Studies on new vasodilators, WS-1228 A and B. II. Structure and synthesis.

Tanaka, Hirokazu; Yoshida, Keizo; Itoh, Yoshikuni; Imanaka, Hiroshi

doi:10.7164/antibiotics.35.157

Cited by 23 publications

(13 citation statements)

References 4 publications

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“…Triacsin C is one of four related compounds (triacsins A, B, C, and D) originally isolated from culture media of Streptomyces sp. strain SK-1894 (15,29,30). All are 11-carbon alkenyl-1-hydroxytriazenes (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Triacsin C is the only one of the four that is readily commercially available. Originally, triacsins C and D were identified as vasodilators (29,30), but subsequently all were found to inhibit ACSLs, with triacsins A and C being the most potent (16). This inhibition was found to be competitive with respect to the fatty acid but noncompetitive with respect to CoA and ATP (16).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of RPE65 Retinol Isomerase Activity by Inhibitors of Lipid Metabolism

Eroglu

Gentleman

Poliakov

et al. 2016

Journal of Biological Chemistry

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RPE65 is the isomerase catalyzing conversion of all-transretinyl ester (atRE) into 11-cis-retinol in the retinal visual cycle. Crystal structures of RPE65 and site-directed mutagenesis reveal aspects of its catalytic mechanism, especially retinyl moiety isomerization, but other aspects remain to be determined. To investigate potential interactions between RPE65 and lipid metabolism enzymes, HEK293-F cells were transfected with expression vectors for visual cycle proteins and co-transfected with either fatty acyl:CoA ligases (ACSLs) 1, 3, or 6 or the SLC27A family fatty acyl-CoA synthase FATP2/SLCA27A2 to test their effect on isomerase activity. These experiments showed that RPE65 activity was reduced by co-expression of ACSLs or FATP2. Surprisingly, however, in attempting to relieve the ACSL-mediated inhibition, we discovered that triacsin C, an inhibitor of ACSLs, also potently inhibited RPE65 isomerase activity in cellulo. We found triacsin C to be a competitive inhibitor of RPE65 (IC 50 ‫؍‬ 500 nM). We confirmed that triacsin C competes directly with atRE by incubating membranes prepared from chicken RPE65-transfected cells with liposomes containing 0 -1 M atRE. Other inhibitors of ACSLs had modest inhibitory effects compared with triascin C. In conclusion, we have identified an inhibitor of ACSLs as a potent inhibitor of RPE65 that competes with the atRE substrate of RPE65 for binding. Triacsin C, with an alkenyl chain resembling but not identical to either acyl or retinyl chains, may compete with binding of the acyl moiety of atRE via the alkenyl moiety. Its inhibitory effect, however, may reside in its nitrosohydrazone/ triazene moiety.The process of vision begins in the photoreceptor outer segments of the retina with absorption of a photon of light by the 11-cis-retinylidene chromophore ligand of photoreceptor visual pigment opsins, such as rhodopsin. This event photoisomerizes the 11-cis-retinal to the all-trans-isomer, thereby activating the rhodopsin to metarhodopsin and initiating the phototransduction pathway that results in transmission of a signal, via retinal interneurons, for central processing in brain visual centers. Upon completion of the phototransduction cascade processes, the all-trans-retinal releases from its Schiff base linkage following decay of metarhodopsin and is reduced to all-trans-retinol and transported to the retinal pigment epithelium (RPE), 2 a monolayer epithelium apposed to the photoreceptor outer segments. To regenerate the visual pigment, input of 11-cis-retinal is required. This is provided by enzymatic isomerization in the RPE of the esterified all-trans-retinol in a process termed the visual cycle. RPE65 is the key isomerase in the RPE visual cycle that catalyzes the conversion of all-transretinyl ester (atRE) into 11-cis-retinol (1-3). RPE65 is a member of a family of carotenoid oxygenases that has evolved to become a retinol isomerase in the vertebrate retinal visual cycle (4). Recent crystal structures of RPE65 (5-7) and site-directed mutagenesis studies (8, 9) have ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of RPE65 Retinol Isomerase Activity by Inhibitors of Lipid Metabolism

Eroglu

Gentleman

Poliakov

et al. 2016

Journal of Biological Chemistry

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“…Various triascin C analogs were synthesized from ( E,E,E )-2,4,7-undecatrienal ( 1 ), which was prepared by a modification of the reported procedure [16, 17] (Scheme 1). Hence, bromination of ( E )-2-hexen-1-ol ( 2 ) with phosphorus tribromide in dichloromethane followed by a displacement reaction with 3-(tetrahydropyranyloxy)propynyl magnesium bromide and a catalytic amount of copper cyanide afforded enyne 3 .…”

Section: Chemistrymentioning

confidence: 99%

Novel triacsin C analogs as potential antivirals against rotavirus infections

Kim

George

Prior

et al. 2012

European Journal of Medicinal Chemistry

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Recently our group has demonstrated that cellular triglycerides (TG) levels play an important role in rotavirus replication. In this study, we further examined the roles of the key enzymes for TG synthesis (lipogenesis) in the replication of rotaviruses by using inhibitors of fatty acid synthase, long chain fatty acid acyl-CoA synthetase (ACSL), and diacylglycerol acyltransferase and acyl-CoA:cholesterol acyltransferase in association with lipid droplets of which TG is a major component. Triacsin C, a natural ACSL inhibitor from Streptomyces aureofaciens, was found to be highly effective against rotavirus replication. Thus, novel triacsin C analogs were synthesized and evaluated for their efficacies against the replication of rotaviruses in cells. Many of the analogs significantly reduced rotavirus replication, and one analog (1e) was highly effective at a nanomolar concentration range (ED50 0.1 μM) with a high therapeutic index in cell culture. Our results suggest a crucial role of lipid metabolism in rotavirus replication, and triacsin C and/or its analogs as potential therapeutic options for rotavirus infections.

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“…Strain SK-1894 [1,2]. Triacsins C and D were initially identified as vasodilators [1]. Subsequently, it was found that triacsins A, B, C, and D were inhibitors of long-chain acyl-CoA synthetase (longchain fatty acid:CoA ligase) [2].…”

Section: Introductionmentioning

confidence: 99%

Characterization of triacsin C inhibition of short‐, medium‐, and long‐chain fatty acid:CoA ligases of human liver

Vessey

Kelley

Warren

2004

J Biochem & Molecular Tox

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Short-, medium-, and long-chain fatty acid:CoA ligases from human liver were tested for their sensitivity to inhibition by triacsin C. The short-chain fatty acid:CoA ligase was inhibited less than 10% by concentrations of triacsin C as high as 80 microM. The two mitochondrial xenobiotic/medium-chain fatty acid:CoA ligases (XM-ligases), HXM-A and HXM-B, were partially inhibited by triacsin C, and the inhibitions were characterized by low affinity for triacsin C (K(I) values > 100 microM). These inhibitions were found to be the result of triacsin C competing with medium-chain fatty acid for binding at the active site. The microsomal and mitochondrial forms of long-chain fatty acid:CoA ligase (also termed long-chain fatty acyl-CoA synthetase, or long-chain acyl-CoA synthetase LACS) were potently inhibited by triacsin C, and the inhibition had identical characteristics for both LACS forms. Dixon plots of this inhibition were biphasic. There is a high-affinity site with a K(I) of 0.1 microM that accounts for a maximum of 70% of the inhibition. There is also a low affinity site with a K(I) of 6 microM that accounts for a maximum of 30% inhibition. Kinetic analysis revealed that the high-affinity inhibition of the mitochondrial and microsomal LACS forms is the result of triacsin C binding at the palmitate substrate site. The high-affinity triacsin C inhibition of both the mitochondrial and microsomal LACS forms was found to require a high concentration of free Mg(2+), with the EC(50) for inhibition being 3 mM free Mg(2+). The low affinity triacsin C inhibition was also enhanced by Mg(2+). The data suggests that Mg(2+) promotes triacsin C inhibition of LACS by enhancing binding at the palmitate binding site. In contrast, the partial inhibition of the XM-ligases by triacsin C, which showed only a low-affinity component, did not require Mg(2+).

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Studies on new vasodilators, WS-1228 A and B. II. Structure and synthesis.

Cited by 23 publications

References 4 publications

Inhibition of RPE65 Retinol Isomerase Activity by Inhibitors of Lipid Metabolism

Inhibition of RPE65 Retinol Isomerase Activity by Inhibitors of Lipid Metabolism

Novel triacsin C analogs as potential antivirals against rotavirus infections

Characterization of triacsin C inhibition of short‐, medium‐, and long‐chain fatty acid:CoA ligases of human liver

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