Naturally-Occurring Cyclopeptides: Structures and Bioactivity

Pomilio, Alicia B.; Battista, Miguel Edgardo; Vitale, Arturo A.

doi:10.2174/138527206778742669

Cited by 70 publications

(46 citation statements)

References 215 publications

(423 reference statements)

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“…Unmodified cyclic peptides have a range of interesting pharmaceutical activities, including antimicrobial, antiplatelet, antimalarial, immunosuppressive, antileukemic, and enzymeinhibiting activities (2,17,22,25). Thus, it has been established that cyclic peptides such as anacyclamides can exhibit interesting bioactivities and warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Highly Diverse Cyanobactins in Strains of the Genus Anabaena

Leikoski

Fewer

Jokela

et al. 2010

Appl Environ Microbiol

112

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Cyanobactins are small, cyclic peptides recently found in cyanobacteria. They are formed through proteolytic cleavage and posttranslational modification of short precursor proteins and exhibit antitumor, cytotoxic, or multi-drug-reversing activities. Using genome project data, bioinformatics, stable isotope labeling, and mass spectrometry, we discovered novel cyclic peptides, anacyclamides, in 27 Anabaena strains. The lengths of the anacylamides varied greatly, from 7 to 20 amino acids. Pronounced sequence variation was also detected, and only one amino acid, proline, was present in all anacyclamides. The anacyclamides identified included unmodified proteinogenic or prenylated amino acids. We identified an 11-kb gene cluster in the genome of Anabaena sp. 90, and heterologous expression in Escherichia coli confirmed that this cluster was responsible for anacyclamide production. The discovery of anacyclamides greatly increases the structural diversity of cyanobactins.Cyanobacteria are a prolific source of secondary metabolites with potential as drug leads or useful probes for cell biology studies (23). They include biomedically interesting compounds, such as the anticancer drug lead cryptophycin (15), and environmentally problematic hepatotoxic peptides, such as microcystins and nodularins produced by bloom-forming cyanobacteria (23). Many of these compounds contain nonproteinogenic amino acids and modified peptides and are produced by nonribosomal peptide synthesis (23,26).The cyanobactins are a new group of cyclic peptides recently found in cyanobacteria (4). They are assembled through posttranslational proteolytic cleavage and head-to-tail macrocyclization of short precursor proteins. The cyanobactins are low-molecular-weight cyclic peptides that contain heterocyclized amino acids and can be prenylated or contain D-amino acids (3, 4). The cyanobactins that contain heterocyclized amino acids include patellamides, ulithiacyclamides, trichamide, tenuecyclamides, trunkamides, patellins, and microcyclamides and are synthesized in this manner (3,4,20,24,28). They possess antitumor, cytotoxic, and multi-drug-reversing activities and have potential as drug leads (4,18,20).Cyanobactins containing heterocyclized amino acids are found in a variety of cyanobacteria (4). A recent study demonstrated that the cyanobactin biosynthetic pathway is prevalent in planktonic bloom-forming cyanobacteria (14). However, the products of these gene clusters encoding new cyanobactins are unknown. Here we report discovery of a novel family of low-molecular-weight cyanobactins and show that these compounds are common in strains of the genus Anabaena. These anacyclamides exhibit pronounced length and sequence variation and contain unmodified or prenylated amino acids. MATERIALS AND METHODSCyanobacterial strains and cultivation. The Anabaena strains were grown in Z8 (12) medium lacking a source of combined nitrogen, except for a few cultures for which nitrogen was included in the medium (Table 1). Strains were grown in 40-ml cultures under co...

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Section: Discussionmentioning

confidence: 99%

Highly Diverse Cyanobactins in Strains of the Genus Anabaena

Leikoski

Fewer

Jokela

et al. 2010

Appl Environ Microbiol

112

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“…Ribosomally as well as non-ribosomally derived cyclic peptides are an important group of compounds because of their wide range biological, toxic and pharmacological activities and they often exhibit unique chemical structures 2,3. For example the cyclic toxins microcystins and nodularins produced by cyanobacteria (Blue-green algae) can wipe out entire fisheries and can cause death in humans 4,5.…”

Section: Introductionmentioning

confidence: 99%

Interpretation of Tandem Mass Spectra Obtained from Cyclic Nonribosomal Peptides

Liu

Meluzzi

et al. 2009

Anal. Chem.

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Natural and non-natural cyclic peptides are a crucial component in drug discovery programs because of their considerable pharmaceutical properties. Cyclosporin, microcystins and nodularins all are notable pharmacologically important cyclic peptides. Because these biologically active peptides are often biosynthesized non-ribosomally, they often contain non-standard amino acids, thus increasing the complexity of the resulting tandem mass spectrometry data. In addition, due to the cyclic nature, the fragmentation patterns of many of these peptides showed much higher complexity when compared to related counterparts. Therefore, at the present time it is still difficult to annotate cyclic peptides MS/MS spectra. In this current work, an annotation program was developed for the annotation and characterization of tandem mass spectra obtained from cyclic peptides. This program, which we call MS-CPA is available as a web tool (http://lol.ucsd.edu/ms-cpa_v1/Input.py). Using this program, we have successfully annotated the sequence of representative cyclic peptides, such as seglitide, tyrothricin, desmethoxymajusculamide C, dudawalamide A and cyclomarins in a rapid manner, and also were able to provide the first-pass structure evidence of a newly discovered natural product base on predicted sequence. This compound is not available in sufficient quantities for structural elucidation by other means such as NMR.1 In addition to the development of this cyclic annotation program, it was observed that some cyclic peptides fragmented in unexpected ways resulting in the scrambling of sequences. In sum, MS-CPA not only provides a platform for rapid confirmation and annotation of tandem mass spectrometry data obtained with cyclic peptides but also enables quantitative analysis of the ion intensities. This program facilitates cyclic peptide analysis, sequencing, but also acts as a useful tool to investigate the uncommon fragmentation phenomena of cyclic peptides and aids the characterization of newly discovered cyclic peptides encountered in drug discovery programs.

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“…This is the first of the class that came to be called Caryophyllaceae-type CP. 2 CPs have been discovered in a wide range of taxa, including eubacteria, fungi, plants, and animals (2)(3)(4)(5)(6)(7)(8).…”

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confidence: 99%

The Two-step Biosynthesis of Cyclic Peptides from Linear Precursors in a Member of the Plant Family Caryophyllaceae Involves Cyclization by a Serine Protease-like Enzyme

Barber

Pujara

Reed

et al. 2013

Journal of Biological Chemistry

140

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Background: In the Caryophyllaceae, cyclic peptides (CP) are biosynthesized from linear precursors via an unknown pathway. Results: Two protease-like enzymes are involved in precursor processing. Conclusion: A serine protease-like enzyme was recruited for the cyclization step in CP biosynthesis. Significance: This represents a very significant advance in our understanding of the mode and evolution of CP biosynthesis in plants.

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Naturally-Occurring Cyclopeptides: Structures and Bioactivity

Cited by 70 publications

References 215 publications

Highly Diverse Cyanobactins in Strains of the Genus Anabaena

Highly Diverse Cyanobactins in Strains of the Genus Anabaena

Interpretation of Tandem Mass Spectra Obtained from Cyclic Nonribosomal Peptides

The Two-step Biosynthesis of Cyclic Peptides from Linear Precursors in a Member of the Plant Family Caryophyllaceae Involves Cyclization by a Serine Protease-like Enzyme

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