The Discovery of Australifungin, a Novel Inhibitor of Sphinganine N-Acyltransferase from Sporormiella australis. Producing Organism, Fermentation, Isolation, and Biological Activity.

Mandala, Suzanne; Thornton, Rosemary; Frommer, Beth R.; Curotto, James E.; Rozdilsky, Walter; Kurtz, Myra B.; Giacobbe, Robert A.; Bills, Gerald F.; Cabello, M. Angeles; Martin, I.; Peláez, Fernando; Harris, Guy H.

doi:10.7164/antibiotics.48.349

Cited by 154 publications

(109 citation statements)

References 19 publications

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“…It is interesting to note that antifungal activity was also strengthened in 2. This result correlates well with that of australifungin, 12 suggesting that the mechanism of action of 2 against fungus will be similar to australifungin. Although the antitumor activity of australifungin is still unknown, 2 possibly inhibits the tumor growth through downregulation of MAPK ( Figure 5).…”

Section: Discussionsupporting

confidence: 79%

“…It is reported that australifungin, but not australifunginol, in which b-ketoaldehyde functional group is reduced to alcohol in australifungin, inhibits sphingolipid biosynthesis and shows a highly potent antifungal activity. 12 Because the structure of 1 was very similar to australifunginol, we hypothesized that a derivative of 1, in which the alcohol functional group was oxidized to the b-ketoaldehyde in 1, could show more potent activity. We therefore synthetically derived 1 into 2, and examined the effect of 2 on tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…12 Because the structure of 1 was very similar to australifunginol, we synthetically derived 1 to NBRI17671al (2), in which the alcohol functional group was oxidized to the b-ketoaldehyde in 1. Selective oxidation of the primary alcohol of 1 should give 2 in a straightforward manner.…”

Section: Synthesis Of Nbri17671al (2)mentioning

confidence: 99%

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NBRI17671, a new antitumor compound, produced by Acremonium sp. CR17671

et al. 2010

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The interaction between the receptor for advanced glycation end-product (RAGE) and amphoterin has an important role in tumor growth and metastasis. Because the abrogation of the interaction results in the inhibition of the tumor growth and metastasis, we designed a screening system for an inhibitor of the interaction between RAGE and amphoterin. In the course of our screening of the inhibitor, we isolated a novel natural compound NBRI17671 (1) from the fermentation broth of Acremonium sp. CR17671. We also modified 1 into a more active NBRI17671al (2). Although 1 at 50 lg ml -1 weakly inhibited binding of various cells to amphoterin, 2 at 50 lg ml -1 inhibited it by >50% of control. Compound 2 effectively inhibited the tumor growth of glioma and lung tumor xenografts in mice at 25 mg kg -1 . Furthermore, 2 was found to downregulate mitogen-activated protein kinase (MAPK) activity in the tumor cells. Keywords: amphoterin; antitumor drug; natural compound; RAGE; tumor growth INTRODUCTIONThe receptor for advanced glycation end-products (RAGE) 1 is a multiligand cell surface receptor and has a critical role in various diseases such as diabetes, 2 Alzheimer's disease 3 and tumor. 4 It is reported that soluble RAGE suppresses accelerated diabetic atherosclerosis by interfering the association between advanced glycation end-products and RAGE in the cells of blood vessels. 5 Because the abrogation of the association between RAGE and a respective ligand is an attractive therapeutic target, we have especially focused on tumor therapy. Amphoterin, also known as HMGB1, is one of the ligands of RAGE,6 and is expressed at high levels in various kinds of cancers. 7 RAGE expression is not restricted to tumor cells, as cells in blood vessels also express RAGE. Thus, the interaction between RAGE and amphoterin involves not only tumor growth and motility directly, but also tumor angiogenesis. 8 Indeed, several papers reported that blockade of RAGE-amphoterin interaction suppresses tumor growth and metastasis using soluble RAGE, truncated amphoterin or antisense. 4,9,10 We therefore hypothesized that a small molecule inhibitor of the interaction between RAGE and amphoterin will become a new antitumor drug. We then designed the screening system and searched for the inhibitor. As a result, we have found a novel natural compound from a fungal strain Acremonium sp. CR17671. In this study we describe the isolation, structure determination and biological activity of NBRI17671 (1) and the synthesis and biological activity of a more active derivative of 1, (2).

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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NBRI17671, a new antitumor compound, produced by Acremonium sp. CR17671

et al. 2010

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“…Cells were disrupted with glass beads as described (12). Glass beads and cell debris were removed by centrifugation at 2000 rpm for 5 min at 4°C.…”

Section: Strains and Media-yeast Strains Listed Inmentioning

confidence: 99%

“…In Vivo Labeling of Yeast Cells-Yeast cells were labeled with either (15)(16)(17)(18)(19)(20) Ci/mmol), and radiolabeled lipids were extracted and resolved on Silica Gel 60 TLC plates as described (12). Labeled lipids were detected and quantitated by PhosphorImager (Storm, Molecular Dynamics) as recommended by the manufacturer.…”

Section: Strains and Media-yeast Strains Listed Inmentioning

confidence: 99%

Identification and Characterization of Saccharomyces cerevisiae Dihydrosphingosine-1-phosphate Phosphatase

Mao

Wadleigh

Jenkins

et al. 1997

Journal of Biological Chemistry

152

131

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We have identified the yeast sphingosine resistance gene (YSR2) of Saccharomyces cerevisiae as encoding a protein that specifically dephosphorylates dihydrosphingosine 1-phosphate (DHS-1-P), and we refer to this protein as dihydrosphingosine-1-phosphate phosphatase. Overexpression of YSR2 conferred sphingosine resistance to the dihydrosphingosine-1-P lyase-defective mutant (JS16) of S. cerevisiae, which is hypersensitive to sphingosine. The ysr2⌬ deletion mutant of S. cerevisiae accumulated DHS-1-P compared with its wild type strain upon labeling with D-erythro-[4,5-3 H]dihydrosphingosine, whereas overexpression of YSR2 increased dephosphorylation of DHS-1-P. An epitopetagged fusion protein (YSR2-Flag) was partially purified and found to specifically dephosphorylate DHS-1-P to yield dihydrosphingosine. YSR2 failed to dephosphorylate ceramide 1-phosphate or phosphatidic acid. Functionally, the mutant bearing the ysr2⌬ deletion decreased labeling of sphingolipids and increased labeling of glycerolipids dramatically following in vivo labeling with D-erythro-[ 3 H]dihydrosphingosine, but it slightly affected labeling of sphingolipids with inositol. Taken together, these results identify YSR2 as dihydrosphingosine-1-phosphate phosphatase. They also raise the intriguing possibility that phosphorylation followed by dephosphorylation is required for incorporation of exogenous long chain sphingoid bases into sphingolipids.Sphingolipids are important components of eukaryotic cell membranes. Animals develop different diseases due to genetically or environmentally altered sphingolipid metabolism (1, 2). Sphingolipids have structural functions in maintaining cell membrane integrity, and they act as anchors to proteins (3). In addition, metabolites of sphingolipids such as ceramide, sphingosine, and sphingosine 1-phosphate (S-1-P) 1 have been demonstrated to be involved as bioeffector molecules and second messengers in key events including cell growth, differentiation, cell senescence, apoptosis, and stress responses (1-5). S-1-P has a proliferative effect on certain quiescent cells and has been shown to trigger intracellular calcium mobilization (5). Platelet-derived growth factor induces an elevation in cellular levels of sphingosine and S-1-P and activates sphingosine kinase in quiescent fibroblasts. These studies imply that S-1-P participates in the mitogenic action of this and other growth factors (6).In the yeast Saccharomyces cerevisiae, sphingolipids have been demonstrated to be essential for cell viability, based on studies of long chain sphingoid base auxotrophs that are defective in serine palmitoyltransferase, the first enzyme in the de novo pathway of sphingolipid synthesis (7). Importantly, at least some sphingolipid-mediated cell events are conserved between mammalian cells and S. cerevisiae (8). For example, ceramide induces S. cerevisiae growth suppression and cell cycle arrest, and the mammalian counterpart of ceramide-activated protein phosphatase has been identified in S. cerevisiae (9).In this report, we ...

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Brave little yeast, please guide us to Thebes: sphingolipid function in S. cerevisiae

Schneiter

1999

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The Discovery of Australifungin, a Novel Inhibitor of Sphinganine N-Acyltransferase from Sporormiella australis. Producing Organism, Fermentation, Isolation, and Biological Activity.

Cited by 154 publications

References 19 publications

NBRI17671, a new antitumor compound, produced by Acremonium sp. CR17671

NBRI17671, a new antitumor compound, produced by Acremonium sp. CR17671

Identification and Characterization of Saccharomyces cerevisiae Dihydrosphingosine-1-phosphate Phosphatase

Brave little yeast, please guide us to Thebes: sphingolipid function in S. cerevisiae

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