Triacsins, new inhibitors of acyl-CoA synthetase produced by Streptomyces sp.

Ōmura, Satoshi; Tomoda, Hiroshi; Xu, Qin; Takahashi, Yōko; Iwai, Yuzuru

doi:10.7164/antibiotics.39.1211

Cited by 79 publications

(51 citation statements)

References 3 publications

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“…An additional level of nutritional regulation of PNPLA3 was revealed by the observation that PNPLA3 protein levels were consistently increased by fatty acid treatment in cultured liver cells stably expressing PNPLA3 under the control of a heterologous promoter. The fatty-acid-induced increase in PNPLA3 protein levels was not blocked by triacsin C, a potent inhibitor of acyl Co-A synthetase (35) and is therefore likely to be a direct effect of fatty acids rather than a secondary consequence of TG accumulation. Taken together, these findings reveal that nutritional control of PNPLA3 is effected by a feed-forward loop that is initiated by transcriptional up-regulation and amplified by coordinate inhibition of protein degradation.…”

Section: Discussionmentioning

confidence: 96%

“…To determine whether the increase in PNPLA3 protein mass was a direct effect of the fatty acids or an indirect consequence of TG accumulation, we treated cells with 400 μM oleic acid in the presence of triacsin C, a fungal metabolite that inhibits long fatty acyl CoA synthetase (35). Inhibition of TG synthesis by triacsin C did not attenuate the increase in PNPLA3 associated with oleate treatment (Fig.…”

Section: Transcriptional Regulation Of Expression Of Pnpla3 By Fastinmentioning

confidence: 99%

“…The boxed sequence matches the recently described SREBP-1 binding motif (32) with a z score of 4.421 (Materials and Methods). 35 S-labeled methionine/cysteine was added. One hour later the medium was changed to complete medium and the cells were grown for the indicated times.…”

Section: Fas Pnpla3mentioning

confidence: 99%

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A feed-forward loop amplifies nutritional regulation of PNPLA3

Huang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

334

347

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The upsurge in prevalence of obesity has spawned an epidemic of nonalcoholic fatty liver disease (NAFLD). Previously, we identified a sequence variant (I148M) in patatin-like phospholipase domaincontaining protein 3 (PNPLA3) that confers susceptibility to both hepatic triglyceride (TG) deposition and liver injury. To glean insights into the biological role of PNPLA3, we examined the molecular mechanisms by which nutrient status controls hepatic expression of PNPLA3. PNPLA3 mRNA levels, which were low in fasting animals, increased ∼90-fold with carbohydrate feeding. The increase was mimicked by treatment with a liver X receptor (LXR) agonist and required the transcription factor SREBP-1c. The site of SREBP-1c binding was mapped to intron 1 of Pnpla3 using chromatin immunoprecipitation and electrophoretic mobility shift assays. SREBP-1c also promotes fatty acid synthesis by activating several genes encoding enzymes in the biosynthetic pathway. Addition of fatty acids (C16:0, C18:1, and C18:2) to the medium of cultured hepatocytes (HuH-7) increased PNPLA3 protein mass without altering mRNA levels. The posttranslational increase in PNPLA3 levels persisted after blocking TG synthesis with triascin C. Oleate (400 μM) treatment prolonged the half-life of PNPLA3 from 2.4 to 6.7 h. These findings are consistent with nutritional control of PNPLA3 being effected by a feed-forward loop; SREBP-1c promotes accumulation of PNPLA3 directly by activating Pnpla3 transcription and indirectly by inhibiting PNPLA3 degradation through the stimulation of fatty acid synthesis.adiponutrin | SREBP-1c | triglycerides | hepatic steatosis

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Section: Discussionmentioning

confidence: 96%

Section: Transcriptional Regulation Of Expression Of Pnpla3 By Fastinmentioning

confidence: 99%

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A feed-forward loop amplifies nutritional regulation of PNPLA3

Huang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

334

347

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“…Triacsin C is a fungal metabolite that resembles polyunsaturated fatty acids and can differentially inhibit various ACLs (Fig. 6, inset) (Omura et al, 1986;Hartman et al, 1989;Kim et al, 2001). The observed IC 50 for triacsin C to inhibit the thioesterification of palmitic acid with CoA by CpPKS1-AL was 6.64 μM (Fig.…”

Section: Enzyme Kinetics Of the Al Domainmentioning

confidence: 99%

Functional characterization of the acyl-[acyl carrier protein] ligase in the Cryptosporidium parvum giant polyketide synthase

Fritzler

Zhu

2007

International Journal for Parasitology

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The apicomplexan Cryptosporidium parvum possesses a unique 1,500-kDa polyketide synthase (CpPKS1) comprised of 29 enzymes for synthesizing a yet undetermined polyketide. This study focuses on the biochemical characterization of the 845-amino acid loading unit containing acyl-[ACP] ligase (AL) and acyl carrier protein (ACP). The CpPKS1-AL domain has a substrate preference for long chain fatty acids, particularly for the C20:0 arachidic acid. When using [ 3 H] palmitic acid and CoA as co-substrates, the AL domain displayed allosteric kinetics towards palmitic acid (Hill coefficient, h = 1.46, K 50 = 0.751 μM, V max = 2.236 μmol mg −1 min −1 ) and CoA (h = 0.704, K 50 = 5.627 μM, V max = 0.557 μmol mg −1 min −1 ), and biphasic kinetics towards adenosine 5′-triphosphate (K m1 = 3.149 μM, V max1 = 373.3 nmol mg −1 min −1 , K m2 = 121.0 μM, and V max2 = 563.7 nmol mg −1 min −1 ). The AL domain is Mg 2+ -dependent and its activity could be inhibited by triacsin C (IC 50 = 6.64 μM). Furthermore, the ACP domain within the loading unit could be activated by the C. parvum surfactin production element-type phosphopantetheinyl transferase. After attachment of the fatty acid substrate to the AL domain for conversion into the fatty-acyl intermediate, the AL domain is able to transfer palmitic acid to the activated holo-ACP in vitro. These observations ultimately validate the function of the CpPKS1-AL-ACP unit, and make it possible to further dissect the function of this megasynthase using recombinant proteins in a stepwise procedure.

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“…Acyl-CoA synthetase (ACS) was assayed by using NEFA C-test kit (Wako Pure Chemical) according to the method described previously [19].…”

Section: Assay For Acyl-coa Synthetasementioning

confidence: 99%

Sespendole, a New Inhibitor of Lipid Droplet Synthesis in Macrophages, Produced by Pseudobotrytis terrestris FKA-25

et al. 2006

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Sespendole was isolated as an inhibitor of lipid droplet formation in macrophages from the culture broth of a fungal strain Pseudobotrytis terrestris FKA-25. The compound inhibited the synthesis of cholesteryl ester and triacylglycerol by mouse macrophages with IC 50 values of 4.0 and 3.2 mM, respectively.Keywords sespendole, lipid droplet synthesis, fungal metabolites, Pseudobotrytis terrestris, indolosesquiterpene IntroductionOur research group has focused on discovery of biological active compounds from microbial metabolites [1ϳ8]. Lipid droplet synthesis in macrophages is an early event in the process of macrophage foam cell formation, which leads to arteriosclerosis. During the course of screening for leads of anti-arteriosclerotic agents from microorganisms [9], a fungal strain FKA-25, identified as Pseudobotrytis terrestris [10,11], was found to produce an inhibitor of lipid droplet synthesis in macrophages. A novel compound designated sespendole with a unique diprenyl indolosesquiterpene skeleton (Fig. 1) was isolated from the culture broth. Previously indoloditerpene terpendoles [12ϳ14] were discovered as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT) isolated from the culture broth of a fungus Albophoma [15]. The structure elucidation and biosynthesis of sespendole will be reported in the near future. In this paper, fermentation, isolation and biological properties of sespendole are described.Furthermore, the inhibitory effects of sespendole and terpendole on lipid droplet formation in macrophages are compared. Materials and Methods Fermentation MediaFor production of sespendole, the seed medium was used containing 2.0% glucose, 0.2% yeast extract (Oriental Yeast Co.), 0.05% MgSO 4 · 7H 2 O, 0.5% Polypepton (Daigo Nutritive Chemicals), 0.1% KH 2 PO 4 and 0.1% agar. The pH was adjusted to 6.0 prior to sterilization. The production

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Triacsins, new inhibitors of acyl-CoA synthetase produced by Streptomyces sp.

Cited by 79 publications

References 3 publications

A feed-forward loop amplifies nutritional regulation of PNPLA3

A feed-forward loop amplifies nutritional regulation of PNPLA3

Functional characterization of the acyl-[acyl carrier protein] ligase in the Cryptosporidium parvum giant polyketide synthase

Sespendole, a New Inhibitor of Lipid Droplet Synthesis in Macrophages, Produced by Pseudobotrytis terrestris FKA-25

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