A Model for Binding of Structurally Diverse Natural Product Inhibitors of Protein Phosphatases PP1 and PP2A

Gupta, Varsha; Ogawa, Anthony K.; Du, Xiaohui; Houk, K. N.; Armstrong, Robert W.

doi:10.1021/jm960873x

Cited by 75 publications

(55 citation statements)

References 43 publications

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“…In order to differentiate between both forms of the enzyme, more selective blockers were used. Endothall (100 nmol/l), a specific blocker of PP2A (Thièry et al 1999), completely mimicked the action of calyculin A (Table 3.2), whereas tautomycin (3 nmol/l), a specific blocker of PP1 (MacKintosh and Klumpp 1990, Gupta et al 1997), was ineffective (Table 3.2).…”

Section: Conditionmentioning

confidence: 99%

Effects of H2O2 at rat myenteric neurones in culture

Pouokam

Rehn

Diener

2009

European Journal of Pharmacology

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Section: Conditionmentioning

confidence: 99%

Effects of H2O2 at rat myenteric neurones in culture

Pouokam

Rehn

Diener

2009

European Journal of Pharmacology

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“…The crystal structure of microcystin-LR bound to PP-1c (28) and molecular modeling studies of microcystins and okadaic acid bound to PP-1 (17,18) suggest that Tyr-134 may be important for interaction with calyculins and clavosines. Three Tyr-134 PP-1c␥ mutants allowed us to thoroughly investigate the role this amino acid residue plays in inhibition of the phosphorylase a phosphatase activity of PP1c␥ by the clavosines and calyculin A (Fig.…”

Section: Inhibition Of Protein Phosphatases 1c and 2ac By The Clavosimentioning

confidence: 99%

“…The Gupta et al (18) publication proposes a direct role for Tyr-134 in calyculin binding to PP-1c. Their modeling studies propose hydrogen bonding between 1) the C-17 phosphate and C-35 hydroxyl of calyculin A with Arg-96 and 2) the C-34 hydroxyl and C-37 methoxy group of calyculin A with Tyr-134.…”

Section: Examination Of Existing Calyculin a Binding Models-a Recent mentioning

confidence: 99%

“…Clavosine A differs from clavosine B in having Z (cis) rather than E (trans) geometry at the C-2ϭC-3 double bond. Despite the large number of calyculins identified and characterized, we lack a detailed understanding of the molecular mechanisms underlying their interactions with the protein phosphatases.The mode of interaction of calyculin family members with protein phosphatases is controversial (17)(18)(19)(20). Several models found in the literature are based on the assumption that the phosphate-containing calyculins bind in the same fashion as a phosphorylated substrate or inhibitor.…”

mentioning

confidence: 99%

“…The mode of interaction of calyculin family members with protein phosphatases is controversial (17)(18)(19)(20). Several models found in the literature are based on the assumption that the phosphate-containing calyculins bind in the same fashion as a phosphorylated substrate or inhibitor.…”

mentioning

confidence: 99%

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Inhibition of Protein Phosphatase-1 by Clavosines A and B

McCready¹,

Islam²,

Schmitz³

et al. 2000

Journal of Biological Chemistry

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Site-directed mutagenesis was used to investigate the mechanism of interaction between the catalytic subunit of human protein phosphatase-1 (PP-1c␥) and members of the calyculin family of toxins. Clavosines A and B are related to calyculins but are glycosylated with a trimethoxy rhamnose group. We provide experimental evidence implicating Tyr-134 as an important residue in PP-1c␥ that mediates interactions with the calyculins. Mutation of Tyr-134 to Phe, to prevent hydrogen bond formation, resulted in a slight increase in sensitivity of PP-1c␥ to clavosines A and B and calyculin A. In contrast, a Y134A mutant was 10-fold less sensitive to inhibition by all three inhibitors. The greatest effect on inhibition was found by substituting an Asp for Tyr-134 in the phosphatase. Clavosine B inhibited PP-1c␥ Y134D with a 310-fold decrease in potency. Clavosine A and calyculin A were also markedly poorer inhibitors of this mutant. These results suggest that a hydrogen bond between Tyr-134 and the calyculins is unlikely to be essential for inhibitor binding to the phosphatase. Serine/threonine protein phosphatases are highly conserved enzymes, which have been isolated from numerous eukaryotic and prokaryotic organisms (1, 2). Eukaryotic protein phosphatases are inhibited by a structurally diverse array of natural product toxins. These include the polyether okadaic acid from marine dinoflagellates, cyclic peptide microcystins and nodularins from cyanobacteria, and the spiroketal calyculins isolated from marine sponges (3).The first member of the calyculin family of phosphatase inhibitors was identified in 1986 (4). Calyculin A was originally purified from a hydrophobic extract of the marine sponge Discodermia calyx. It was found to be cytotoxic toward P388 and L1210 leukemia cells and to be a strong inhibitor of starfish egg development (4, 5). It was subsequently characterized as a powerful inhibitor of the catalytic subunits of type 1 and 2A protein phosphatases, PP-1c 1 and PP-2Ac, two of the four major eukaryotic serine/threonine protein phosphatases (6). Calyculin A was also shown to have tumor-promoting activity as potent as that of okadaic acid (7). Many additional calyculins (8 -13), and the structurally related calyculinamides (11,14), have since been identified.Recently we reported the isolation of two novel glycosylated members of the calyculin family, clavosines A and B from the marine sponge Myriastra clavosa (15). Clavosines A and B are potent inhibitors of mammalian PP-1c and PP-2Ac and were found to be more cytotoxic overall than the calyculins and the calyculinamides (14, 15) in the National Cancer Institute (NCI) screening panel of tumor cell lines (16). The polyfunctional structure of clavosines A and B and calyculin A is depicted in linear diagrams (Fig. 1a) and space filling models (Fig. 1b). The clavosines (Fig. 1) have many structural features in common with the calyculins but differ markedly from them in having a methyl group at C-32 and an unusual trimethoxy rhamnose group at position C-21. Like the...

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Totalsynthese des marinen Naturstoffs 7-Desoxyokadasäure, eines starken Inhibitors der Serin/Threonin-spezifischen Proteinphosphatasen

1999

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Eine nur kleine Veränderung an der Struktur von Okadasäure 1, das Fehlen der Hydroxygruppe an C7, führt zum präparativ erheblich besser zugänglichen Derivat 7‐Desoxyokadasäure 2. Die Konformation von 2 stimmt mit der von 1 überein, und die Wirkung als Inhibitor der Serin/Threonin‐spezifischen Proteinphosphatasen PP‐1 und PP‐2A wird, wie kürzlich berichtet wurde, durch diese minimale Strukturvariation kaum beeinflußt.

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A Model for Binding of Structurally Diverse Natural Product Inhibitors of Protein Phosphatases PP1 and PP2A

Cited by 75 publications

References 43 publications

Effects of H2O2 at rat myenteric neurones in culture

Effects of H2O2 at rat myenteric neurones in culture

Inhibition of Protein Phosphatase-1 by Clavosines A and B

Totalsynthese des marinen Naturstoffs 7-Desoxyokadasäure, eines starken Inhibitors der Serin/Threonin-spezifischen Proteinphosphatasen

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