InChI=1S/C13H24N6O3/c1-5(2)9(14)11(20)18-10(12(21)22)7-3-6(17-13(15)16)8-4-19(7)8/h5-10H,3-4,14H2,1-2H3,(H,18,20)(H,21,22)(H4,15,16,17) |
DGIHWRUPUISVIZ-UHFFFAOYSA-N |
CC(C)C(C(=O)NC(C1CC(C2N1C2)NC(N)=N)C(=O)O)N |
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Streptomyces ficellus
(NCBI:txid1977088)
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of strain
NRRL8067
See:
PubMed
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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antibacterial agent
A substance (or active part thereof) that kills or slows the growth of bacteria.
DNA synthesis inhibitor
Any substance that inhibits the synthesis of DNA.
bacterial metabolite
Any prokaryotic metabolite produced during a metabolic reaction in bacteria.
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
(via alkaloid )
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View more via ChEBI Ontology
Yue R, Li M, Wang Y, Guan Y, Zhang J, Yan Z, Liu F, Lu F, Zhang H (2020) Insight into enzyme-catalyzed aziridine formation mechanism in ficellomycin biosynthesis. European journal of medicinal chemistry 204, 112639 (Source: SUBMITTER) [PubMed:32712437] [show Abstract] Ficellomycin is an aziridine-containing antibiotic, produced by Streptomyces ficellus. Based on the newly identified ficellomycin gene cluster and the assigned functions of its genes, a possible pathway for aziridine ring formation in ficellomycin was proposed, which is a complex process involving at least 3 enzymatic steps. To obtain support for the proposed mechanism, the targeted genes encoding sulfate adenylyltransferase, adenylsulfate kinase, and a putative sulfotransferase were respectively disrupted and the subsequent analysis of their fermentation products revealed that all the three genes were involved in aziridine formation. To further confirm the mechanism, the key gene encoding a putative sulfotransferase was over expressed in Escherichia coli Rosseta (DE3). Enzyme assays indicated that the expressed sulfotransferase could specifically transfer a sulfo group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) onto the hydroxyl group of (R)-(-)-2-pyrrolidinemethanol. This introduces a good leaving group in the form of the sulfated hydroxyl moiety, which is then converted into an aziridine ring through an intramolecular nucleophilic attack by the adjacent secondary amine. The sulfation/intramolecular cyclization reaction sequence maybe a general strategy for aziridine biosynthesis in microorganisms. Discovery of this mechanism revealed an enzyme-catalyzed route for the synthesis of aziridine-containing reagents and provided an important insight into the functional diversity of sulfotransferases. | Kurosawa S, Matsuda K, Hasebe F, Shiraishi T, Shin-Ya K, Kuzuyama T, Nishiyama M (2020) Guanidyl modification of the 1-azabicyclo[3.1.0]hexane ring in ficellomycin essential for its biological activity. Organic & biomolecular chemistry 18, 5137-5144 (Source: SUBMITTER) [PubMed:32582897] [show Abstract] The 1-azabicyclo[3.1.0]hexane ring is a key moiety in natural products for biological activities against bacteria, fungi, and tumor through DNA alkylation. Ficellomycin is a dipeptide that consists of l-valine and a non-proteinogenic amino acid with the 1-azabicyclo[3.1.0]hexane ring structure. Although the biosynthetic gene cluster of ficellomycin has been identified, the biosynthetic pathway currently remains unclear. We herein report the final stage of ficellomycin biosynthesis involving ring modifications and successive dipeptide formation. After the ring is formed, the hydroxy group of the ring is converted into the guanidyl unit by three enzymes, which include an aminotransferase with a novel inter ω-ω amino-transferring activity. In the last step, the resulting 1-azabicyclo[3.1.0]hexane ring-containing amino acid is connected with l-valine by an amino acid ligase to yield ficellomycin. The present study revealed a new machinery that expands the structural and biological diversities of natural products. | He X, Li M, Song S, Wu X, Zhang J, Wu G, Yue R, Cui H, Song S, Ma C, Lu F, Zhang H (2018) Ficellomycin: an aziridine alkaloid antibiotic with potential therapeutic capacity. Applied microbiology and biotechnology 102, 4345-4354 (Source: SUBMITTER) [PubMed:29602982] [show Abstract] Ficellomycin is an aziridine antibiotic produced by Streptomyces ficellus, which displays high in vitro activity against Gram-positive bacteria including multidrug resistant strains of Staphylococcus aureus. Compared to currently available antibiotics, ficellomycin exhibits a unique mechanism of action-it impairs the semiconservative DNA replication by inducing the formation of deficient 34S DNA fragments, which lack the ability to integrate into larger DNA pieces and eventually the complete bacterial chromosome. Until recently, some important progress has been made in research on ficellomycin synthesis and biosynthesis, opening the perspective to develop a new generation of antibiotics with better clinical performance than the currently used ones. In this review, we will cover the discovery and biological activity of ficellomycin, its biosynthesis, mode of action, and related synthetic analogs. The role of ficellomycin and its analogs as an important source of drug prototypes will be discussed together with future research prospects. | Liu Y, Li M, Mu H, Song S, Zhang Y, Chen K, He X, Wang H, Dai Y, Lu F, Yan Z, Zhang H (2017) Identification and characterization of the ficellomycin biosynthesis gene cluster from Streptomyces ficellus. Applied microbiology and biotechnology 101, 7589-7602 (Source: SUBMITTER) [PubMed:28894917] [show Abstract] Ficellomycin is a peptide-like antibiotic which exhibits potent in vitro activity against Penicillium oxalicum and Staphylococcus aureus, even against strains resistant to most clinically used antibiotics. The gene cluster responsible for ficellomycin biosynthesis was cloned from Streptomyces ficellus and sequenced. It was found to contain 26 ORFs and is located within 30 kb of contiguous DNA. Targeted disruption of the encoding genes revealed that most were involved in the functional section of ficellomycin biosynthesis, such as peptide assembly, regulation, resistance, and biosynthesis of the precursor of ficellomycin 2-[4-guanidyl-1-azabicyclo[3.1.0]hexan-2-yl] glycine (2-GAHG). Within the 2-GAHG synthesis pathway, a sulfate adenylyltransferase appears to be involved in the synthesis of the pharmaceutically important 1-azabicyclo[3.1.0]hexane ring moiety, which has been reported to cause DNA cross-linking or impairment of semiconservative DNA replication. | Foulke-Abel J, Agbo H, Zhang H, Mori S, Watanabe CM (2011) Mode of action and biosynthesis of the azabicycle-containing natural products azinomycin and ficellomycin. Natural product reports 28, 693-704 (Source: SUBMITTER) [PubMed:21327255] [show Abstract] Only a handful of aziridine-containing natural products have been identified out of the more than 100,000 natural products characterized to date. Among this class of compounds, only the azinomycins (azinomycin A and B) and ficellomycin contain an unusual 1-azabicyclo[3.1.0]hexane ring system, which has been reported to be the reason for theDNAcrosslinking abilities and cytotoxicity of these metabolites. Both families of natural products are produced by Streptomyces species, Streptomyces sahachiroi and Streptomyces ficellus, respectively. Up until recently, much of the work on these molecules has focused on the synthesis of these natural products or their corresponding analogs for in vitro investigations evaluating their DNA selectivity. While one of the most intriguing aspects of these natural products is their biosynthesis, progress made in this area was largely impeded by difficulties with obtaining a reliable culture method and securing a consistent source of these natural products. In this review, we will cover the discovery and biological activity of the azinomycins, their mode of action, related synthetic analogs and biosynthesis, and finish with a discussion on the less studied metabolite, ficellomycin. | Kuo MS, Yurek DA, Mizsak SA (1989) Structure elucidation of ficellomycin. The Journal of antibiotics 42, 357-360 (Source: SUBMITTER) [PubMed:2708128] [show Abstract] The structure of ficellomycin, an antibiotic previously discovered by Argoudelis et al., is elucidated as valyl-2-[4-guanidyl-1-azabicyclo[3.1.0]hexan-2-yl]glycine (1) by NMR, MS, and derivatization studies. The 1-azabicyclo[3.1.0]hexane moiety in 1 represents an unusual ring system making ficellomycin a unique natural product compound. | Reusser F (1977) Ficellomycin and feldamycin; inhibitors of bacterial semiconservative DNA replication. Biochemistry 16, 3406-3412 (Source: SUBMITTER) [PubMed:329871] [show Abstract] The two peptide-like antibiotics ficellomycin and feldamycin impair semiconservative DNA replication but not DNA repair synthesis in bacteria. Specifically both antibiotics cause the accumulation of a 34S DNA species in toluenized Escherichia coli cells which lacks the capability of being integrated into larger DNA pieces and eventually the complete bacterial chromosome. Novobiocin, a known inhibitor of replicative DNA synthesis, was investigated for comparative purposes. The action of this latter antibiotic differs from the ones exerted by ficellomycin and feldamycin in the novobiocin appears to block an event associated with the initiation of Okazaki fragments. The fact that novobiocin impairs DNA gyrase suggests that this enzyme plays an essential role during the initiation of Okazaki pieces. | Argoudelis AD, Reusser F, Whaley HA, Baczynskyj L, Mizsak SA, Wnuk RJ (1976) Antibiotics produced by Streptomyces ficellus. I. Ficellomycin. The Journal of antibiotics 29, 1001-1006 (Source: SUBMITTER) [PubMed:994319] [show Abstract] Ficellomycin is a new basic antibiotic produced by Streptomyces ficellus. Ficellomycin, C13H24N6O3, inhibits the growth of gram-positive bacteria in vitro and is effective in the treatment of experimental Staphylococcus aureus infections in mice. |
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