Long-chain fatty acyl-coenzyme A-induced inhibition of glucokinase in pancreatic islets from rats depleted in long-chain polyunsaturated ω3 fatty acids

We determined the structural features necessary for fatty acids to exert their action on K+ channels of gastric smooth muscle cells. Examination of the effects of a variety of synthetic and naturally occurring lipid compounds on K+ channel activity in cell-attached and excised membrane patches revealed that negatively charged analogs of medium to long chain fatty acids (but not short chain analogs) as well as certain other negatively charged lipids activate the channels. In contrast, positively charged, medium to long chain analogs suppress activity, and neutral analogs are without effect. The key requirements for effective compounds seem to be a sufficiently hydrophobic domain and the presence of a charged group. Furthermore, those negatively charged compounds unable to "flip" across the bilayer are effective only when applied at the cytosolic surface of the membrane, suggesting that the site of fatty acid action is also located there. Finally, because some of the effective compounds, for example, the fatty acids themselves, lysophosphatidate, acyl Coenzyme A, and sphingosine, are naturally occurring substances and can be liberated by agonist-activated or metabolic enzymes, they may act as second messengers targeting ion channels.

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Steady-state concentrations of coenzyme A, acetyl-coenzyme A and long-chain fatty acyl-coenzyme A in rat-liver mitochondria oxidizing palmitate

Biochemical Journal ◽

10.1042/bj0970587 ◽

1965 ◽

Vol 97 (2) ◽

pp. 587-594 ◽

Cited By ~ 206

Author(s):

PB Garland ◽

D Shepherd ◽

DW Yates

Keyword(s):

Rat Liver ◽

Coenzyme A ◽

Liver Mitochondria ◽

Fatty Acyl ◽

Rat Liver Mitochondria ◽

Beta Oxidation ◽

Acetyl Coa ◽

Acetyl Coenzyme A ◽

Acyl Coenzyme A ◽

Long Chain

1. Fluorimetric assays are described for CoASH, acetyl-CoA and long-chain fatty acyl-CoA, and are sensitive to at least 50mumumoles of each. 2. Application of these assays to rat-liver mitochondria oxidizing palmitate in the absence and presence of carnitine indicated two pools of intramitochondrial CoA. One pool could be acylated by palmitate and ATP, and the other pool acylated by palmitate with ATP and carnitine, or by palmitoylcarnitine alone. 3. The intramitochondrial content of acetyl-CoA is increased by the oxidation of palmitate both in the absence and presence of l-malate. 4. The conversion of palmitoyl-CoA into acetyl-CoA by beta-oxidation takes place without detectable accumulation of acyl-CoA intermediates.

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Long-Chain Acyl–Coenzyme A Esters and Fatty Acids Directly Link Metabolism to KATPChannels in the Heart

Circulation Research ◽

10.1161/hh0901.089881 ◽

2001 ◽

Vol 88 (9) ◽

pp. 918-924 ◽

Cited By ~ 70

Author(s):

Gong Xin Liu ◽

Peter J. Hanley ◽

John Ray ◽

ürgen Daut;

Keyword(s):

Fatty Acids ◽

Coenzyme A ◽

Chain Acyl ◽

Acyl Coenzyme A ◽

Coenzyme A Esters ◽

Long Chain

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Acyl Coenzyme a Synthetase and the Transport of Long-Chain Fatty Acids

Frontiers in Bioactive Lipids ◽

10.1007/978-1-4615-5875-0_2 ◽

1996 ◽

pp. 7-14 ◽

Cited By ~ 2

Author(s):

Paul N. Black

Keyword(s):

Fatty Acids ◽

Coenzyme A ◽

Long Chain Fatty Acids ◽

Acyl Coenzyme A ◽

Long Chain ◽

Chain Fatty Acids

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Effect of estradiol and progesterone on long chain fatty acyl-coenzyme A levels in the rat uterus

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/0167-4889(91)90159-u ◽

1991 ◽

Vol 1092 (2) ◽

pp. 211-217 ◽

Cited By ~ 1

Author(s):

Allen J. Young ◽

Kenneth L. Barker

Keyword(s):

Coenzyme A ◽

Fatty Acyl ◽

Rat Uterus ◽

Acyl Coenzyme A ◽

Long Chain

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Long-Chain Fatty Acyl Coenzyme A Ligase FadD2 Mediates Intrinsic Pyrazinamide Resistance in Mycobacterium tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02130-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 8

Author(s):

Brandon C. Rosen ◽

Nicholas A. Dillon ◽

Nicholas D. Peterson ◽

Yusuke Minato ◽

Anthony D. Baughn

Keyword(s):

Mycobacterium Tuberculosis ◽

Coenzyme A ◽

Fatty Acyl ◽

Wild Type ◽

Intrinsic Resistance ◽

First Line ◽

Minimum Concentration ◽

Content Type ◽

Acyl Coenzyme A ◽

Long Chain

ABSTRACT Pyrazinamide (PZA) is a first-line tuberculosis (TB) drug that has been in clinical use for 60 years yet still has an unresolved mechanism of action. Based upon the observation that the minimum concentration of PZA required to inhibit the growth of Mycobacterium tuberculosis is approximately 1,000-fold higher than that of other first-line drugs, we hypothesized that M. tuberculosis expresses factors that mediate intrinsic resistance to PZA. To identify genes associated with intrinsic PZA resistance, a library of transposon-mutagenized Mycobacterium bovis BCG strains was screened for strains showing hypersusceptibility to the active form of PZA, pyrazinoic acid (POA). Disruption of the long-chain fatty acyl coenzyme A (CoA) ligase FadD2 enhanced POA susceptibility by 16-fold on agar medium, and the wild-type level of susceptibility was restored upon expression of fadD2 from an integrating mycobacterial vector. Consistent with the recent observation that POA perturbs mycobacterial CoA metabolism, the fadD2 mutant strain was more vulnerable to POA-mediated CoA depletion than the wild-type strain. Ectopic expression of the M. tuberculosis pyrazinamidase PncA, necessary for conversion of PZA to POA, in the fadD2 transposon insertion mutant conferred at least a 16-fold increase in PZA susceptibility under active growth conditions in liquid culture at neutral pH. Importantly, deletion of fadD2 in M. tuberculosis strain H37Rv also resulted in enhanced susceptibility to POA. These results indicate that FadD2 is associated with intrinsic PZA and POA resistance and provide a proof of concept for the target-based potentiation of PZA activity in M. tuberculosis.

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