Structure of Curacin A, a Novel Antimitotic, Antiproliferative and Brine Shrimp Toxic Natural Product from the Marine Cyanobacterium Lyngbya majuscula

Gerwick, William H.; Proteau, Philip; Nagle, Dale G.; Hamel, Ernest; Blokhin, Andrei V.; Slate, Doris L.

doi:10.1021/jo00085a006

Cited by 346 publications

(211 citation statements)

References 0 publications

Supporting

Mentioning

199

Contrasting

Unclassified

Order By: Relevance

“…In this regard, most investigations have focused on cytotoxic metabolites, particularly those compounds that inhibit growth and viability of cancer cells. Pahayokolide A was moderately cytotoxic, inhibiting various human cancer cell lines (Table 2), as has been reported for many of the compounds isolated from Lyngbya (e.g., Gerwick et al, 1994;Marquez et al, 1998;Luesch et al, 2000Luesch et al, , 2001Tan et al, 2000Tan et al, , 2002Tan et al, , 2003Williams et al, 2003). In fact, cytotoxicity of pahayokolide A (see Table 2) is similar in potency to that of many of the metabolites previously isolated from Lyngbya Luesch et al, 2000;Tan et al, 2000Tan et al, , 2002Tan et al, , 2003.…”

Section: Discussionsupporting

confidence: 71%

“…Pharmacological activity of such Lyngbya-derived compounds ranges from microtubule inhibitors, such as curacin A (Gerwick et al, 1994), to potent sodium channel blockers and activators, such as kalkitoxin (Wu et al, 2000) and antillatoxin (Li et al, 2001). On the other hand, exposure to Lyngbya toxins have also been associated with various human health effects (Izumi and Moore, 1987;Osborne et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacology and toxicology of pahayokolide A, a bioactive metabolite from a freshwater species of Lyngbya isolated from the Florida Everglades

Berry

Gantar

Gawley

et al. 2004

Comparative Biochemistry and Physiology Part C: Toxicology &

View full text Add to dashboard Cite

The genus of filamentous cyanobacteria, Lyngbya, has been found to be a rich source of bioactive metabolites. However, identification of such compounds from Lyngbya has largely focused on a few marine representatives. Here, we report on the pharmacology and toxicology of pahayokolide A from a freshwater isolate, Lyngbya sp. strain 15−2, from the Florida Everglades. Specifically, we investigated inhibition of microbial representatives and mammalian cell lines, as well as toxicity of the compound to both invertebrate and vertebrate models. Pahayokolide A inhibited representatives of Bacillus, as well as the yeast, Saccharomyces cerevisiae. Interestingly, the compound also inhibited several representatives of green algae that were also isolated from the Everglades. Pahayokolide A was shown to inhibit a number of cancer cell lines over a range of concentrations (IC 50 varied from 2.13 to 44.57 μM) depending on the cell-type. When tested against brine shrimp, pahayokolide was only marginally toxic at the highest concentrations tested (1 mg/mL). The compound was, however, acutely toxic to zebrafish embryos (LC 50 =2.15 μM). Possible biomedical and environmental health aspects of the pahayokolides remain to be investigated; however, the identification of bioactive metabolites such as these demonstrates the potential of the Florida Everglades as source of new toxins and drugs.

show abstract

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Pharmacology and toxicology of pahayokolide A, a bioactive metabolite from a freshwater species of Lyngbya isolated from the Florida Everglades

Berry

Gantar

Gawley

et al. 2004

Comparative Biochemistry and Physiology Part C: Toxicology &

View full text Add to dashboard Cite

show abstract

“…the initial TE serine ester hydrolysis product) (9). The CurM TE assures decarboxylation and sulfate group elimination in vivo, as the corresponding carboxylated and sulfated curacin A intermediate was not detected in cultures of L. majuscula (Scheme 1) (37). Through interactions with the oxyanion hole and Arg 205 , the carboxylic acid hydrolysis product remains bound to CurM TE long enough for the enzyme to promote loss of CO 2 and SO 4 2-in one concerted step.…”

Section: Discussionmentioning

confidence: 99%

Terminal Alkene Formation by the Thioesterase of Curacin A Biosynthesis

Gehret

Gerwick

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Curacin A is a polyketide synthase (PKS)-non-ribosomal peptide synthetase-derived natural product with potent anticancer properties generated by the marine cyanobacterium Lyngbya majuscula. Type I modular PKS assembly lines typically employ a thioesterase (TE) domain to off-load carboxylic acid or macrolactone products from an adjacent acyl carrier protein (ACP) domain. In a striking departure from this scheme the curacin A PKS employs tandem sulfotransferase and TE domains to form a terminal alkene moiety. Sulfotransferase sulfonation of ␤-hydroxy-acyl-ACP is followed by TE hydrolysis, decarboxylation, and sulfate elimination (Gu, L., Wang, B., Kulkarni, A., Gehret, J. J., Lloyd, K. R., Gerwick, L., Gerwick, W. H., Wipf, P.

show abstract

“…Intermediates are tethered via thioester linkage to the phosphopantetheine arms of acyl carrier protein (ACP) domains in PKSs and peptidyl carrier protein (PCP) domains in NRPSs. Curacin A, from the marine cyanobacterium Lyngbya majuscula, is an unusual natural product with a cyclopropane ring, a thiazoline ring, an internal cis double bond, and a terminal alkene (3). The natural product exhibits antimitotic activity and inhibits the binding of colchicine to tubulin (4,5).…”

Section: Cryptic Chlorination | Natural Products | Polyketide Synthasesmentioning

confidence: 99%

Conformational switch triggered by α-ketoglutarate in a halogenase of curacin A biosynthesis

Khare¹,

Wang

et al. 2010

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

Self Cite

View full text Add to dashboard Cite

The CurA halogenase (Hal) catalyzes a cryptic chlorination leading to cyclopropane ring formation in the synthesis of the natural product curacin A. Hal belongs to a family of enzymes that use Fe 2þ , O 2 and α-ketoglutarate (αKG) to perform a variety of halogenation reactions in natural product biosynthesis. Crystal structures of the enzyme in five ligand states reveal strikingly different open and closed conformations dependent on αKG binding. The open form represents ligand-free enzyme, preventing substrate from entering the active site until both αKG and chloride are bound, while the closed form represents the holoenzyme with αKG and chloride coordinated to iron. Candidate amino acid residues involved in substrate recognition were identified by site-directed mutagenesis. These new structures provide direct evidence of a conformational switch driven by αKG leading to chlorination of an early pathway intermediate.cryptic chlorination | natural products | polyketide synthases

show abstract

Structure of Curacin A, a Novel Antimitotic, Antiproliferative and Brine Shrimp Toxic Natural Product from the Marine Cyanobacterium Lyngbya majuscula

Cited by 346 publications

References 0 publications

Pharmacology and toxicology of pahayokolide A, a bioactive metabolite from a freshwater species of Lyngbya isolated from the Florida Everglades

Pharmacology and toxicology of pahayokolide A, a bioactive metabolite from a freshwater species of Lyngbya isolated from the Florida Everglades

Terminal Alkene Formation by the Thioesterase of Curacin A Biosynthesis

Conformational switch triggered by α-ketoglutarate in a halogenase of curacin A biosynthesis

Contact Info

Product

Resources

About