynthesis and biological functions of the four groups of P. oryzae secondary metabolites.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The control of secondary metabolism in fungi is essential for the regulation of various cellular functions. In this study, we searched the RIKEN Natural Products Depository (NPDepo) chemical library ...for inducers of tenuazonic acid (TeA) production in the rice blast fungus Pyricularia oryzae and identified NPD938. NPD938 transcriptionally induced TeA production. We explored the mode of action of NPD938 and observed that this compound enhanced TeA production via LAE1, a global regulator of fungal secondary metabolism. NPD938 could also induce production of terpendoles and pyridoxatins in Tolypocladium album RK99-F33. Terpendole production was induced transcriptionally. We identified the pyridoxatin biosynthetic gene cluster among transcriptionally induced secondary metabolite biosynthetic gene clusters. Therefore, NPD938 is useful for the control of fungal secondary metabolism.
Recent improvements in technologies such as omics analysis have enabled us to acquire a large amount of data regarding the biological changes in cells treated with bioactive small molecules. Using ...such data, a variety of profiling methods have been established for target identification of such bioactive compounds. In this chapter, we describe a proteomic profiling system, ChemProteoBase, based on proteome analysis using two-dimensional difference gel electrophoresis. This system compares the similarities in protein expression of 296 spots detected in the gel among the test compounds.
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