Abstract
In the course of our screening program for a new Ca2+-signal transduction inhibitor using the hypersensitive mutant strain of Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ), new eremophilane sesquiterpenoid compounds eremoxylarins A and B were found to restore the growth inhibition caused by the hyperactivated Ca2+-signal. These compounds showed lethal activity against the mpk1Δ strain, specifically, compared to the cnb1D strain, and ion-sensitive activity against the wild-type strain in the presence of LiCl, indicating that their molecular target might be the calcineurin pathway. They inhibited calcineurin directly without immunophilins at IC50 = 2.7 and 1.4μM with competitive inhibition in vitro. The eremophilane sesquiterpenoid structure in eremoxylarins could be a good leading compound for immunosuppressants and anti-allergy drugs.
Similar content being viewed by others
Article PDF
References
Clapham DE . Calcium signaling. Cell 80: 259–268 ( 1995)
Mizunuma M, Hirata D, Miyahara K, Tsuchiya E, Miyakawa T . Role of calcineurin and Mpk 1 in regulating the onset of mitosis in budding yeast. Nature 392: 303–306 ( 1998)
Shitamukai A, Mizunuma M, Hirata D, Takahashi H, Miyakawa T . A positive screening for drugs that specifically inhibit the Ca2+-signaling activity on the basis of the growth promoting effect on a yeast mutant with a peculiar phenotype. Biosci Biotechnol Biochem 64: 1942–1946 ( 2000)
Miyakawa T, Mizunuma M . Physiological roles of calcineurin in Saccharomyces cerevisiae with special emphasis on its roles in G2/M cell-cycle regulation. Biosci Biotechnol Biochem 71: 633–645 ( 2007)
Chanklan R, Aihara E, Koga S, Takahashi H, Mizunuma M, Miyakawa T . Inhibition of Ca2+-signal-dependent growth regulation by radicicol in budding yeast. Biosci Biotechnol Biochem 72: 132–138 ( 2008)
Cunningham KW, Fink GR . Ca2+ transport in Saccharomyces cerevisiae. J Exp Biol 196: 157–166 ( 1994)
Breuder T, Hemenway CS, Movva NR, Cardenas ME, Heitman J . Calcineurin is essential in cyclosporine A- and FK506-sensitive yeast strains. Proc Natl Acad Sci USA 91: 5372–5376 ( 1994)
Mizunuma M, Hirata D, Miyaoka R, Miyakawa T . GSK-3 kinase Mck1 and calcineurin coordinately mediate Hsl1 down-regulation by Ca2+ in budding yeast. EMBO J. 20: 1074–1085 ( 2001)
Mizunuma M, Hirata D, Miyakawa T . Implication of Pkc1p protein kinase C in sustaining Cln2p level and polarized bud growth in response to calcium signaling in Saccharomyces cerevisiae. J Cell Sci 118: 4219–4229 ( 2005)
Coghlan MP, Culbert AA, Cross DAE, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Cox LR, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC . Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 7: 793–803 ( 2000)
Mann J . Natural products as immunosuppressive agents. Nat Prod Rep 18: 417–430 ( 2001)
Liu J, Farmer JDJ, Lane WS, Friedman J, Weissman I, Schreiber SL . Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66: 807–815 ( 1991)
Schwartz DJ, Wasserstrom JA, Fozzard HA . Therapeutic uses of calcium-blocking agents: verapamil, nifedipine, and diltiazem. Compr Ther 7: 25–33 ( 1981)
Martinez A, Alonso M, Castro A, Pérez C, Moreno FJ . First non-ATP competitive glycogen synthase kinase 3β (GSK-3β) inhibitors: Thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease. J Med Chem 45: 1292–1299 ( 2002)
Shiono Y, Murayama T . New eremophilane-type sesquiterpenoids, eremoxylarins A and B from Xylariaceous endophytic fungus YUA-026. Z Naturforsch 60b: 885–890 ( 2005)
Nakamura T, Ohmoto T, Hirata D, Tsuchiya E, Miyakawa T . Genetic evidence for the functional redundancy of the calcineurin- and Mpk1-mediated pathways in the regulation of cellular events important for growth in Saccharomyces cerevisiae. Mol Gen Genet 251: 211–219 ( 1996)
Nakamura T, Liu Y, Hirata D, Namba H, Harada S, Hirokawa T, Miyakawa T . Protein phosphatase type 2B (calcineurin)-mediated, FK506-sensitive regulation of intracellular ions in yeast is an important determinant for adaptation to high salt stress conditions. EMBO J 12: 4063–4071 ( 1993)
Andreeva L, Heads R, Green CJ . Cyclophilins and their possible role in the stress response. Int J EXP Path 80: 305–315 ( 1999)
Baba Y, Hirukawa N, Tanohira N, Sodeoka M . Structure based design of a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (Calcineurin). J Am Chem Soc 125: 9740–9749 ( 2003)
Singh SB, Zink D, Polishook J, Valentino D, Shafiee A, Silverman K, Felock P, Teran A, Vilella D, Hazuda DJ, Lingham RB . Structure and absolute stereochemistry of HIV-1 integrase inhibitor integric acid. A novel eremophilane sesquiterpenoid produced by Xylaria sp. Tetrahedron Lett 40: 8775–8779 ( 1999)
Puar MS, Barrabee E, Hallade M, Patel M . Sch 420789: A novel fungal metabolite with phospholipase D inhibitory activity. J Antibiot 53: 837–838 ( 2000)
McDonald LA, Barbieri LR, Bernan VS, Janso J, Lassota P, Carter GT . 07H239-A, a new cytotoxic eremophilane sesquiterpene from the marine-derived Xylariaceous Fungus LL-07H239. J Natl Prod 67: 1565–1567 ( 2004)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ogasawara, Y., Yoshida, J., Shiono, Y. et al. New Eremophilane Sesquiterpenoid Compounds, Eremoxylarins A and B Directly Inhibit Calcineurin in a Manner Independent of Immunophilin. J Antibiot 61, 496–502 (2008). https://doi.org/10.1038/ja.2008.66
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ja.2008.66
Keywords
This article is cited by
-
Studies of novel bioprobes isolated from rare natural sources using mutant yeasts
The Journal of Antibiotics (2019)
-
A new eremophilane sesquiterpene from the fungus Xylaria sp. V-27 and inhibition activity against degranulation in RBL-2H3 cells
The Journal of Antibiotics (2017)
-
New eremophilane and dichlororesorcinol derivatives produced by endophytes isolated from Ficus ampelas
The Journal of Antibiotics (2017)
-
Allantopyrone A activates Keap1–Nrf2 pathway and protects PC12 cells from oxidative stress-induced cell death
The Journal of Antibiotics (2017)
-
(4Z,15Z)‐Octadecadienoic Acid Inhibits Glycogen Synthase Kinase‐3β and Glucose Production in H4IIE Cells
Lipids (2017)