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)

Oxidation of straight-chain fatty acids in mitochondria involves the complicated interaction between a large variety of different enzymes. So far four different mitochondrial straight-chain acyl-CoA dehydrogenases have been identified. The physiological function of three of the four acyl-CoA dehydrogenases has been resolved in recent years especially from studies on patients suffering from certain inborn errors of mitochondrial fatty acid beta-oxidation. The physiological role of long-chain acyl-CoA dehydrogenase (LCAD) has remained obscure, however. The results described in this paper provide strong evidence suggesting that LCAD plays a central role in branched-chain fatty acid metabolism since it turns out to be the major acyl-CoA dehydrogenase reacting with 2,6-dimethylheptanoyl-CoA, a metabolite of pristanic acid, which itself is the alpha-oxidation product of phytanic acid.
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PMID:2,6-Dimethylheptanoyl-CoA is a specific substrate for long-chain acyl-CoA dehydrogenase (LCAD): evidence for a major role of LCAD in branched-chain fatty acid oxidation. 971 23

Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid beta-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established.
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PMID:Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. 997 85

To investigate the structure of porcine genes involved in the beta-oxidation of fatty acid, we isolated the short-chain acyl-CoA dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD) genes from the pig. The cDNA of SCAD, MCAD and LCAD genes were 1899 bp, 1835 bp 1835 bp and 1704 bp long and coded for 413-aa, 422-aa and 430-aa precursor proteins, respectively. Three genes, SCAD, MCAD and LCAD were mapped to 14p16.2-23.2, 6q32.4-33, and 15q24.2-26.3, respectively.
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PMID:Cloning and mapping of three pig acyl-CoA dehydrogenase genes. 1034 94

Two sisters were investigated at the ages of 20 and 13 years owing to persistently increased serum creatine kinase and recurrent episodes of rhabdomyolysis after emotional stress in the older and myalgias in the younger. The finding of increased levels of cis-5-tetradecenoic acid (C14:1) in plasma, severe hypocarnitinaemia and the absence of a pathological dicarboxylic aciduria in both sisters suggested a very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Reduced [1-(14)C]palmitate oxidation and deficient mitochondrial VLCAD activity in fibroblasts were found. Mutation analysis revealed compound heterozygosity for Asp365His and Arg410His changes. This late-onset, milder clinical presentation differs from the other two more severe infantile phenotypes described, since there is no hypoglycaemia or cardiac disease. Fatty acid oxidation defects should be investigated in all cases with rhabdomyolysis beginning in adolescence or early adulthood.
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PMID:Adolescent myopathic presentation in two sisters with very long-chain acyl-CoA dehydrogenase deficiency. 1051 80

Very-long-chain acyl-CoA dehydrogenase (VLCAD) is one of a family of nuclear-encoded enzymes that catalyze the initial step in mitochondrial fatty acid beta-oxidation (FAO). Previous studies have indicated that two other members of the AD gene family (medium-chain AD and long-chain AD) are controlled at the transcriptional level by nuclear hormone receptors. In this study, we have cloned and characterized the human VLCAD gene promoter region to identify cis-acting elements involved in its transcriptional control. VLCAD gene promoter-luciferase reporter (VLCAD-Luc) constructs were found to be transcriptionally active in a variety of mammalian cell lines and in primary rat cardiomyocytes when driven by varying lengths of the VLCAD promoter region. Removal of a 20-bp DNA segment of the proximal VLCAD gene promoter markedly reduced the transcriptional activity of VLCAD-Luc constructs. Gel mobility shift assays identified a DNA-binding activity in nuclear extracts prepared from human hepatoma G2 cells that interacted with the 20-bp regulatory region. Competition studies revealed that this DNA-binding activity could be abolished by a molar excess of unlabeled specific oligonucleotide as well as a DNA fragment containing an activator protein 2 (AP-2)-binding site but not by an unrelated nonspecific DNA fragment. These results provide an initial characterization of the human VLCAD gene promoter, identify AP-2 as a candidate activator of VLCAD gene transcription, and suggest that VLCAD gene transcription may be regulated by pathways distinct from that of other AD genes.
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PMID:Characterization of the human very-long-chain acyl-CoA dehydrogenase gene promoter region: a role for activator protein 2. 1060 78

Long-chain fatty acids are the most important substrates for the heart. In addition, they have been shown to affect signalling pathways and gene expression. To explore the effects of long-chain fatty acids on cardiac gene expression, neonatal rat ventricular myocytes were cultured for 48 h with either glucose (10 mm), fatty acids (palmitic and oleic acid, 0.25 mm each), or a combination of both as exogenous substrates. Exposure to fatty acids (both in the absence or presence of glucose) neither affected cellular morphology and protein content nor induced alterations in the expression of phenotypic marker genes like atrial natriuretic factor and the Ca-ATPase SERCA2. However, incubation with fatty acids (with or without glucose) resulted in up to 4-fold increases of the mRNA levels of fatty acid translocase (FAT/CD36), heart-type fatty acid-binding protein, acyl-CoA synthetase, and long-chain acyl-CoA dehydrogenase. In contrast, the expression of genes coding for proteins involved in glucose uptake and metabolism, i.e., glucose transporter GLUT4, hexokinase II, and glyceraldehyde 3-phosphate dehydrogenase, remained constant or even declined under these conditions. These changes corresponded with a 60% increase in cardiomyocyte fatty acid oxidation capacity. Interestingly, the peroxisome proliferator-activated receptor-alpha (PPARalpha)-ligand Wy 14,643, but not the PPARgamma-ligand ciglitazone, also resulted in increased mRNA levels of genes involved in fatty acid metabolism. In conclusion, fatty acids specifically and co-ordinately up-regulate transcription of genes coding for proteins involved in cardiac fatty acid transport and metabolism, most likely through activation of PPARalpha.
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PMID:Long-chain fatty acid-induced changes in gene expression in neonatal cardiac myocytes. 1062

Fasting elicits a progressive increase in lipid metabolism within skeletal muscle. To determine the effects of fasting on the transcriptional regulation of genes important for metabolic control in skeletal muscle composed of different fiber types, nuclei from control and fasted (24 and 72 h) rats were subjected to nuclear run-on analysis using an RT-PCR-based technique. Fasting increased (P < 0.05) transcription rate of the muscle-specific uncoupling protein-3 gene (UCP3) 14.3- to 21.1-fold in white gastrocnemius (WG; fast-twitch glycolytic) and 5.5- to 7.5-fold in red gastrocnemius (RG; fast-twitch oxidative) and plantaris (PL; mixed) muscles. No change occurred in soleus (slow-twitch oxidative) muscle. Fasting also increased transcription rate of the lipoprotein lipase (LPL), muscle carnitine palmitoyltransferase I (CPT I), and long-chain acyl-CoA dehydrogenase (LCAD) genes 1.7- to 3.7-fold in WG, RG, and PL muscles. Transcription rate responses were similar after 24 and 72 h of fasting. Surprisingly, increasing metabolic demand during the initial 8 h of starvation (two 2-h bouts of treadmill running) attenuated the 24-h fasting-induced transcriptional activation of UCP3, LPL, CPT I, and LCAD in RG and PL muscles, suggesting the presence of opposing regulatory mechanisms. These data demonstrate that fasting elicits a fiber type-specific coordinate increase in the transcription rate of several genes involved in and/or required for lipid metabolism and indicate that exercise may attenuate the fasting-induced transcriptional activation of specific metabolic genes.
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PMID:Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle. 1082 11

An increasing number of women with inborn errors of metabolism are now reaching child-bearing age. For certain disorders there are maternal risks associated with pregnancy. These may be related to an increased likelihood of metabolic decompensation (e.g. disorders of the urea cycle) or to increased stress to systems already compromised by disease (e.g. cardiomyopathy in GSD III). Detrimental effects upon the fetus may also be caused by maternal disease, as occurs with phenylketonuria, or from medication used to treat the mother's condition. Less commonly, fetal inborn errors may adversely effect the mother's health--e.g. fetal long-chain acyl-CoA dehydrogenase deficiency and the maternal HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and AFLP (acute fatty liver of pregnancy). Because of the rarity of individual disorders, our knowledge of risks associated with pregnancy is limited. Even for more common inborn errors such as phenylketonuria, there remain a number of questions that have not been fully answered.
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PMID:Inborn errors of metabolism and pregnancy. 1086 39

Type 1 diabetes mellitus is a devastating disorder affecting both glucose and lipid metabolism. Using the nonobese diabetic (NOD) mouse model, we found that diabetic mice had a liver-specific increase in steady state mRNA levels for enzymes involved in oxidation of fatty acids. Increased mRNA abundance was observed in very long-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase (LCAD), medium-chain acyl-CoA dehydrogenase (MCAD), carnitine palmitoyltransferase I (CPT-1a), and the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, whereas short-chain acyl-CoA dehydrogenase mRNA remained unchanged. In contrast, minimal elevations in LCAD and CPT-1a mRNA were observed in hearts of diabetic mice with no significant differences found for the other enzymes. We developed NOD mice with transgenes containing regulatory elements of human MCAD gene controlling a reporter gene to determine if the increase in MCAD gene expression occurred via the well-characterized nuclear receptor response element (NRRE-1). These results demonstrated that the transgene containing the NRRE-1 and adjacent 5' sequences had elevated liver expression in diabetic mice compared with prediabetic or normal control mice. Surprisingly, the transgene that contains NRRE-1 with adjacent 3' sequences and the transgene with the NRRE-1 deleted showed minimal response to the fulminant diabetic condition.Collectively, these results indicate that in type 1 diabetes there exists an excessive and liver-specific activation of fatty acid oxidation gene expression. Using human MCAD as a prototype gene, we have shown that this increased expression is mediated at the transcriptional level but does not occur via the well-characterized NRRE-1 site responsible for baseline expression in normal mice.
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PMID:Transgenic studies of fatty acid oxidation gene expression in nonobese diabetic mice. 1110 40

Acyl-CoA dehydrogenase activity has been measured in homogenates of post-imbibition to 14-day-old hydroponically grown pea seeds at daily intervals, using C(4), C(12) and C(16) acyl-CoA substrates. The activity peaks of the different chain-length acyl-CoA dehydrogenases did not transpose at all points and the ratios of the chain-length activities were not constant. It therefore has to be concluded that more than one dehydrogenase is present in pea mitochondria. There was a post-imbibition initial surge of activity with short- and mid-chain-length substrates. The C(16)-handling enzyme first peaked at 3-4 days, which coincided with the onset of plumule unfurling and greening. Further peaks were observed with all three substrates, coinciding with secondary root formation and leaf enlargement and later with cotyledon degeneration. Overall activity showed that the long-chain acyl-CoA dehydrogenase was much more active than the short-chain acyl-CoA dehydrogenase.
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PMID:Acyl-CoA dehydrogenase activity in pea cotyledon tissue during germination and initial growth. 1117 Nov 98


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