Smooth muscle myosin phosphatase inhibition and force enhancement by black sponge toxin

Takai, Akira; Bialojan, Corinna; Troschka, Monika; Rüegg, J. C.

doi:10.1016/0014-5793(87)81247-4

Cited by 269 publications

(141 citation statements)

References 10 publications

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“…If okadaic acid and calyculin A acted on only protein phosphatases which dephosphorylate substrates phosphorylated by these protein kinases, they would potentiate glucose-induced insulin release by increasing the phosphorylation state as they inhibited the myosin light chain phosphatase and enhanced tension development in smooth muscle fibers [9,11]. Our experiments show this is not the case.…”

mentioning

confidence: 85%

Effects of the Protein Phosphatase Inhibitors Okadaic Acid and Calyculin A on Insulin Release from Rat Pancreatic Islets.

et al. 1992

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mentioning

confidence: 85%

Effects of the Protein Phosphatase Inhibitors Okadaic Acid and Calyculin A on Insulin Release from Rat Pancreatic Islets.

et al. 1992

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“…In 1987 it was realized that okadaic acid potently and specifically inhibits PP-1c and PP-2Ac (48), with the IC 50 for the toxin being two orders of magnitude lower for PP-2Ac inhibition (IC 50 of 0.2 nM) than for PP-1c inhibition (IC 50 of 20 nM) (49) (Note: the IC 50 values discussed in this article are in vitro values and are for comparison purposes.…”

Section: Okadaic Acid As a Potent Inhibitor Of Protein Phosphatasesmentioning

confidence: 99%

Molecular mechanisms underlying inhibition of protein phosphatases by marine toxins

Dawson¹

1999

Front Biosci

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“…OA is a tumor-promoting C 38 polyether fatty acid produced by marine dinoflagellates (1,(3)(4)(5)(6). OA contains acidic and hydrophobic moieties and is cyclic (via an intramolecular hydrogen bond) (6).…”

mentioning

confidence: 99%

Crystal Structure of the Tumor-promoter Okadaic Acid Bound to Protein Phosphatase-1

Maynes¹,

Bateman²,

Cherney³

et al. 2001

Journal of Biological Chemistry

154

143

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Protein phosphatase-1 (PP1) plays a key role in dephosphorylation in numerous biological processes such as glycogen metabolism, cell cycle regulation, smooth muscle contraction, and protein synthesis. Microorganisms produce a variety of inhibitors of PP1, which include the microcystin class of inhibitors and okadaic acid, the latter being the major cause of diarrhetic shellfish poisoning and a powerful tumor promoter. We have determined the crystal structure of the molecular complex of okadaic acid bound to PP1 to a resolution of 1.9 Å. This structure reveals that the acid binds in a hydrophobic groove adjacent to the active site of the protein and interacts with basic residues within the active site. Okadaic acid exhibits a cyclic structure, which is maintained via an intramolecular hydrogen bond. This is reminiscent of other macrocyclic protein phosphatase inhibitors. The inhibitor-bound enzyme shows very little conformational change when compared with two other PP1 structures, except in the inhibitor-sensitive ␤12-␤13 loop region. The selectivity of okadaic acid for protein phosphatases-1 and -2A but not PP-2B (calcineurin) may be reassessed in light of this study.The phosphorylation and dephosphorylation of proteins is vital to the regulation of many cellular pathways and processes. Two classes of enzymes in the cell that catalyze cellular dephosphorylation activity are tyrosine phosphatases and serine/threonine phosphatases (1). Classification of serine/threonine phosphatases can be subdivided into four categories: protein phosphatase-1 (PP1), 1 -2A (PP2A), -2B(PP2B) and -2C (PP2C) (2). The first three of these categories comprise what is known as the PPP family of protein phosphatases since they contain extensive sequence similarity in their catalytic domains and little or no sequence homology to PP2C or to tyrosine phosphatases. There are several natural toxin inhibitors of the PPP family of enzymes. These include microcystins, calyculins, tautomycin and okadaic acid (OA) ( Fig. 1) (1).OA is a tumor-promoting C 38 polyether fatty acid produced by marine dinoflagellates (1, 3-6). OA contains acidic and hydrophobic moieties and is cyclic (via an intramolecular hydrogen bond) (6). This toxin can accumulate in filter-feeding organisms and is the principle cause of diarrhetic shellfish poisoning worldwide (4).There have been many biochemical and modeling studies on the inhibition of the PPP family of phosphatases by the natural toxins, but the lone crystal structure is of microcystin-LR (MCLR) bound to PP1 (␣ isoform) (8). Here we describe the crystal structure of OA bound to the recombinant catalytic subunit of PP1 (␥ isoform). EXPERIMENTAL PROCEDURESCrystallization-The catalytic subunit of protein phosphatase-1 ␥ isoform was purified as described previously (9, 10). OA was purified from Prorocentrum lima (9, 10). Crystals were obtained by the hanging drop vapor diffusion method at room temperature. The enzyme and inhibitor were mixed in a 1:2 molar ratio with the concentration of protein being ϳ0.4 mM. The P...

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Smooth muscle myosin phosphatase inhibition and force enhancement by black sponge toxin

Cited by 269 publications

References 10 publications

Effects of the Protein Phosphatase Inhibitors Okadaic Acid and Calyculin A on Insulin Release from Rat Pancreatic Islets.

Effects of the Protein Phosphatase Inhibitors Okadaic Acid and Calyculin A on Insulin Release from Rat Pancreatic Islets.

Molecular mechanisms underlying inhibition of protein phosphatases by marine toxins

Crystal Structure of the Tumor-promoter Okadaic Acid Bound to Protein Phosphatase-1

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