Diketopiperazines: biological activity and synthesis

Martins, Maristela B.; Carvalho, Ivone

doi:10.1016/j.tet.2007.04.105

Cited by 371 publications

(238 citation statements)

References 41 publications

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“…This class of compounds has recently gained interest due to its wide array of biological activities, including antibacterial, antifungal, antiviral, antiprion, antitumor, and immunosuppressive functions (1,2). Most cyclodipeptide biosynthesis pathways involve nonribosomal peptide synthetases (NRPSs) (3,4).…”

mentioning

confidence: 99%

Structural basis for nonribosomal peptide synthesis by an aminoacyl-tRNA synthetase paralog

Bonnefond

Arai

Sakaguchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

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Cyclodipeptides are secondary metabolites biosynthesized by many bacteria and exhibit a wide array of biological activities. Recently, a new class of small proteins, named cyclodipeptide synthases (CDPS), which are unrelated to the typical nonribosomal peptide synthetases, was shown to generate several cyclodipeptides, using aminoacyl-tRNAs as substrates. The Mycobacterium tuberculosis CDPS, Rv2275, was found to generate cyclodityrosine through the formation of an aminoacyl-enzyme intermediate and to have a structure and oligomeric state similar to those of the class Ic aminoacyl-tRNA synthetases (aaRSs). However, the poor sequence conservation among CDPSs has raised questions about the architecture and catalytic mechanism of the identified homologs. Here we report the crystal structures of Bacillus licheniformis CDPS YvmC-Blic, in the apo form and complexed with substrate mimics, at 1.7-2.4-Å resolutions. The YvmC-Blic structure also exhibits similarity to the class Ic aaRSs catalytic domain. Our mutational analysis confirmed the importance of a set of residues for cyclodileucine formation among the conserved residues localized in the catalytic pocket. Our biochemical data indicated that YvmC-Blic binds tRNA and generates cyclodileucine as a monomer. We were also able to detect the presence of an aminoacyl-enzyme reaction intermediate, but not a dipeptide tRNA intermediate, whose existence was postulated for Rv2275. Instead, our results support a sequential catalytic mechanism for YvmC-Blic, with the successive attachment of two leucine residues on the enzyme via a conserved serine residue. Altogether, our findings suggest that all CDPS enzymes share a common aaRS-like architecture and a catalytic mechanism involving the formation of an enzyme-bound intermediate.X-ray crystallography | pulcherrimin | diketopiperazine | divergent evolution | thioesterase domain

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mentioning

confidence: 99%

Structural basis for nonribosomal peptide synthesis by an aminoacyl-tRNA synthetase paralog

Bonnefond

Arai

Sakaguchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

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“…They are the smallest possible cyclic peptides. DKPs are commonly biosynthesized from amino acids by different organisms, including mammals, and are considered to be secondary metabolites (Martin & Carvalho, 2007). Some proteases, such as dipeptidyl peptidases, cleave the terminal ends of proteins to generate dipeptides, which naturally cyclize to form DKPs.…”

Section: Discussionmentioning

confidence: 99%

“…No antimycobacterial activity was reported earlier for the test compounds except cyclo(pro-leu). Martin and Carvalho (2007) reported that organic extracts from cultures of the marine bacterium Bacillus pumilus furnished inhibitory fractions against Mycobacterium marinum, a genetically similar experimental model for M. tuberculosis. Among the active compounds isolated and identified was the DKP of leucine and proline.…”

Section: Discussionmentioning

confidence: 99%

Antimycobacterial activity of cyclic dipeptides isolated fromBacillussp. N strain associated with entomopathogenic nematode

Kumar

Mohandas

2013

Pharmaceutical Biology

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Context: Tuberculosis (TB) is one of the leading causes of morbidity and mortality with a global mortality rate of two million deaths per year; one-third of the world's population is infected with Mycobacterium tuberculosis. Objective: The aim of this study was to determine the antimycobacterial activity of six diketopiperazines (DKPs) purified from a Bacillus sp. N strain associated with entomopathogenic nematode Rhabditis (Oscheius) sp. Materials and methods: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration of DKPs were determined using the broth dilution method on Middlebrook 7H11 against M. tuberculosis H 37 Rv. Time-kill assay was used to determine the rate of killing of M. tuberculosis H 37 Rv by DKPs. The cytotoxicity of the DKPs was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay against the VERO cell line. Results: Out of six DKP-tested cyclo-(D-Pro-L-Leu), cyclo-(L-Pro-L-Met) and cyclo-(D-Pro-L-Phe)recorded antimycobacterial activity, the cyclo-(L-Pro-L-Met) showed the highest activity and MIC values of 4 mg/ml for M. tuberculosis H 37 Rv. The MIC value for rifampicin was 0.06 mg/ml. Growth curve study by the MIC concentration of cyclic dipeptides recorded significant inhibition when compared with control. Time-kill curve showed maximum reduction of colony count was between 3 and 5 weeks. The DKPs are nontoxic to the VERO cell line up to 200 mg/ml. The antimycobacterial activity of cyclo-(D-Pro-L-Leu), cyclo-(L-Pro-L-Met) and cyclo-(D-Pro-L-Phe) is reported in this study for the first time. Discussion and conclusion: In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for treatment against TB.

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“…While toxic to mammalian cells, studies have suggested that certain sporidesmins, namely bis-ETPs chetomin (Waksman & Bugie, 1944) and chaetocin (Hauser et al, 1970), may possess anticancer activity due to their ability to suppress neovascularization (Waksman & Bugie, 1944;Hauser et al, 1970;McInnes et al, 1976;Brewer et al, 1978;Kung et al, 2004). In order to understand better the chemistry and biology of the bridged bis-ETPs, diketopiperazines (1,4-piperazine-2,5-diones, DKPs) (Martins & Carvalho, 2007) and bridged bis-DKP structures lacking a disulfide bridge must also be studied. Even in the absence of the disulfide bridge many compounds of this class exhibit a broad spectrum of interesting biological activity.…”

Section: Commentmentioning

confidence: 99%

Polymorphism and phase transition behavior of 6,6′-bis(chloromethyl)-1,1′,4,4′-tetramethyl-3,3′-(p-phenylenedimethylene)bis(piperazine-2,5-dione)

2009

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A crystallographic investigation of the title compound, C22H28Cl2N4O4, using crystals obtained under different crystallization conditions, revealed the presence of two distinct polymorphic forms. The molecular conformation in the two polymorphs is very different: one adopts a `C' shape, whereas the other adopts an `S' shape. In the latter, the molecule lies across a crystallographic twofold axis. The `S'‐shaped polymorph undergoes a reversible orthorhombic‐to‐monoclinic phase transition on cooling, whereas the structure of the `C'‐shaped polymorph is temperature insensitive.

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Diketopiperazines: biological activity and synthesis

Cited by 371 publications

References 41 publications

Structural basis for nonribosomal peptide synthesis by an aminoacyl-tRNA synthetase paralog

Structural basis for nonribosomal peptide synthesis by an aminoacyl-tRNA synthetase paralog

Antimycobacterial activity of cyclic dipeptides isolated fromBacillussp. N strain associated with entomopathogenic nematode

Polymorphism and phase transition behavior of 6,6′-bis(chloromethyl)-1,1′,4,4′-tetramethyl-3,3′-(p-phenylenedimethylene)bis(piperazine-2,5-dione)

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