The Action Mechanism of Cerulenin

Nomura, Setsuzō; Horiuchi, Tadashi; Ōmura, Satoshi; Hata, Tōju

doi:10.1093/oxfordjournals.jbchem.a129827

Cited by 91 publications

(32 citation statements)

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“…Occurs following Introduction of Inositol-Cerulenin, an antibiotic known to block de novo fatty acid biosynthesis, has been used in a number of other studies in yeast to block de novo fatty acid biosynthesis (29,32,33). We observed a decrease of ϳ50% in total label from 14 C acetate incorporated into both phospholipids and neutral lipids during the first 30 min of exposure to cerulenin in wild type cells treated with 10 g/ml cerulenin compared with an untreated control.…”

Section: Blocking De Novo Fatty Acid Metabolism With Cerulenin Substamentioning

confidence: 75%

“…Short Time Course Labeling in the Presence of Cerulenin-In order to measure the effects of inhibition of de novo fatty acid synthesis on phospholipid synthesis, wild type cells were grown in I Ϫ C ϩ medium at midlogarithmic phase (A 600 ϭ 0.5) and were exposed to different concentrations of cerulenin, an inhibitor of de novo fatty acid synthesis (29). Protocols similar to those described above for short term labeling with either 1 Ci/ml [1-14 C]acetate or 100 Ci/ml [ 32 P]orthophosphate were carried out.…”

Section: Methodsmentioning

confidence: 99%

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Inositol Induces a Profound Alteration in the Pattern and Rate of Synthesis and Turnover of Membrane Lipids in Saccharomyces cerevisiae

Gaspar

Aregullin

Jesch

et al. 2006

Journal of Biological Chemistry

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The addition of inositol to actively growing yeast cultures causes a rapid increase in the rate of synthesis of phosphatidylinositol and, simultaneously, triggers changes in the expression of hundreds of genes. We now demonstrate that the addition of inositol to yeast cells growing in the presence of choline leads to a dramatic reprogramming of cellular lipid synthesis and turnover. The response to inositol includes a 5-6-fold increase in cellular phosphatidylinositol content within a period of 30 min. The increase in phosphatidylinositol content appears to be dependent upon fatty acid synthesis. Phosphatidylcholine turnover increased rapidly following inositol addition, a response that requires the participation of Nte1p, an endoplasmic reticulum-localized phospholipase B. Mass spectrometry revealed that the acyl species composition of phosphatidylinositol is relatively constant regardless of supplementation with inositol or choline, whereas phosphatidylcholine acyl species composition is influenced by both inositol and choline. In medium containing inositol, but lacking choline, high levels of dimyristoylphosphatidylcholine were detected. Within 60 min following the addition of inositol, dimyristoylphosphatidylcholine levels had decreased from ϳ40% of total phosphatidylcholine to a basal level of less than 5%. nte1⌬ cells grown in the absence of inositol and in the presence of choline exhibited lower levels of dimyristoylphosphatidylcholine than wild type cells grown under these same conditions, but these levels remained largely constant after the addition of inositol. These results are discussed in relationship to transcriptional regulation known to be linked to lipid metabolism in yeast.

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Section: Blocking De Novo Fatty Acid Metabolism With Cerulenin Substamentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Inositol Induces a Profound Alteration in the Pattern and Rate of Synthesis and Turnover of Membrane Lipids in Saccharomyces cerevisiae

Gaspar

Aregullin

Jesch

et al. 2006

Journal of Biological Chemistry

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“…For all strains that we have examined (5; this paper), cerulenin has consistently shown low MICs and increased levels of activity when used in combination with antimicrobial agents at sublethal concentrations. Cerulenin is an inhibitor of fatty acid synthesis but is not useful as an antimicrobial agent because it is metabolized rapidly in the host (25,26). Even so, the data in this paper suggest that the fatty acid synthetase system would be a plausible biosynthetic target for drugs developed in the future.…”

Section: Discussionmentioning

confidence: 99%

Potential drug targets for Mycobacterium avium defined by radiometric drug-inhibitor combination techniques

Rastogi

Goh

Wright

et al. 1994

Antimicrob Agents Chemother

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Previously established radiometric techniques were used to assess the effectiveness of combined antimicrobial drug-inhibitory drug (drug-inhibitor) treatment on two clinical isolates of the Mycobacterium avium complex representing three colony variants: smooth opaque (dome) (SmO), smooth transparent (SmT), and rough (Rg). All variants were identified as members of the M. avium complex; however, only the SmT colony type of strain 373 possessed characteristic serovar-specific glycopeptidolipid (GPL) antigens. MICs, determined radiometrically, of drugs with the potential to inhibit the biosynthesis of GPL antigens or other cell envelope constituents were similar for all strains. These drugs included cerulenin, N-carbamyl-DL-phenylala- 581-2139. Fax: (205) 581-2877. properties (3,9,27) and may play a role in pathogenicity, in addition to their possible contribution to drug resistance.In an effort to design effective drug therapy for the treatment ofM. avium, we used a combined drug-inhibitor treatment that would potentially inhibit GPL biosynthesis, thereby affecting cell envelope architecture and thus allowing more effective use of antimicrobial agents that have demonstrated efficacy in M. avium therapy. For this strategy, we used drugs that have the potential to affect GPL biosynthesis at three sites: glycosylation, peptide biosynthesis, and fatty acid biosynthesis. We have reported that this approach is capable of producing a synergistic effect when drugs which potentially inhibit GPL biosynthesis are used in combination with amikacin, sparfloxacin, and clarithromycin (5). Those studies were an extension of an earlier report of combined treatment with m-fluoro-phenylalanine, an inhibitor GPL biosynthesis (14), and ethambutol, an inhibitor of arabinogalactan biosynthesis (36). That combination was effective in producing synergistic growth inhibition of M. avium (32).In our most recent publication regarding this combined drug-inhibitor treatment we used laboratory-maintained isolates: a smooth opaque (dome) (SmO) and a rough (Rg) variant of M. avium serovar 4 (5). In this report we extend our observations to a clinical isolate which presented with the SmO colony morphology upon initial isolation on LowensteinJensen medium but, upon successive subculturing on 7H9 agar, segregated into distinct colony morphotypes: smooth transparent (SmT), SmO, and Rg. All three morphotypes were identified as members of the M. avium complex. We also examined the effects of combined drug-inhibitor treatment on another Rg clinical isolate to confirm the difference in susceptibility that we observed for Rg and Sm colony variants. Internal radiolabeling techniques were used to confirm the presence or

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“…It is known that cerulenin inhibits fatty acid synthetase (26,27) (or important to overall cell envelope integrity) in the rough variant than in the smooth variant. This would be one explanation for the synergistic effect of N-carbamyl-L-isoleucine and m-fluorophenylalanine observed with the antimicrobial agents sparfloxacin, clarithromycin, and amikacin.…”

Section: Discussionmentioning

confidence: 99%

“…This may be further evidence substantiating our suggestions regarding the importance of the phenylalanine-containing lipopeptides in cell envelope integrity. Because cerulenin is an inhibitor of fatty acid synthetase (26), it is very likely that those lipid-containing components are also affected by treatment with cerulenin.…”

Section: Discussionmentioning

confidence: 99%

Activities of fluoroquinolone, macrolide, and aminoglycoside drugs combined with inhibitors of glycosylation and fatty acid and peptide biosynthesis against Mycobacterium avium

Barrow

Wright

Goh

et al. 1993

Antimicrob Agents Chemother

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Smooth-and rough-colony variants of Mycobacterium avium serovar 4 were treated with three classes of drugs. The drugs were chosen for their potential inhibitory effects on the biosynthesis of the cell envelopeassociated serovar-specific glycopeptidolipid antigens. Growth was monitored radiometrically with a BACTEC 460-TB instrument, and MICs were determined for each drug. Both variants were then treated with inhibitory drugs in combination with antimicrobial agents that have demonstrated effectiveness against M. avium. No growth inhibition was observed with 6-fluoro-6-deoxy-D-glucose or avidin. Inhibitors of glycosylation, i.e., 2-deoxy-D-glucose, bacitracin, and ethambutol, were inhibitory to smooth-and rough-colony variants, whereas drugs that inhibit peptide synthesis, i.e., N-carbamyl-L-isoleucine and m-fluoro-phenylalanine, were more inhibitory for the rough-colony variant. Cerulenin, which affects fatty acid synthesis, was inhibitory for both variants, but it appeared to be more effective at inhibiting the growth of the smooth-colony variant at equivalent concentrations. Generally, when inhibitors of glycosylation were used with sparfloxacin and amikacin, a synergistic effect was observed for only the smooth variant. When drugs that affect peptide synthesis were used in combination with amikacin, a synergistic effect was observed for the rough variant, and when cerulenin was used in combination with sparfloxacin or amikacin, a synergistic effect was observed for both variants. Lipid analysis revealed that although the rough variant lacks the serovar-specific glycopeptidolipid antigens, it does possess a group of phenylalanine-isoleucine-containing lipopeptides that may explain its different susceptibility patterns to m-fluoro-phenylalanine and N-carbamyl-L-isoleucine. The significance of these results is discussed with reference to various components in the cell envelope and their importance in cell wall permeability.The new emphasis of the National Institute of Allergy and Infectious Diseases is "to spark efforts" to better understand the opportunistic infections associated with AIDS so that new and effective treatments can be developed (45). A major obstacle preventing the development of better therapies for those opportunistic pathogens is a "basic lack of knowledge about the pathogens that cause such diseases" (45). The Mycobacterium avium complex represents one of the most important groups of opportunistic pathogens infecting patients with AIDS (23,45 Rastogi et al. (33) proposed that a polysaccharide outer layer may be responsible for the impermeability of smoothtransparent variants to various substrates and drugs and also increased pathogenicity. The presence of the fibrillar material described by Draper (13) and Kim et al. (21) and later referred to as the superficial L, layer (2) may also be important as a barrier because of the polar glycopeptidolipids (GPLs) that make up its superficial location (4, 6, 44). Crowle et al. (9) suggested that both the polysaccharide layer (32, 33) and the GPL layer...

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The Action Mechanism of Cerulenin

Cited by 91 publications

References 0 publications

Inositol Induces a Profound Alteration in the Pattern and Rate of Synthesis and Turnover of Membrane Lipids in Saccharomyces cerevisiae

Inositol Induces a Profound Alteration in the Pattern and Rate of Synthesis and Turnover of Membrane Lipids in Saccharomyces cerevisiae

Potential drug targets for Mycobacterium avium defined by radiometric drug-inhibitor combination techniques

Activities of fluoroquinolone, macrolide, and aminoglycoside drugs combined with inhibitors of glycosylation and fatty acid and peptide biosynthesis against Mycobacterium avium

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