Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q3SYG4 (C18)
 23,707 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Carnitine esters of erucic acid (22:1 n-9 cis), cetoleic acid (22:1 n-11 cis), brassidic acid (22:1 n-9 trans), gadoleic acid (20:1 n-9 cis) and oleic acid (18:1 n-9 cis) have been compared as mitochondrial substrates and as inhibitors of palmitoylcarnitine oxidation in heart and liver mitochondria. 2. Both the rate of intramitochondrial-CoA acylation and the rate of beta-oxidation decreases as the chain length increases from C18 to C22. There are no significant differences among the three C22 isomers as oxidizable substrates. 3. All the tested acylcarnitines inhibit palmitoylcarnitine oxidation. The C18 and C20 acylcarnitines inhibit by virtue of being competing substrates; i.e. the respiration is not inhibited. The C22-isomers inhibit also respiration; this shows that the inhibition of palmitolycarnitine oxidation is not compensated for by oxidation of C22-acylcarnitines. Brassidoylcarnitine inhibits the oxidation of palmitoylcarnitine and respiration less than erucoyl-and cetoleoylcarnitine. The different behaviour of the C22-isomers is probably due to the difference in their competitive properties with respect to long-chain acyl-CoA dehydrogenase. 4. All C22 acylcarnitines seem to be relatively better oxidized in the liver than in the heart mitochondria while their inhibitory effect on the usage of the radioactive palmitoylcarnitine is very similar. 5. Palmitoylcarnitine inhibits almost completely the "endogenous" formation of acetyl-CoA presumably from malate via pyruvate in the liver mitochondria while the C22-acylcarnitines cause only a partial inhibiton of this acetyl-CaO formation.
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PMID:Monoethlenic C20 and C22 fatty acids in marine oil and rapeseed oil. Studies on their oxidation and on their relative ability to inhibit palmitate oxidation in heart and liver mitochondria. 87 57

Fibroblasts from patients with long-chain acyl-CoA dehydrogenase deficiency were found to oxidize [1-14C]linoleate at an average rate of 60% of normal but [9,10(n)-3H]myristate at an average rate of only 37% of normal, a relationship reverse from that predicted by the chain-length specificities of the three known straight-chain mitochondrial acyl-CoA dehydrogenases. The residual long-chain beta-oxidative activity was found to be mitochondrial and associated with the accumulation of tetradecadienoate (C14:2w6) when the mutant fibroblasts were incubated with 100 mumol/L linoleate (C18:2w6) or eicosadienoate (C20:2w6). The results suggest the presence in human fibroblasts of a novel acyl-CoA dehydrogenase with activity toward 15 to 20 carbon-length fatty acids.
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PMID:Beta-oxidation of long-chain fatty acids by human fibroblasts: evidence for a novel long-chain acyl-coenzyme A dehydrogenase. 154 Jan 49

At least 12 fatty acid oxidation disorders are known to be responsible for cases of sudden and unexpected death in early childhood. A specific diagnosis of these disorders is essential for genetic counseling and for the screening of siblings potentially at risk for life-threatening episodes of fasting intolerance. Postmortem blood and urine samples often are not available for further biochemical studies, and currently only medium-chain acyl-CoA dehydrogenase (MCAD) deficiency can be diagnosed by the molecular analysis of tissues. We developed a postmortem screening method for fatty acid oxidation disorders by the simultaneous measurement of C8-C20 fatty acids, glucose, lactate, and other metabolites from the methanol wash of a pellet obtained by ultracentrifugation of liver homogenate. Cis-4-decenoic acid was present in five confirmed cases with MCAD deficiency and in one case with glutaric aciduria type II and was absent in 97 of 100 randomly chosen sudden death cases, at least 81 of which were diagnosed as sudden infant death syndrome (SIDS). C14-C18 monounsaturated fatty acids were significantly elevated in the one examined case affected with long-chain acyl-CoA dehydrogenase (LCAD) deficiency. The metabolite profiles in two cases with carnitine uptake deficiency were less informative, but they shared with all the other disease controls a very low glucose concentration, a finding compatible with premortem hypoglycemia. This method is proposed as a simple and practical means of biochemical screening to follow up the postmortem finding of liver fat infiltration.
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PMID:Biochemical diagnosis of fatty acid oxidation disorders by metabolite analysis of postmortem liver. 805 17

A stable isotope dilution gas chromatography chemical ionization mass spectrometry (GC-CI-MS) method was developed for the quantitative profiling of plasma acylcarnitines. The clean-up procedure was comprised of a solid-phase cation exchange extraction using PRS-columns from which the acylcarnitines were eluted with a barium chloride solution. Isolated acylcarnitines were transformed into acyloxylactones and analyzed by positive GC-CI-MS using isobutane as reactant gas. The selected monitoring of a common ion at m/z [85]+ and the protonated molecular ion enabled a selective and sensitive detection of all C2-C18 acylcarnitines. An accurate quantitation was achieved by the use of stable isotope-labeled internal standards (C2-C18) and acylcarnitines could be analyzed in the sub-nanomolar range. Control values for C2-C18 acylcarnitines in plasma were established. Concentrations ranged from 0.02 micromol/L for C14-acylcarnitine to 4.90 micromol/L for C2-acylcarnitine. The diagnostic suitability of the method was demonstrated for patients with medium-chain acyl-CoA dehydrogenase deficiency and very long-chain acyl-CoA dehydrogenase deficiency.
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PMID:Quantitative analysis of plasma acylcarnitines using gas chromatography chemical ionization mass fragmentography. 903 11

Long-chain-acyl-CoA dehydrogenase (LCADH) has been produced by recombinant techniques from the human cDNA and purified after expression in Escherichia coli. Pig kidney LCADH was purified using an optimized method which also produces apparently pure short-chain-acyl-CoA dehydrogenase (SCADH) and medium-chain-acyl-CoA dehydrogenase (MCADH) in good yields. LCADH from both sources has a maximal turnover rate (Vmax of 650-700 min(-1) at pH 7.6) with the best substrates, which is approximately fivefold higher than reported previously. The human enzyme has an approximately fivefold higher Km compared with the pig kidney enzyme with substrates of chain length from C10 to C18 and a significantly different dependence of Vmax on the chain length. Pig kidney LCADH has a similar Vmax/Km with C10 to C14 substrates as MCADH does with C6 to C10 substrates. Recombinant human LCADH, however, is significantly less efficient (approximately fourfold with C12) than purified pig kidney enzyme. We conclude that human LCADH is either quantitatively less important in beta-oxidation than in the pig, or that post-translational modifications, not present in the recombinant human enzyme, are required to optimize human LCADH activity. Our results demonstrate that LCADH is as important as the other acyl-CoA dehydrogenases in fatty acid oxidation at physiological, mitochondrial pH with optimal substrates of chain length C10-C14. The extent of the LCADH-flavin cofactor reduction observed with most substrates and the rate of the subsequent reoxidation with oxygen are markedly different from those found with human medium chain acyl-CoA dehydrogenase. Both LCADH are inactivated by the substrate analogue 2-octynoyl-CoA, possibly via covalent modification of Glu261, the active-site residue involved in deprotonation of the substrate (alpha)C-H.
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PMID:Characterization of human and pig kidney long-chain-acyl-CoA dehydrogenases and their role in beta-oxidation. 918 95

We studied a 10-year-old patient with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency who was originally (mis)diagnosed as having systemic carnitine deficiency. He was subjected to a fasting test, a long-chain triglyceride (LCT) loading test (1.5 g/kg) and an intravenous carnitine clearance test (0.25 mumol/kg per min). Plasma acylcarnitines were analysed using a quantitative GC-CI-MS method. During fasting, all long-chain acylcarnitines with a chain length of C14 and higher (especially C14:1) increased dramatically. Total plasma long-chain acylcarnitine reached a concentration of 28.6 mumol/L. LCT loading resulted in a moderate increase, mainly of the C18 esters. The carnitine infusion, which led to a supranormal plasma free carnitine concentration, gave only a slight but generalized rise of long-chain acylcarnitines. Although only one patient could be tested, the results suggest that the accumulation of potentially toxic long-chain acylcarnitines in VLCAD deficiency is provoked by fasting, LCT loading and carnitine supplementation. Therapy should be adjusted accordingly.
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PMID:The effect of fasting, long-chain triglyceride load and carnitine load on plasma long-chain acylcarnitine levels in mitochondrial very long-chain acyl-CoA dehydrogenase deficiency. 970 May 96

Acyl-CoA dehydrogenases (ACADs) are a family of mitochondrial enzymes catalyzing the initial rate-limiting step in the beta-oxidation of fatty acyl-CoA. The reaction provides main source of energy for human heart and skeletal muscle. Eight human ACADs have been described. Deficiency of these enzymes, especially very long-chain acyl-CoA dehydrogenase (VLCAD), usually leads to severe human organic diseases, such as sudden death in infancy, infantile cardiomyopathy (CM), hypoketotic hypoglycemia, or hepatic dysfunction. By large-scale random sequencing, we identified a novel homolog of ACADs from human dendritic cell (DC) cDNA library. It contains an open reading frame (ORF) of 1866bp, which encodes a 621 amino acid protein. It shares approximately 47% amino acid identity and 65% similarity with human VLCAD. So, the novel molecule is named as acyl-CoA dehydrogenase-9 (ACAD-9), the ninth member of ACADs. The new gene consists of 18 exons and 17 introns, and is mapped to chromosome 3q26. It contains the two signatures shared by all members of the ACADs. ACAD-9 mRNA is ubiquitously expressed in most normal human tissues and cancer cell lines with high level of expression in heart, skeletal muscles, brain, kidney, and liver. Enzymatic assay proved that the recombinant ACAD-9 protein has the dehydrogenase activity on palmitoyl-coenzyme A (C16:0) and stearoyl-coenzyme A (C18:0). Our results indicate that ACAD-9 is a novel member of ACADs.
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PMID:Cloning and functional characterization of ACAD-9, a novel member of human acyl-CoA dehydrogenase family. 1235 60

Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) results in accumulation of C14-C18 acylcarnitines and low free carnitine. Carnitine supplementation is still controversial. VLCAD knockout (VLCAD(+/-)) mice exhibit a similar clinical and biochemical phenotype to those observed in humans. VLCAD(+/-) mice were fed with carnitine dissolved in drinking water. Carnitine, acylcarnitines, and gamma-butyrobetaine were measured in blood and tissues. Measurements were performed under resting conditions, after exercise and after 24 h of regeneration. HepG2 cells were incubated with palmitoyl-CoA and palmitoyl-carnitine, respectively, to examine toxicity. With carnitine supplementation, acylcarnitine production was significantly induced. Nevertheless, carnitine was low in skeletal muscle after exercise. Without carnitine supplementation, liver carnitine significantly increased after exercise, and after 24 h of regeneration, carnitine concentrations in skeletal muscle completely replenished to initial values. Incubation of hepatic cells with palmitoyl-CoA and palmitoyl-carnitine revealed a significantly reduced cell viability after incubation with palmitoyl-carnitine. The present study demonstrates that carnitine supplementation results in significant accumulation of potentially toxic acylcarnitines in tissues. The expected prevention of low tissue carnitine was not confirmed. The principle mechanism regulating carnitine homeostasis seems to be endogenous carnitine biosynthesis, also under conditions with increased demand of carnitine such as in VLCAD-deficiency.
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PMID:Carnitine supplementation induces acylcarnitine production in tissues of very long-chain acyl-CoA dehydrogenase-deficient mice, without replenishing low free carnitine. 1831 32

Long-chain acylcarnitines accumulate in long-chain fatty acid oxidation defects, especially during periods of increased energy demand from fat. To test whether this increase in long-chain acylcarnitines in very long-chain acyl-CoA dehydrogenase (VLCAD(-/-)) knock-out mice correlates with acyl-CoA content, we subjected wild-type (WT) and VLCAD(-/-) mice to forced treadmill running and analyzed muscle long-chain acyl-CoA and acylcarnitine with tandem mass spectrometry (MS/MS) in the same tissues. After exercise, long-chain acyl-CoA displayed a significant increase in muscle from VLCAD(-/-) mice [C16:0-CoA, C18:2-CoA and C18:1-CoA in sedentary VLCAD(-/-): 5.95 +/- 0.33, 4.48 +/- 0.51, and 7.70 +/- 0.30 nmol x g(-1) wet weight, respectively; in exercised VLCAD(-/-): 8.71 +/- 0.42, 9.03 +/- 0.93, and 14.82 +/- 1.20 nmol x g(-1) wet weight, respectively (P < 0.05)]. Increase in acyl-CoA in VLCAD-deficient muscle was paralleled by a significant increase in the corresponding chain length acylcarnitine. Exercise resulted in significant lowering of the free carnitine pool in VLCAD(-/-) muscle. This is the first study demonstrating that acylcarnitines and acyl-CoA directly correlate and concomitantly increase after exercise in VLCAD-deficient muscle.
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PMID:Corresponding increase in long-chain acyl-CoA and acylcarnitine after exercise in muscle from VLCAD mice. 1898 Sep 43

The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family is a key regulator of mitochondrial function, and reduced mRNA expression may contribute to muscle lipid accumulation in obesity and type 2 diabetes. To characterize the effects of PGC-1 on lipid metabolism, we overexpressed PGC-1alpha and PGC-1beta in C2C12 myotubes using adenoviral vectors. Both PGC-1alpha and -1beta increased palmitate oxidation [31% (P<0.01) and 26% (P<0.05), respectively] despite reductions in cellular uptake [by 6% (P<0.05) and 21% (P<0.001)]. Moreover, PGC-1alpha and -1beta increased mRNA expression of genes regulating both lipid oxidation (e.g., CPT1b and ACADL/M) and synthesis (FAS, CS, ACC1/2, and DGAT1). To determine the net effect, we assessed lipid composition in PGC-1-expressing cells. Total lipid content decreased by 42% in palmitate-loaded serum-starved cells overexpressing PGC-1alpha (P<0.05). In contrast, in serum-replete cells, total lipid content was not significantly altered, but fatty acids C14:0, C16:0, C18:0, and C18:1 were increased 2- to 4-fold for PGC-1alpha/beta (P<0.05). Stable isotope-based dynamic metabolic profiling in serum-replete cells labeled with (13)C substrates revealed both increased de novo fatty acid synthesis from glucose and increased fatty acid synthesis by chain elongation with either PGC-1alpha or -1beta expression. These results indicate that PGC-1 can promote both lipid oxidation and synthesis, with net balance determined by the nutrient/hormonal environment.-Espinoza, D. O., Boros, L. G., Crunkhorn, S., Gami, H., Patti, M.-E. Dual Modulation of both lipid oxidation and synthesis by peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta in cultured myotubes.
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PMID:Dual modulation of both lipid oxidation and synthesis by peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta in cultured myotubes. 1990 80


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