Eusynstyelamide, a Highly Modified Dimer Peptide from the Ascidian Eusynstyela misakiensis

Jc, Swersey; Cm, Ireland; Lm, Cornell; Rw, Peterson

doi:10.1021/np50108a027

Cited by 42 publications

(34 citation statements)

References 3 publications

(3 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The remarkable diversity of marine natural products containing indole derivatives is briefly summarized in Table II (see Ref. 46 for other brominated marine products). Of the brominated compounds isolated from marine products, only jaspamide (47), eusynstyelamide (48), halocyamine A, and halocyamine B (49) contain brominated …”

Section: Discussionmentioning

confidence: 99%

A Novel Post-translational Modification Involving Bromination of Tryptophan

Craig

Jimenéz

Dykert

et al. 1997

Journal of Biological Chemistry

100

View full text Add to dashboard Cite

We report a novel post-translational modification involving halogenation of tryptophan in peptides recovered from the venom of carnivorous marine cone snails (Conus). The residue, L-6-bromotryptophan, was identified in the sequence of a heptapeptide, isolated from Conus imperialis, a worm-hunting cone. This peptide does not elicit gross behavioral symptoms when injected centrally or peripherally in mice. L-6-Bromotryptophan was also identified in a 33-amino acid peptide from Conus radiatus; this peptide has been shown to induce a sleep-like state in mice of all ages and is referred to as bromosleeper peptide. The sequences of the two peptides Pca-Cys-Gly-Gln-Ala-Trp*-Cys-NH 2 were determined using a combination of mass spectrometry, amino acid, and chemical sequence analyses, where Pca ‫؍‬ pyroglutamic acid, Hyp ‫؍‬ hydroxyproline, Gla ‫؍‬ ␥-carboxyglutamate, and Trp* ‫؍‬ L-6-bromotryptophan. The precise structure and stereochemistry of the modified residue were determined as L-6-bromotryptophan by synthesis, co-elution, and enzymatic hydrolysis experiments. To our knowledge this is the first documentation of tryptophan residues in peptides/proteins being modified in a eukaryotic system and the first report of halogenation of tryptophan in vivo. SEQUENCE 1 andPolypeptides encoded by genes are primarily made up of the 20 common amino acids that are directly translated using the genetic code. However, many of these amino acids can be further modified post-translationally to yield a set of additional amino acids that contribute to the function of the mature protein. Together the 20 primary amino acids and these "secondary" amino acids which are found in proteins comprise the set of proteinogenous amino acids.These modified amino acids include amino acid conjugates where the side chain is linked to a glycosyl, phosphate, or sulfate group and amino acids such as 5-hydroxylysine, 4-hydroxyproline, and ␥-carboxyglutamate. One notable set of modified amino acids are halogenated derivatives of tyrosine and histidine. Naturally occurring halogenated tyrosine and histidine residues have previously been identified from proteins (1-4). A particularly well documented example of in vivo posttranslational halogenation of an amino acid residue in a protein is afforded by thyroglobulin (5). After iodination of several tyrosine residues, selective cleavages release the iodinated thyroid hormones thyroxine (3,5,3Ј,5Ј-tetraiodothyronine or T 4 ) 1 ; 3,5,3Ј-triiodothyronine (T 3 ), and 3,3Ј-di-iodothyronine. The presence of free T 3 and T 4 has also been shown in protochordates, suggesting a primitive thyroid function exists in tunicates (2).Of the 20 common amino acids, alanine, glycine, isoleucine, leucine, and valine, which lack side chain functional groups, have not been implicated in post-translational modifications (6). In 1907 it was proposed that hydroxytryptophan was a proteinogenous amino acid (7), but this proposal has not been verified (1), and chemical oxidation of tryptophan is likely to be responsible for the observed ...

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Post-translational Modification Involving Bromination of Tryptophan

Craig

Jimenéz

Dykert

et al. 1997

Journal of Biological Chemistry

100

View full text Add to dashboard Cite

show abstract

“…For example, the structure proposed in 1994 for the ascidian metabolite eusynstyelamide (Table 1) was based on extensive 1D and 2D NMR analyses. 145 While, it was noted that dehydration of the proposed α-keto amide hydrate did not occur in aprotic solvents, this was presumed to occur during FABMS since the highest molecular weight ion observed was m/z 787, assigned as [M+H-H 2 O] + . In 2009, three metabolites named eusynstyelamides A–C were isolated from a different Eusynstyela species.…”

Section: Detection and Revision Of Marine Natural Product Misassigmentioning

confidence: 99%

Survey of marine natural product structure revisions: A synergy of spectroscopy and chemical synthesis

Suyama

Gerwick

McPhail

2011

Bioorganic & Medicinal Chemistry

164

175

View full text Add to dashboard Cite

The structural assignment of new natural product molecules supports research in a multitude of disciplines that may lead to new therapeutic agents and or new understanding of disease biology. However, reports of numerous structural revisions, even of recently elucidated natural products, inspired the present survey of techniques used in structural misassignments and subsequent revisions in the context of constitutional or configurational errors. Given the comparatively recent development of marine natural products chemistry, coincident with the modern spectroscopy, it is of interest to consider the relative roles of spectroscopy and chemical synthesis in the structure elucidation and revision of those marine natural products which were initially misassigned. Thus, a tabulated review of all marine natural product structural revisions from 2005 to 2010 is organized according to structural motif revised. Misassignments of constitution are more frequent than perhaps anticipated by reliance on HMBC and other advanced NMR experiments, especially considering the full complement of all natural products. However, these techniques also feature prominently in structural revisions, specifically of marine natural products. Nevertheless, as is the case for revision of relative and absolute configuration, total synthesis is a proven partner for marine, as well as terrestrial, natural products structure elucidation. It also becomes apparent that considerable ‘detective work’ remains in structure elucidation, in spite of the spectacular advances in spectroscopic techniques.

show abstract

“…87 Compound 159 was found to be nontoxic against the colon tumor cell line HCT-116 at concentrations of up to 100 mg/mL. 85 Compounds 159-161 were similarly nontoxic against three other tumor cell lines, namely, MCF-7 (breast), H-460 (lung), and SF-268 (CNS) at concentrations up to 32 mM, 86 while 165 and 166 exhibited weak activity (IC 50 57 and 114.3 mM, respectively) against the melanoma cell line A-2058. 87 Compounds 159 and 160 displayed mild antimicrobial activity (IC 50 5.6 and 6.5 mM, respectively) against S. aureus, 86 while similar MIC data were determined against S. aureus for compounds 164 and 167 (6.25 mg/mL) and 165 and 166 (12.5 mg/mL), respectively.…”

Section: Isolation and Bioactivitymentioning

confidence: 99%

“…85 dimers, eusynstyelamide A-C (159-161), were later isolated from the ascidian Eusynstyela latericius collected from the Great Barrier Reef 86 (Figure 1.13). While the determination of the absolute configuration of these three compounds was inconclusive, Tapiolas et al were satisfied that 159-161 had not been isolated as racemates 86 and further noted that NMR, MS, and IR spectral data of the originally reported 158 85 were almost identical with those of 159, with an opposite specific rotation, suggesting that the antipode of 159 was a more accurate structural representation of 158. ent-eusynstyelamide A (162) 86 (Figure 1.13).…”

Section: Isolation and Bioactivitymentioning

confidence: 99%