Mechanism of Action of CM-55, a Synthetic Analogue of the Antilipogenic Antibiotic Cerulenin

Ohno, Tadao; Awaya, Juichi; Kesado, Tadataka; Nomura, Setsuzō; Ōmura, Satoshi

doi:10.1128/aac.6.4.387

Cited by 11 publications

(10 citation statements)

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“…If the latter is true, exogenous fatty acids should require several hours to reverse the inhibited sporulation when added at 12 h or later to the sporulation medium. Figure 5 illustrates the results of the experiment in which the FAF from the sporulated yeast was added at 6,12,18, and 24 h after the cells were trans- Table 1, footnote b. The yeast was grown in the presporulation medium for 24 h (presporulated) and then incubated in the sporulation medium for 24 h (sporulated).…”

Section: Present Address: National Institute Of Radiologicalmentioning

confidence: 99%

“…Cells incubated in the presporulation or the sporulation medium were washed once with deionized water, and total lipids were extracted by Folch's method (3) and then saponified with 15% KOH in methanol at 65 C for 3 h, followed by the addition of an equal volume of water. After the non-saponifiable fraction had been extracted three times with light petroleum ether, the water layer was acidified with 6 (6) and yeast (18) by cerulenin thy (16). Ergosterol (To-was reversed by the addition of fatty acids and vas recrystallized in eth-ergosterol.…”

Section: Present Address: National Institute Of Radiologicalmentioning

confidence: 99%

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Inhibition of Sporulation by Cerulenin and Its Reversion by Exogenous Fatty Acids in Saccharomyces cerevisiae

Ohno

Awaya

Ōmura

1976

Antimicrob Agents Chemother

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Sporulation of Saccharomyces cerevisiae G2-2 was inhibited by the antibiotic cerulenin which is known to be a specific inhibitor of fatty acid and sterol synthesis. This inhibition was reversed by various fatty acids, especially by oleic acid (C18l:) and pentadecanoic acid (C15:0). Ergosterol showed only slight reversibility of this inhibition. When cerulenin was added to the sporulation medium later than 12 h after the start of incubation, the marked inhibition disappeared. When the fatty acid fraction extracted from the sporulated yeasts was added to the cells pretreated with cerulenin for more than 6 h, sporulation became evident 6 h after the fatty acid fraction addition. Therefore, sufficient synthesis of fatty acids required for sporulation was assumed to occur during the first 6 h in phase I of yeast sporulation. Illingworth et al. (11). Recently, Henry and Halvorson (10) tried precise analysis of this process and their study showed that much of the lipid synthesis is not sporulation specific, and that, if the necessary diploids from the auxotrophs for saturated (22) and unsaturated (23) fatty acids were constructed, these strains could be used to determine the lipid requirement during sporulation.Since it has been found that the antibiotic cerulenin is a specific inhibitor of the condensing enzyme in the fatty acid synthetase complex (24), f-ketoacyl-acyl carrier protein synthetase (1), and 3-hydroxy-3-methyl-coenzyme A synthase (19) in sterol synthesis, it was possible to examine the lipid requirement in autotrophic yeast by supplying the proper lipids in the medium containing cerulenin. This paper deals with the inhibition of sporulation of S. cerevisiae by cerulenin and its reversion by externally added fatty acids. I Present address: National Institute of RadiologicalSciences, 4-9-1, Anagawa, Chiba, Japan. 42 MATERIALS AND METHODS Culture conditions. The diploid strain of S. cerevisiae G2-2, which was kindly supplied by K. Tanaka of the Institute of Applied Microbiology, University of Tokyo, was grown on nutrient agar (14) at 27 C for 2 to 7 days. This was inoculated at a concentration of about 0.3 optical density units at 660 nm into 100 ml of the synthetic presporulation medium containing (per liter): potassium acetate, 10 g; (NH4)2SO4, 4 g; K2SO4, 4 g; Na2HPO4 12H2O, 4 g-, MgSO4-7H2O, 0.5 g; CuSO4 5H2O, 0.01 mg; ZnSO4, 7H20, 0.2 mg; FeSO4 7H2O, 20 mg; CaCl2 2H2O, 100 mg-, thiamine-hydrochloride, 0.4 mg; riboflavine, 0.2 mg; nicotinic acid, 5 mg; p-aminobenzoic acid, 0.3 mg; pyridoxine*hydrochloride, 1 mg; calcium pantothenate, 1 mg; inositol, 75 mg; biotin, 0.02 mg.Assay of sporulation. After 22 h of cultivation at 27 C on a reciprocating shaker, cells were collected by centrifugation, washed once with deionized water, and then inoculated into 6 ml of the sporulation medium (1% potassium acetate) (21) in a Monod-type tube to a population density of 0.5 optical density units at 660 nm (2.7 x 107 cells/ml), usually followed by incubation at 27 C for 24 h. Cells and two-spored (or more) asci wer...

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Section: Present Address: National Institute Of Radiologicalmentioning

confidence: 99%

Section: Present Address: National Institute Of Radiologicalmentioning

confidence: 99%

Inhibition of Sporulation by Cerulenin and Its Reversion by Exogenous Fatty Acids in Saccharomyces cerevisiae

Ohno

Awaya

Ōmura

1976

Antimicrob Agents Chemother

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“…The search for such analogs or for other antilipogenic compounds is difficult mainly because of two reasons: (i) these compounds are produced by various fungi in relatively low concentrations and usually together with other compounds such as steroidal antibiotics (9), and (ii) no sensitive, rapid, and specific method is available for the bioassay of antilipogenic compounds.…”

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confidence: 99%

“…CM-55 is a synthetic analog of cerulenin, having antilipogenic activity (9). Its mechanism of action is quite different from that of cerulenin (9).…”

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Sensitive, Rapid, and Specific Bioassay for the Determination of Antilipogenic Compounds

Ulitzur¹,

Goldberg

1977

Antimicrob Agents Chemother

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Oxidant‐Resistant Hydrogen‐Bond‐Donating Organocatalyst for Enantioselective Nucleophilic Epoxidation of α,β‐Unsaturated Amides

Kobayashi¹,

Li²,

Takemoto³

2014

Asian J Org Chem

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Bifunctional benzothiadiazine-catalyzed epoxidation of a,b-unsaturated amides proceeds efficiently to give chiral 2-oxiranecarboxamides in excellent yields of 89-99 % and with good enantioselectivity of up to 84 % ee. A synthetic application of the oxiranecarboxamides is also described.Chiral epoxides are important building blocks and can be ring-opened with a wide range of nucleophiles, with high or often complete stereo-and/or regioselectivity, to afford two continuous stereogenic centers. [1] Considerable attention has therefore been paid to, and enormous progress has been made in, the development of chiral epoxide synthesis in the last few decades. Compared with asymmetric electrophilic epoxidations, [2] including Sharpless-Katsuki epoxidation, [2a] of electron-rich alkenes, asymmetric nucleophilic epoxidations of electron-deficient alkenes have been less explored, [3] despite the importance of the produced epoxides. Among these, there has been much interest in 2-oxiranecarboxylic acids [4] and 2-oxiranecarboxamides [5] because of their high potential for further derivatization, and because they occur in several naturally occurring products such as cerulenin, [6] fusarin C, [7] and cyclopenin, [8] which have interesting biological activities (Scheme 1).Metal-catalyzed asymmetric nucleophilic epoxidation of a,b-unsaturated carboxylic acid surrogates has been developed as a method of accessing this class of oxiranes. [9] However, the synthesis is difficult to achieve using organocatalysts [10] because such catalysts are themselves potentially oxidized under the epoxidation conditions. In recent decades, however, great progress has been achieved in organocatalyzed stereoselective epoxidations of electron-poor alkenes such as a,b-unsaturated aldehydes 1 and ketones (Scheme 2, eq. 2). [11] These substrates can generally be activated by chiral primary and secondary amines via covalent bonds, and the asymmetric epoxidation proceeds highly stereoselectively through the generated chiral iminium cation intermediate. [11] Although the produced chiral oxiranecarboxaldehydes 2 can be derivatized to give the corresponding amides 4, [12] the direct synthesis of these amides by asymmetric epoxidation of a,b-unsaturated amides 3 is highly desirable in terms of redox economy (Scheme 2, eq. 2). [13] However, only a few examples have been reported to date, and the [a] Dr.

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Mechanism of Action of CM-55, a Synthetic Analogue of the Antilipogenic Antibiotic Cerulenin

Cited by 11 publications

References 11 publications

Inhibition of Sporulation by Cerulenin and Its Reversion by Exogenous Fatty Acids in Saccharomyces cerevisiae

Inhibition of Sporulation by Cerulenin and Its Reversion by Exogenous Fatty Acids in Saccharomyces cerevisiae

Sensitive, Rapid, and Specific Bioassay for the Determination of Antilipogenic Compounds

Oxidant‐Resistant Hydrogen‐Bond‐Donating Organocatalyst for Enantioselective Nucleophilic Epoxidation of α,β‐Unsaturated Amides

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