An appraisal of the functional significance of the inhibitory effect of long chain acyl‐CoAs on mitochondrial transports

Morel, Frédéric; Lauquin, Guy J.‐M.; Lunardi, Joël; Duszyński, Jerzy; Vignais, Pierre V.

doi:10.1016/0014-5793(74)80035-9

Cited by 123 publications

(43 citation statements)

References 24 publications

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“…If mitochondria were present in the absence of divalent cations, about two third of the radioactivity was recovered from the interphase of 25%/55% sucrose where mitochondria were accumulated. This agrees fairly well with the finding [3] that the distribution between bound to mitochondria and free palmitoyl-CoA is 2: 1. However, when Mg" was added after mitochondria, practically all palmitoyl-CoA accumulated at the 25%/55% interphase, indicating its stronger binding to mitochondria in this case.…”

Section: Resultssupporting

confidence: 93%

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Effect of metal cations on the inhibition of adenine nucleotide translocation by acyl‐coa

Duszyński

Wojtczak

1975

FEBS Letters

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Section: Resultssupporting

confidence: 93%

“…In both sucrose and KC1 media the competitive character of this inhibition [3] was maintained ( fig.2), but the Ki value was four times higher in KC1 than in sucrose whereas K,,, value for ADP remained practically unchanged.…”

Section: Resultsmentioning

confidence: 95%

Effect of metal cations on the inhibition of adenine nucleotide translocation by acyl‐coa

Duszyński

Wojtczak

1975

FEBS Letters

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“…Since the peroxisome is the sole site of fatty acid b-oxidation in fungi it is conceivable that the acyl-CoA levels inside peroxisomes increase. The inhibitory effect of (long-chain) acyl-CoAs on mitochondrial carrier proteins is well documented (Morel et al, 1974) and we speculate that peroxisomal metabolite transporters may be inhibited in a similar way in the fox2D/D mutant. It is also possible that, due to their amphipathic nature, the acyl-CoAs insert into the peroxisomal membrane, thereby changing its physical properties and transport capabilities.…”

Section: Discussionmentioning

confidence: 69%

The activity of the glyoxylate cycle in peroxisomes of Candida albicans depends on a functional β-oxidation pathway: evidence for reduced metabolite transport across the peroxisomal membrane

et al. 2008

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The glyoxylate cycle, a metabolic pathway required for generating C 4 units from C 2 compounds, is an important factor in virulence, in both animal and plant pathogens. Here, we report the localization of the key enzymes of this cycle, isocitrate lyase (Icl1; EC 4.1.3.1) and malate synthase (Mls1; EC 2.3.3.9), in the human fungal pathogen Candida albicans. Immunocytochemistry in combination with subcellular fractionation showed that both Icl1 and Mls1 are localized to peroxisomes, independent of the carbon source used. Although Icl1 and Mls1 lack a consensus type I peroxisomal targeting signal (PTS1), their import into peroxisomes was dependent on the PTS1 receptor Pex5p, suggesting the presence of non-canonical targeting signals in both proteins. Peroxisomal compartmentalization of the glyoxylate cycle is not essential for proper functioning of this metabolic pathway because a pex5D/D strain, in which Icl1 and Mls1 were localized to the cytosol, grew equally as well as the wild-type strain on acetate and ethanol. Previously, we reported that a fox2D/D strain that is completely deficient in fatty acid boxidation, but has no peroxisomal protein import defect, displayed strongly reduced growth on non-fermentable carbon sources such as acetate and ethanol. Here, we show that growth of the fox2D/D strain on these carbon compounds can be restored when Icl1 and Mls1 are relocated to the cytosol by deleting the PEX5 gene. We hypothesize that the fox2D/D strain is disturbed in the transport of glyoxylate cycle products and/or acetyl-CoA across the peroxisomal membrane and discuss the possible relationship between such a transport defect and the presence of giant peroxisomes in the fox2D/D mutant.

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“…Interestingly, palmitoyl-CoA, the acyl donor for protein palmitoylation, inhibits several enzymes including rat adipocyte pyruvate dehydrogenase (7), rat liver ADP/ATP translocase (8), bovine liver glutamate dehydrogenase (9), and bovine liver methylmalonyl semialdehyde dehydrogenase (MMSDH) 1 (10,11). Whereas MMSDH was shown to be fatty-acylated, preliminary studies also indicated that bovine liver glutamate dehydrogenase is likely to be fatty-acylated (10).…”

mentioning

confidence: 99%

Regulation of Mitochondrial Carbamoyl-phosphate Synthetase 1 Activity by Active Site Fatty Acylation

Corvi¹,

Soltys²,

Berthiaume³

2001

Journal of Biological Chemistry

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In addition to its role in reversible membrane localization of signal-transducing proteins, protein fatty acylation could play a role in the regulation of mitochondrial metabolism. Previous studies have shown that several acylated proteins exist in mitochondria isolated from COS-7 cells and rat liver. Here, a prominent fatty-acylated 165-kDa protein from rat liver mitochondria was identified as carbamoyl-phosphate synthetase 1 (CPS 1). Covalently attached palmitate was linked to CPS 1 via a thioester bond resulting in an inhibition of CPS 1 activity at physiological concentrations of palmitoyl-CoA. This inhibition corresponds to irreversible inactivation of CPS 1 and occurred in a time-and concentration-dependent manner. Fatty acylation of CPS 1 was prevented by preincubation with N-ethylmaleimide and 5-p-fluorosulfonylbenzoyladenosine, an ATP analog that reacts with CPS 1 active site cysteine residues. Our results suggest that fatty acylation of CPS 1 is specific for long-chain fatty acyl-CoA and very likely occurs on at least one of the essential cysteine residues inhibiting the catalytic activity of CPS 1. Inhibition of CPS 1 by long-chain fatty acylCoAs could reduce amino acid degradation and urea secretion, thereby contributing to nitrogen sparing during starvation.The covalent modification of proteins by lipids alters their physical and functional properties. Several types of lipids are covalently bound to proteins as follows: isoprenoids, glycosylphosphatidylinositols, cholesterol, and fatty acids (1-4). Protein fatty acylation is the modification of proteins by fatty acids. It is divided into two categories, myristoylation and palmitoylation. In myristoylation, the 14-carbon myristate is co-translationally attached to the N-terminal glycine residue of a protein via a stable amide bond. Palmitoylation is characterized by the post-translational attachment of the 16-carbon fatty acid palmitate to cysteine residues of a protein via a thioester bond. Due to its reversible nature, palmitoylation has been shown recently to regulate the subcellular localization of several proteins involved in signal transduction processes (1,5,6). For protein palmitoylation to occur, palmitate needs to be activated in the form of its coenzyme A derivative, palmitoyl-CoA.Interestingly, palmitoyl-CoA, the acyl donor for protein palmitoylation, inhibits several enzymes including rat adipocyte pyruvate dehydrogenase (7), rat liver ADP/ATP translocase (8), bovine liver glutamate dehydrogenase (9), and bovine liver methylmalonyl semialdehyde dehydrogenase (MMSDH)

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An appraisal of the functional significance of the inhibitory effect of long chain acyl‐CoAs on mitochondrial transports

Cited by 123 publications

References 24 publications

Effect of metal cations on the inhibition of adenine nucleotide translocation by acyl‐coa

Effect of metal cations on the inhibition of adenine nucleotide translocation by acyl‐coa

The activity of the glyoxylate cycle in peroxisomes of Candida albicans depends on a functional β-oxidation pathway: evidence for reduced metabolite transport across the peroxisomal membrane

Regulation of Mitochondrial Carbamoyl-phosphate Synthetase 1 Activity by Active Site Fatty Acylation

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