Microcyclamide, a Cytotoxic Cyclic Hexapeptide from the Cyanobacterium Microcystis aeruginosa

Ishida, Keishi; Nakagawa, Hidenori; Murakami, Masahirô

doi:10.1021/np000159p

Cited by 75 publications

(93 citation statements)

References 25 publications

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“…There are many cyclic peptides possessing thiazole and oxazole rings such as microcyclamide from cyanobacteria. 23) Similar cyclic peptides were also isolated from marine origins as shown in Fig. 18; westellamide (cycloxazole) was discovered in both marine and freshwater origins.…”

Section: Structurally Related Peptides From Freshwater and Marine Orimentioning

confidence: 62%

“…13). 23,24) Microviridine is a tricyclic peptide composed of only L-amino acids. Microviridines have been produced by both toxic and non-toxic cyanobacteria.…”

Section: Structural Classification Of Isolated Compoundsmentioning

confidence: 99%

“…These results indicated that aeruginopeptins were mainly produced by M. aeruginosa. 28) Microcyclamide was isolated from Japanese M. aeruginosa NIES-298 strain and a cyclic peptide with one oxazole and two thiazoles 23,24) : Very recently, we had an opportunity Figure 16 shows the HPLC chromatogram of the extract of this bloom sample, in which microcyclamide was detected together with microcystin-LR as the main product. 30) These experimental results clearly show that secondary metabolites from strains are also produced under natural environmental conditions.…”

Section: Isolation Of Similar Peptides From Laboratory Strains and Blmentioning

confidence: 99%

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Production of Secondary Metabolites by Freshwater Cyanobacteria

Harada

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Freshwater cyanobacteria produce lethal toxins such as microcystins and anatoxins. During the purification of microcystins in bloom samples we found that a toxic cyanobacterium produced not only microcystins but also other types-peptides in early 1990. Since then we have isolated approximately thirty peptides from freshwater cyanobacteria. In this manuscript we focused on the following topics concerning the isolated peptides: 1) how to isolate desired compounds and to determine their structures, 2) structural classification of isolated compounds, 3) isolation of similar peptides from laboratory strains and bloom materials, 4) structurally related peptides from freshwater and marine origins, 5) b b-amino acid containing peptides from cyanobacteria, 6) comprehensive analysis system for the biosynthetic study of peptides produced by cyanobacteria, 7) biological activities of isolated compounds.

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Section: Structurally Related Peptides From Freshwater and Marine Orimentioning

confidence: 62%

“…13). 23,24) Microviridine is a tricyclic peptide composed of only L-amino acids. Microviridines have been produced by both toxic and non-toxic cyanobacteria.…”

Section: Structural Classification Of Isolated Compoundsmentioning

confidence: 99%

Section: Isolation Of Similar Peptides From Laboratory Strains and Blmentioning

confidence: 99%

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Production of Secondary Metabolites by Freshwater Cyanobacteria

Harada

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…This experimental breakthrough has revealed the large biotechnological potential of cyanobacterial natural product biosyntheses. An increasing number of further cyclic peptides containing heterocyclic amino acids have recently been isolated from other symbiotic and free-living cyanobacteria, including nostocyclamide (16), tenuecyclamide (1), venturamides (19), dendroamides (25), and microcyclamide (14). The variety of structures is reflected in an equally large variety of bioactivities, such as antibacterial, cytotoxic, and antimalarial activities.…”

mentioning

confidence: 99%

Microcyclamide Biosynthesis in Two Strains ofMicrocystis aeruginosa: from Structure to Genes and Vice Versa

Ziemert

Ishida

Quillardet

et al. 2008

Appl Environ Microbiol

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112

133

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Comparative analysis of related biosynthetic gene clusters can provide new insights into the versatility of these pathways and allow the discovery of new natural products. The freshwater cyanobacterium Microcystis aeruginosa NIES298 produces the cytotoxic peptide microcyclamide. Here, we provide evidence that the cyclic hexapeptide is formed by a ribosomal pathway through the activity of a set of processing enzymes closely resembling those recently shown to be involved in patellamide biosynthesis in cyanobacterial symbionts of ascidians. Besides two subtilisin-type proteases and a heterocyclization enzyme, the gene cluster discovered in strain NIES298 encodes six further open reading frames, two of them without similarity to enzymes encoded by the patellamide gene cluster. Analyses of genomic data of a second cyanobacterial strain, M. aeruginosa PCC 7806, guided the discovery and structural elucidation of two novel peptides of the microcyclamide family. The identification of the microcyclamide biosynthetic genes provided an avenue by which to study the regulation of peptide synthesis at the transcriptional level. The precursor genes were strongly and constitutively expressed throughout the growth phase, excluding the autoinduction of these peptides, as has been observed for several peptide pheromone families in bacteria.Cyanobacteria are known as a prolific source of secondary metabolites exhibiting unique structural features and biological activities. Various cyanobacterial compounds (e.g., curacin A, aeruginosin, and cryptophycin) have great potential for drug development (33, 36). However, due to their adverse effects on higher organisms, several cyanobacterial metabolites are regarded as health-threatening toxins and have caused serious concern among water authorities worldwide. A majority of these compounds, in particular, those that were isolated from planktonic freshwater cyanobacteria belonging to the genera Microcystis, Planktothrix, Nostoc, and Anabaena, can be classified as peptides or possess peptidic substructures often comprising highly modified amino acid moieties. Several of these peptides, such as the hepatotoxin microcystin or the protease inhibitors aeruginosin and anabaenopeptolide, were shown to be produced by nonribosomal peptide synthetase assembly lines (13,27,34).The recent characterization of the patellamide biosynthetic pathway from the as-yet-nonculturable cyanobacterial symbiont of the ascidian Lissoclinum patella has revealed that there are biosynthetic pathways independent from nonribosomal peptide synthetase systems capable of producing modified and cyclic peptide structures in cyanobacteria (29). The patellamide family of cyclic pseudosymmetrical octapeptides is characterized by the presence of thiazole and oxazole moieties. Although nonribosomal biosynthesis was anticipated for the formation of these peptides, heterologous expression of a microcin-like gene cluster discovered in the genome of the symbiotic cyanobacterium Prochloron didemni unambiguously showed that these peptide...

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“…Cyanobactins include compounds with antitumor and multidrug reversing activities with potential as drug leads (9,17,19). These bacteriocin-like peptides are produced by cyanobacteria isolated from soil (1,2,17) as well as marine (19,20,22) and freshwater (10,11,25) environments. Cyanobactins are produced through the proteolytic cleavage and macrocyclization of short precursor proteins (7,20,22).…”

mentioning

confidence: 99%

Widespread Occurrence and Lateral Transfer of the Cyanobactin Biosynthesis Gene Cluster in Cyanobacteria

Leikoski

Fewer

Sivonen

2009

Appl Environ Microbiol

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Cyanobactins are small cyclic peptides produced by cyanobacteria. Here we demonstrate the widespread but sporadic occurrence of the cyanobactin biosynthetic pathway. We detected a cyanobactin biosynthetic gene in 48 of the 132 strains included in this study. Our results suggest that cyanobactin biosynthetic genes have a complex evolutionary history in cyanobacteria punctuated by a series of ancient horizontal gene transfer events.

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Microcyclamide, a Cytotoxic Cyclic Hexapeptide from the Cyanobacterium Microcystis aeruginosa

Cited by 75 publications

References 25 publications

Production of Secondary Metabolites by Freshwater Cyanobacteria

Production of Secondary Metabolites by Freshwater Cyanobacteria

Microcyclamide Biosynthesis in Two Strains ofMicrocystis aeruginosa: from Structure to Genes and Vice Versa

Widespread Occurrence and Lateral Transfer of the Cyanobactin Biosynthesis Gene Cluster in Cyanobacteria

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