Belizeanic Acid: A Potent Protein Phosphatase 1 Inhibitor Belonging to the Okadaic Acid Class, with an Unusual Skeleton

Cruz, Patricia G.; Fernández, José J.; Norte, Manuel; Daranas, Antonio Hernández

doi:10.1002/chem.200800593

Cited by 28 publications

(19 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Published data indicate that the affinity of PP2A for DTX-1 is 1.6-fold higher, and for DTX-2 is 2-fold lower than for OA [17]. However, other OA analogs such as 19- epi -okadaic acid or belizeanic acid were recently found to induce lower inhibitory potencies, mainly related to PP1 [18,19]. Particularly, a concentration of 150 nM of 19- epi -okadaic acid was required to induce the same neurotoxic effects observed at 0.5 nM OA or at 2.5 nM DTX-1 treatments [20].…”

Section: Introductionmentioning

confidence: 99%

Okadaic Acid: More than a Diarrheic Toxin

et al. 2013

View full text Add to dashboard Cite

Okadaic acid (OA) is one of the most frequent and worldwide distributed marine toxins. It is easily accumulated by shellfish, mainly bivalve mollusks and fish, and, subsequently, can be consumed by humans causing alimentary intoxications. OA is the main representative diarrheic shellfish poisoning (DSP) toxin and its ingestion induces gastrointestinal symptoms, although it is not considered lethal. At the molecular level, OA is a specific inhibitor of several types of serine/threonine protein phosphatases and a tumor promoter in animal carcinogenesis experiments. In the last few decades, the potential toxic effects of OA, beyond its role as a DSP toxin, have been investigated in a number of studies. Alterations in DNA and cellular components, as well as effects on immune and nervous system, and even on embryonic development, have been increasingly reported. In this manuscript, results from all these studies are compiled and reviewed to clarify the role of this toxin not only as a DSP inductor but also as cause of alterations at the cellular and molecular levels, and to highlight the relevance of biomonitoring its effects on human health. Despite further investigations are required to elucidate OA mechanisms of action, toxicokinetics, and harmful effects, there are enough evidences illustrating its toxicity, not related to DSP induction, and, consequently, supporting a revision of the current regulation on OA levels in food.

show abstract

Section: Introductionmentioning

confidence: 99%

Okadaic Acid: More than a Diarrheic Toxin

et al. 2013

View full text Add to dashboard Cite

show abstract

“…), 3) fostriecin13 and 4) cantharidin14 (blister beetles, ~1500 species). Finally, a new PP1 inhibitor, belizeanic acid, was recently extracted from the dinoflagellate Prorocentrum belizeanum 15. Because the biochemically best studied ser/thr phosphatases PP1, PP2A (Protein phosphatase 2A) and, to some extent, PP2B (calcineurin), have highly similar active sites, these toxins also inhibit PP2A and PP2B (PP1, and PP2A and PP2B form the PPP subfamily of protein phosphatases).…”

mentioning

confidence: 99%

Crystal Structures of Protein Phosphatase-1 Bound to Nodularin-R and Tautomycin: A Novel Scaffold for Structure-based Drug Design of Serine/Threonine Phosphatase Inhibitors

Kelker

Page

Peti

2009

Journal of Molecular Biology

112

125

View full text Add to dashboard Cite

Summary Protein Phosphatase 1 is ubiquitously distributed throughout all tissues and regulates many diverse pathways ranging from cell cycle progression to carbohydrate metabolism. Many naturally occurring, molecular toxins modulate PP1 activity, though the exact mechanism of this differential regulation is not understood. A detailed elucidation of these interactions is crucial for understanding the cellular basis of phosphatase function and signaling pathways, but, more importantly, they can serve as the basis for highly specific therapeutics, i.e. against cancer. We report the crystal structures of PP1 in complex with Nodularin-R at 1.63 Å and Tautomycin at 1.70 Å resolution. The PP1:Nodularin-R complex was used to demonstrate the utility of our improved PP1 production technique which produces highly active, soluble PP1. Tautomycin is one of the few toxins that reportedly preferentially binds PP1>PP2A. Therefore, the PP1:tautomycin structure is the first complex structure with a toxin with preferred PP1 specificity. Furthermore, since tautomycin is a linear non-peptide based toxin, our reported structure will critically aid in the design of lead compounds for novel PP1 specific pharmaceuticals.

show abstract

“…OA cellular contents have been reported to range from 0.5 pg cell −1 to 192 pg cell −1 , though large variability due to environmental factors is reported [50]. However, the importance of this strain does not lie solely in the production of OA; OA analogues (lipophilic dinophysistoxins (DTX1–3) and the water-soluble derivatives (DTX4 and DTX5a–c)) and linear polycyclic compounds and macrolides (e.g., corozalic acid, belizeanolide, belizeanic acid) are also of great interest [7,8,9,10,11,12]. Unfortunately, the monitoring of the synthesis of these metabolites in culture is not possible, since the corresponding reference standards are not commercially available, and/or a routine laboratory-scale methodology for determining them has not been reported.…”

Section: Resultsmentioning

confidence: 99%

“…P. belizeanum is commonly associated with floating detritus and sediments in tropical bays of the Caribbean Sea [45]. P. belizeanum is a known producer of okadaic acid and derivatives thereof [8,11], dinophysistoxin-1 [14] and cytotoxic macrolides [10]. …”

Section: Methodsmentioning

confidence: 99%

“…The marine dinoflagellate Prorocentrum belizeanum was selected because it is a recent source of okadaic acid analogues, polyketides and macrolides of interest (e.g., corozalic acid, belizeanolide, belizeanic acid) [7,8,9,10,11,12]. Marine dinoflagellates of the genus Prorocentrum are famous for the production of okadaic acid (OA) and its analogues, which are inhibitors of protein phosphatases types 1 (PP1) and 2A (PP2A), and causative toxins of diarrhetic shellfish poisoning (DSP) [13].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Simultaneous Effect of Temperature and Irradiance on Growth and Okadaic Acid Production from the Marine Dinoflagellate Prorocentrum belizeanum

López-Rosales

Gallardo

Sánchez-Mirón

et al. 2014

Toxins

View full text Add to dashboard Cite

Benthic marine dioflagellate microalgae belonging to the genus Prorocentrum are a major source of okadaic acid (OA), OA analogues and polyketides. However, dinoflagellates produce these valuable toxins and bioactives in tiny quantities, and they grow slowly compared to other commercially used microalgae. This hinders evaluation in possible large-scale applications. The careful selection of producer species is therefore crucial for success in a hypothetical scale-up of culture, as are appropriate environmental conditions for optimal growth. A clone of the marine toxic dinoflagellate P. belizeanum was studied in vitro to evaluate its capacities to grow and produce OA as an indicator of general polyketide toxin production under the simultaneous influence of temperature (T) and irradiance (I0). Three temperatures and four irradiance levels were tested (18, 25 and 28 °C; 20, 40, 80 and 120 µE·m−2·s−1), and the response variables measured were concentration of cells, maximum photochemical yield of photosystem II (PSII), pigments and OA. Experiments were conducted in T-flasks, since their parallelepipedal geometry proved ideal to ensure optically thin cultures, which are essential for reliable modeling of growth-irradiance curves. The net maximum specific growth rate (µm) was 0.204 day−1 at 25 °C and 40 µE·m−2·s−1. Photo-inhibition was observed at I0 > 40 μEm−2s−1, leading to culture death at 120 µE·m−2·s−1 and 28 °C. Cells at I0 ≥ 80 µE·m−2·s−1 were photoinhibited irrespective of the temperature assayed. A mechanistic model for µm-I0 curves and another empirical model for relating µm-T satisfactorily interpreted the growth kinetics obtained. ANOVA for responses of PSII maximum photochemical yield and pigment profile has demonstrated that P. belizeanum is extremely light sensitive. The pool of photoprotective pigments (diadinoxanthin and dinoxanthin) and peridinin was not able to regulate the excessive light-absorption at high I0-T. OA synthesis in cells was decoupled from optimal growth conditions, as OA overproduction was observed at high temperatures and when both temperature and irradiance were low. T-flask culture observations were consistent with preliminary assays outdoors.

show abstract

Belizeanic Acid: A Potent Protein Phosphatase 1 Inhibitor Belonging to the Okadaic Acid Class, with an Unusual Skeleton

Cited by 28 publications

References 46 publications

Okadaic Acid: More than a Diarrheic Toxin

Okadaic Acid: More than a Diarrheic Toxin

Crystal Structures of Protein Phosphatase-1 Bound to Nodularin-R and Tautomycin: A Novel Scaffold for Structure-based Drug Design of Serine/Threonine Phosphatase Inhibitors

Simultaneous Effect of Temperature and Irradiance on Growth and Okadaic Acid Production from the Marine Dinoflagellate Prorocentrum belizeanum

Contact Info

Product

Resources

About