Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzymes of mitochondrial beta-oxidation are thought to be organized in at least two functional complexes, a membrane-bound, long-chain-specific beta-oxidation system and a matrix system consisting of soluble enzymes with preferences for medium-chain and short-chain substrates. This hypothesis is supported by the observation that the inactivation of long-chain 3-ketoacyl-CoA thiolase by 4-bromotiglic acid (4-bromo-2-methylbut-2-enoic acid) causes the complete inhibition of palmitate beta-oxidation even though 3-ketoacyl-CoA thiolase, which acts on 3-ketopalmitoyl-CoA, remains partly active. The observed substrate specificities of long-chain acyl-CoA dehydrogenase (LCAD) and very-long-chain acyl-CoA dehydrogenase prompt the suggestion that LCAD is a functional component of the long-chain-specific beta-oxidation system. Altogether, a view is emerging of the organization of beta-oxidation enzymes in mitochondria that supports the idea of intermediate channelling and explains the apparent absence of true intermediates of beta-oxidation from mitochondria.
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PMID:Impact of the intramitochondrial enzyme organization on fatty acid oxidation. 1135 67

The fatty acid composition was determined of liver, skeletal muscle and heart obtained post mortem from patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD), multiple acyl-CoA dehydrogenase deficiency (MADD) and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Increased amounts of 4-decenoic acid 10:1(n-6), 5-dodecenoic acid 12:1(n-7), 5-tetradecenoic acid 14:1(n-9), 5,8-tetradecadienoic acid 14:2(n-6) and 7,10-hexadecadienoic acid 16:2(n-6)--intermediates of unsaturated fatty acid oxidation--were found. Fractionation into different lipid classes showed that these fatty acids were exclusively present in the triglyceride fraction. They could not be detected in the free fatty acid fraction or in the phospholipid fraction. Our results suggest that intermediates of unsaturated fatty acid oxidation that accumulate as a consequence of MCADD, MADD and VLCADD are transported to the endoplasmic reticulum for esterification into neutral glycerolipids. The pattern of accumulation is characteristic for each disease, which makes fatty acid analysis of total lipid of post-mortem tissues a useful tool in the detection of mitochondrial fatty acid oxidation defects in patients who died unexpected, for example with sudden infant death syndrome.
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PMID:Intermediates of unsaturated fatty acid oxidation are incorporated in triglycerides but not in phospholipids in tissues from patients with mitochondrial beta-oxidation defects. 1148 98

Docosahexaenoic acid (DHA, C22:6n-3) is essential for normal brain and retinal development. The nature and subcellular location of the terminal steps in DHA biosynthesis have been controversial. Rather than direct Delta4-desaturation of C22:5n-3, it has been proposed that this intermediate is elongated to C24:5n-3, desaturated to C24:6n-3, and "retroconverted" to DHA via peroxisomal beta-oxidation. However, this hypothesis has recently been challenged. The goal of this study was to determine the mechanism and specific enzymes required for the retroconversion step in human skin fibroblasts. Cells from patients with deficiencies of either acyl-CoA oxidase or D-bifunctional protein, the first two enzymes of the peroxisomal straight-chain fatty acid beta-oxidation pathway, exhibited impaired (5-20% of control) conversion of either [1-14C]18:3n-3 or [1-14C]22:5n-3 to DHA as did cells from peroxisome biogenesis disorder patients comprising eight distinct genotypes. In contrast, normal DHA synthesis was observed in cells from patients with rhizomelic chondrodysplasia punctata, Refsum disease, X-linked adrenoleukodystrophy, and deficiency of mitochondrial medium- or very long-chain acyl-CoA dehydrogenase. Acyl-CoA oxidase-deficient cells accumulated 2-5 times more radiolabeled C24:6n-3 than did controls. Our data are consistent with the retroconversion hypothesis and demonstrate that peroxisomal beta-oxidation enzymes acyl-CoA oxidase and D-bifunctional protein are essential for this process in human skin fibroblasts.
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PMID:Peroxisomal straight-chain Acyl-CoA oxidase and D-bifunctional protein are essential for the retroconversion step in docosahexaenoic acid synthesis. 1150 May 17

Although many patients have been found to have very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, none have been documented with long-chain acyl-CoA dehydrogenase (LCAD) deficiency. In order to understand the metabolic pathogenesis of long-chain fatty acid oxidation disorders, we generated mice with VLCAD deficiency (VLCAD(-/-)) and compared their pathologic and biochemical phenotypes of mice with LCAD deficiency (LCAD(-/-)) and wild-type mice. VLCAD(-/-) mice had milder fatty change in liver and heart. Dehydrogenation of various acyl-CoA substrates by liver, heart and skeletal muscle mitochondria differed among the three genotypes. The results for liver were most informative as VLCAD(-/-) mice had a reduction in activity toward palmitoyl-CoA and oleoyl-CoA (58 and 64% of wild-type, respectively), whereas LCAD(-/-) mice showed a more profoundly reduced activity toward these substrates (35 and 32% of wild-type, respectively), with a significant reduction of activity toward the branched chain substrate 2,6-dimethylheptanoyl-CoA. C(16) and C(18) acylcarnitines were elevated in bile, blood and serum of fasted VLCAD(-/-) mice, whereas abnormally elevated C(12) and C(14) acylcarnitines were prominent in LCAD(-/-) mice. Progeny with the combined LCAD(+/+)//VLCAD(+/-) genotype were over-represented in offspring from sires and dams heterozygous for both LCAD and VLCAD mutations. In contrast, no live mice with a compound LCAD(-/-)//VLCAD(-/-) genotype were detected.
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PMID:Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse. 1159 Jan 24

Nutritional management of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is based on the avoidance of fasting and substitution of medium-chain triglycerides for long- and very long-chain triglycerides. We report two cases of this disease, which developed omega-6 essential fatty acid deficiency after three and five months from the beginning of nutritional therapy (SHS product: Monogen). This alteration could be especially dangerous in these patients owing to their possible susceptibility to the development of pigmentary retinopathy. The incorporation of linoleic acid as 3-4% of total caloric intake supported as soybean oil ameliorates this deficiency. We wish to remark on this early complication in the nutritional management of VLCAD deficiency and the possibility of rescue by the incorporation of soybean oil into the diet.
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PMID:Polyunsaturated fatty acid deficiency during dietary treatment of very long-chain acyl-CoA dehydrogenase deficiency. Rescue with soybean oil. 1159 52

During fasting, when overall metabolism changes, the contribution of glucose and fatty acids (FA) to cardiac energy production alters as well. Here, we examined if the heart is able to adapt to such fasting-induced changes by modulation of its gene expression. Rats were fed ad libitum or fasted for 46 h, resulting in reduced circulating glucose levels and a 3-fold rise in FA. Besides changes in the cardiac activity or content of proteins involved in glucose or FA metabolism, mRNA levels also altered. The cardiac expression of genes coding for glucose-handling proteins (glucose transporter GLUT4, hexokinase I and II) was up to 70% lower in fasted than in fed rats. In contrast, the mRNA levels of various genes involved in FA transport and metabolism (FA translocase/CD36, muscle-type carnitine palmitoyl transferase 1, long-chain acyl-CoA dehydrogenase) and of the uncoupling protein UCP-3 increased over 50% in hearts of fasted rats. Surprisingly, mRNA levels of the fatty acid- activated transcription factors PPARalpha and PPARbeta/delta were reduced in hearts of fasted rats, whereas in livers, fasting led to a marked rise in PPARalpha mRNA. Reducing FA levels by nicotinic acid administration during the final 8 h of fasting did not affect the expression of the majority of metabolic genes, but totally abolished the induction of UCP-3. In conclusion, the adult rat heart responds to changes in nutritional status, as provoked by 46 h fasting, through adjustment of glucose as well as FA metabolism at the level of gene expression.
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PMID:Fasting-induced changes in the expression of genes controlling substrate metabolism in the rat heart. 1171 44

We hypothesized that liver fatty acid oxidation (FAO) is compromised in the leptin-deficient obese (Lep(ob)/Lep(ob)) mouse model, and that this would be further challenged when these mice were fed a high-fat diet. Obese mice had a 3.8-fold increased body fat content and a 9-fold increased liver fat content as compared to control mice when both groups were fed a low-fat diet. The expression of liver FAO enzymes, carnitine palmitoyltransferase-1a, long-chain acyl-CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase, was not affected in obese mice as compared to controls on either a low-fat or a high-fat diet. The expression of very-long-chain acyl-CoA dehydrogenase was elevated in obese mice on the control diet, as compared to control mice. For all measures evaluated, increasing the level of fat in the diet had a smaller effect than leptin deficiency. In summary, despite obese mice having an excess of fat available for mitochondrial beta-oxidation in liver, overall energy balance appeared to dictate that the net liver FAO remained at control levels.
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PMID:Evaluation of liver fatty acid oxidation in the leptin-deficient obese mouse. 1191 33

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is clinically classified into severe, intermediate, and myopathic forms. We identified mutations in three unrelated Japanese patients with VLCAD deficiency: two with the myopathic form and one with the intermediate form, all compound heterozygotes of K264E/M437V, A416T/1798delA, and P89S/IVS16-3delAA, respectively. We characterized four missense mutations, K264E, M437V, A416T, and P89S, by transisent expression analysis, using SV40-transformed fibroblasts derived from a VLCAD-null patient, as recipient cells. In transient expression of the wild-type VLCAD cDNA, VLCAD activity at 30 degrees C was higher than at 37 degrees C. Moreover, this temperature-sensitive character is more evident in all the mutant proteins tested than in wild type. Based on characterization of the five missense mutations identified in four Japanese patients, including data on one patient with the myopathic form previously reported, patients with the nonsevere forms (intermediate or myopathic forms) have missense mutations with residual activities in at least one allele. Expression analysis at 30 degrees C may be more useful for evaluating these missense mutations, compared with that at 37 degrees C.
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PMID:Identification and characterization of temperature-sensitive mild mutations in three Japanese patients with nonsevere forms of very-long-chain acyl-CoA dehydrogenase deficiency. 1191 34

Mitochondrial beta-oxidation of fatty acids is vital for energy production in periods of fasting and other metabolic stress. Human patients have been identified with inherited disorders of mitochondrial beta-oxidation of fatty acids with enzyme deficiencies identified at many of the steps in this pathway. Although these patients exhibit a range of disease processes, Reye-like illness (hypoketotic-hypoglycemia, hyperammonemia and fatty liver) and cardiomyopathy are common findings. There have been several mouse models developed to aid in the study of these disease conditions. The characterized mouse models include inherited deficiencies of very long-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein-alpha, and medium-/short-chain hydroxyacyl-CoA dehydrogenase. Mouse mutants developed, but presently incompletely characterized as models, include carnitine palmitoyltransferase-1a and medium-chain acyl-CoA dehydrogenase deficiencies. In general, the mouse models of disorders of mitochondrial fatty acid beta-oxidation have shown clinical signs that include Reye-like syndrome and cardiomyopathy, and many are cold intolerant. It is expected that these mouse models will provide vital contributions in understanding the mechanisms of disease pathogenesis of fatty acid oxidation disorders and the development of appropriate treatments and supportive care.
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PMID:Mouse models for disorders of mitochondrial fatty acid beta-oxidation. 1191 57

The VLDL (very low-density lipoprotein) receptor is a peripheral lipoprotein receptor expressing in fatty acid active tissues abundantly. In the Balb/c fasting mice, VLDL receptor as well as LPL (lipoprotein lipase), FAT (fatty acid translocase)/CD36, H-FABP (heart-type fatty acid-binding protein), ACS (acyl-CoA synthetase) and LCAD (long-chain acyl-CoA dehydrogenase) expressions increased. An electron microscopic examination indicated the lipid droplets that accumulated in the hearts of fasting Balb/c mice. During the development of SD (Sprague-Dawley) rats, VLDL receptor, LPL, FAT/CD36, H-FABP, ACS, and LCAD mRNAs concomitantly increased with growth. However, PK (pyruvate kinase) mRNA expression was negligible. In cultured neonatal rat cardiomyocytes, VLDL receptor expression increased with days in culture. Oil red-O staining showed that cardiomyocytes after 7 days in culture (when the VLDL receptor protein is present) accumulated beta-migrating VLDL. Thereby, we showed that the cardiac VLDL receptor pathway for delivery of remnant lipoprotein particles might be part of a cardiac fatty acid metabolism.
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PMID:Remnant lipoprotein particles are taken up into myocardium through VLDL receptor--a possible mechanism for cardiac fatty acid metabolism. 1205 60


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