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)

We report a novel mild variant of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) diagnosed in four infants who, in neonatal screening, showed abnormal acylcarnitine profiles indicative of MCADD. Three patients showed completely normal urinary organic acids and phenylpropionic acid loading tests were normal in all four patients. Enzyme studies showed residual MCAD activities between "classical" MCADD and heterozygotes. ACADM gene analysis revealed compound heterozygosity for the common mutation K329E and a novel mutation, Y67H, in two cases, and homozygosity for mutation G267R and the novel mutation S245L, respectively, in two children of consanguineous parents. As in other metabolic disorders, the distinction between "normal" and "disease" in MCAD deficiency is blurring into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing.
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PMID:Molecular and functional characterisation of mild MCAD deficiency. 1140 68

Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype-phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype-phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders.
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PMID:Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. 1152 29

Lipid contributes greatly in cardiac metabolism to produce high energy ATPs, and is suggested to be related to the progression and deterioration of heart disease. It is fortunate that the I-123-betamethyliodophenylpentadecanoic acid (BMIPP) imaging technique is now available in determining heart condition, but we must be cautious about the interpretation of images obtained with this new tracer. From the uptake of BMIPP into the cell to breakdown and catabolism of it, there exist so many critical enzymatical pathways relating to the modification of BMIPP imaging. In clinical evaluation, the image will be translated as the integral effects of these pathways. In other words, we must be aware of these critical pathways regulating lipid metabolism and modifying factors in order to correctly understand BMIPP imaging. Lipid transport is affected by the albumin/FFA ratio in the blood, and extraction with membrane transporter proteins. Fatty acid binding protein (FABP) in the cytosole will play an important role in regulating lipid flux and following metabolism. Lipid will be utilized either for oxidation, triglyceride or phospholipid formation. For oxidation, carnitine palmitoil transferase is the key enzyme for the entrance of lipid into mitochondria, and oxidative enzymes such as acyl CoA dehydrogenase (MCAD, LCAD, HAD) will determine lipid use for the TCA cycle. ATPs produced in the mitochondria again limit the TG store. It is well known that BMIPP imaging completely changes in the ischemic condition, and is also shown that lipid metabolical regulation completely differs from normal in the very early phase of cardiac hypertrophy. In the process of deteriorating heart failure, metabolical switching of lipid with glucose will take place. In such a different heart disease conditions, it is clear that lipid metabolical regulation, including many lipid enzymes, works differently from in the healthy condition. These lipid enzymes are regulated by nuclear factor peroxisome proliferator-activated receptors (PPAR) just like a conductor of an orchestra. Most of the regulating mechanisms of the PPAR are still unknown, but reduction of this nuclear factor is shown in the process of decompensated heart failure. This review is based by mostly on our fundamental and Japanese clinical data. BMIPP has been used clinically in abundant cases in Japan. In such situations, further correct information on lipid metabolism, including BMIPP, will contribute to the understanding of deteriorating heart disease and its prognosis.
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PMID:Lipid metabolism in the heart--contribution of BMIPP to the diseased heart. 1175 44

The estrogen-related receptor alpha (ERRalpha) is one of the first orphan nuclear receptors identified. Still, we know little about the mechanisms that regulate its expression and its activity. In this study, we show that the transcriptional coactivator PGC-1, which is implicated in the control of energy metabolism, regulates ERRalpha at two levels. First, PGC-1 induces the expression of ERRalpha. Consistent with this induction, levels of ERRalpha mRNA in vivo are highest in PGC-1 expressing tissues, such as heart, kidney, and muscle, and up-regulated in response to signals that induce PGC-1, such as exposure to cold. Second, PGC-1 interacts physically with ERRalpha and enables it to activate transcription. Strikingly, we find that PGC-1 converts ERRalpha from a factor with little or no transcriptional activity to a potent regulator of gene expression, suggesting that ERRalpha is not a constitutively active nuclear receptor but rather one that is regulated by protein ligands, such as PGC-1. Our findings suggest that the two proteins act in a common pathway to regulate processes relating to energy metabolism. In support of this hypothesis, adenovirus-mediated delivery of small interfering RNA for ERRalpha, or of PGC-1 mutants that interact selectively with different types of nuclear receptors, shows that PGC-1 can induce the fatty acid oxidation enzyme MCAD (medium-chain acyl-coenzyme A dehydrogenase) in an ERRalpha-dependent manner.
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PMID:The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha). 1252 4

Cardiac fatty acid oxidation (FAO) enzyme gene expression is known to be downregulated during hypoxia in concordance with reduced FAO rates. To evaluate this metabolic switch, the transcriptional control of a cardiac FAO enzyme-encoding gene (medium-chain acyl-CoA dehydrogenase, MCAD) was characterized in response to hypobaric hypoxia. Transgenic mice harboring 560-bp of the human MCAD gene promoter fused to the bacterial chloramphenicol acetyl transferase (CAT) reporter gene were exposed to moderate (14% O2) or severe (8% O2) hypoxia for 2 or 7 days. MCAD-CAT activity and gene expression were significantly downregulated following 7 days of moderate hypoxia versus normoxic controls (p < 0.05). In parallel two known transcriptional regulators of MCAD expression, PPARalpha and Sp3, were concordantly downregulated at 7 days hypoxia. In contrast, severe hypoxia increased MCAD-CAT activity by 31 +/- 1.4% after 2 days hypoxia, returning to base +/- 4% after 2 days (p < 0.001) and returned to control levels after 7 days of hypoxia. These data demonstrate that MCAD gene expression is downregulated after 7 days of moderate hypoxia and inversely regulated with severe hypoxia. The known MCAD transcriptional regulators PPARalpha and Sp3 mirror MCAD expression. These data indicate that the transcriptional regulatory circuits involved in the control of MCAD gene expression under hypoxic conditions are modulated by upstream factors that are sensitive to the levels of oxygen.
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PMID:Counter-regulatory effects of incremental hypoxia on the transcription of a cardiac fatty acid oxidation enzyme-encoding gene. 1296 53

Mitochondrial fatty acid oxidation deficiencies are due to genetic defects in enzymes of fatty acid beta-oxidation and transport proteins. Genetic defects have been identified in most of the genes where nearly all types of sequence variations (mutation types) have been associated with disease. In this paper, we will discuss the effects of the various types of sequence variations encountered and review current knowledge regarding the genotype-phenotype relationship, especially in patients with acyl-CoA dehydrogenase deficiencies where sufficient material exists for a meaningful discussion. Because mis-sense sequence variations are prevalent in these diseases, we will discuss the implications of these types of sequence variations on the processing and folding of mis-sense variant proteins. As the prevalent mis-sense variant K304E MCAD protein has been studied intensively, the investigations on biogenesis, stability and kinetic properties for this variant enzyme will be discussed in detail and used as a paradigm for the study of other mis-sense variant proteins. We conclude that the total effect of mis-sense sequence variations may comprise an invariable--sequence variation specific--effect on the catalytic parameters and a conditional effect, which is dependent on cellular, physiological and genetic factors other than the sequence variation itself.
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PMID:Genetic defects in fatty acid beta-oxidation and acyl-CoA dehydrogenases. Molecular pathogenesis and genotype-phenotype relationships. 1472 74

Virtually all patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD) are homozygous or compound heterozygous for the 985A > G mutation, which limits the study of a possible genotype/phenotype correlation. A newborn Palestinian infant died suddenly on the second day of life. A previous sibling had also died in similar circumstances aged 3 weeks. Urine organic acid and bloodspot acylcarnitine analysis were consistent with MCADD. He was homozygous for a novel MCAD splice mutation, IVS3-1G > C. This mutation leads to deletion of 7 bp and introduction of a premature termination codon as a result of complete missplicing of MCAD mRNA. This misspliced MCAD mRNA encodes a non-functional protein and is furthermore reduced in amounts due to nonsense-mediated decay, resulting in total lack of functional MCAD enzyme. This is the first molecular identification of MCADD in an Arab patient and the first reported splice mutation in the MCAD gene that has been functionally characterized. The association of homozygosity for a null mutation with lethal neonatal presentation in the index patient and presumably the previous infant suggested a genotype/phenotype correlation. However, a 6-year-old completely asymptomatic sibling also had the characteristic MCADD biochemical phenotype and was homozygous for the same IVS3-1G > C mutation. As a first candidate to modify the disease presentation, by modulating the overlapping enzyme activity, we tested the entire family for the prevalent SCAD gene 625G > A susceptibility variant. Interestingly, all family members were 625G > A homozygous. Additional genetic and/or environmental factors must play a major role in determining the phenotypic diversity of MCADD.
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PMID:Homozygosity for a severe novel medium-chain acyl-CoA dehydrogenase (MCAD) mutation IVS3-1G > C that leads to introduction of a premature termination codon by complete missplicing of the MCAD mRNA and is associated with phenotypic diversity ranging from sudden neonatal death to asymptomatic status. 1517 99

The retinal pigment epithelium (RPE) and the choriocapillaris are affected early in the retinopathy associated with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. RPE in culture possesses the machinery needed for mitochondrial fatty acid beta-oxidation in vitro. To further elucidate pathogenesis of LCHAD retinopathy, we performed immunohistochemistry of the human eye and brain with antibodies to beta-oxidation enzymes. Human eye and brain sections were stained with antibodies to medium-chain (MCAD) and very long-chain acyl-CoA dehydrogenase (VLCAD), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and mitochondrial trifunctional protein (MTP) harboring LCHAD. Antibodies to 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) and cytochrome c oxidase subunit I (COX I) were used as a reference. VLCAD, MTP, MCAD, SCHAD, MHBD, and COX I antibodies labeled most retinal layers and tissues of the human eye actively involved in oxidative metabolism (extraocular and intraocular muscle, the RPE, the corneal endothelium, and the ciliary epithelium). MTP and COX I antibodies labeled the inner segments of photoreceptors. The choriocapillaris was labeled only with SCHAD and MCAD antibodies. In the brain, the choroid plexus and nuclei of the brain stem were most intensely labeled with beta-oxidation antibodies, whereas COX I antibodies strongly labeled neurons in several regions of the brain. Mitochondrial fatty acid beta-oxidation likely plays a role in ocular energy production in vivo. The RPE rather than the choriocapillaris could be the critical affected cell layer in LCHAD retinopathy. Reduced energy generation in the choroid plexus may contribute to the cerebral edema observed in patients with beta-oxidation defects.
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PMID:Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. 1534 68

Mitochondrial medium-chain acyl-CoA dehydrogenase is a key enzyme for the beta-oxidation of fatty acids, which catalyzes the FAD-dependent oxidation of a variety of acyl-CoA substrates to the corresponding trans-2-enoyl-CoA thioesters. Oct-4-en-2-ynoyl-CoA was identified as a new irreversible inhibitor of acyl-CoA dehydrogenase, and kinetic parameters K(I) and k(inact) were determined to be 11 microM and 0.025 min(-1), respectively. Triple bond between C2 and C3 of the inhibitor was identified as the functional group responsible for enzyme inactivation, and Michael addition is proposed as the mechanism for this inactivation, which is a new pathway for inactivation of MCAD by inhibitors. The inhibitor may become a lead for further development for treating non-insulin-dependent diabetes mellitus.
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PMID:Inactivation of medium-chain acyl-CoA dehydrogenase by oct-4-en-2-ynoyl-CoA. 1629 16

Heart failure is associated with downregulation of the fatty acid oxidation pathway in the ventricular myocardium. Since angiotensin II plays a critical role in myocardial phenotypic changes associated with heart failure, we investigated the effect of chronic angiotensin II stimulation on the fatty acid oxidation pathway in transgenic (TG) mice with targeted overexpression of angiotensinogen in the myocardium (TG1306/1R mice). TG1306/R1 mice progressively developed left ventricular hypertrophy. After 12 months, approximately half of the mice exhibited signs of heart failure including increased lung weight index [>+2 SD of age-matched wild-type (WT) mice] and 5-fold increase of myocardial brain natriuretic peptide expression. Myocardial mRNA and protein expression of peroxisome proliferator-activated receptor alpha (PPARalpha) progressively decreased in both WT and TG1306/R1 mice during the 12 months observation period, but much more pronounced in TG1306/R1 mice. Concomitantly, mRNA expression of enzymes of fatty acid oxidation (medium-chain acyl CoA dehydrogenase, MCAD; carnitine palmitoyl transferase I, CPT-I) was reduced in TG1306/R1 compared with age-matched WT mice. However, protein expression of MCAD and CPT-I was decreased concomitantly only in TG mice with criteria of heart failure. Correspondingly, myocardial oxidation of palmitate, measured during ex vivo working heart perfusion, was reduced by 25% in TG1306/R1 mice with heart failure. These results demonstrate that angiotensin II-induced cardiac hypertrophy is associated with reduction of PPARalpha and of mRNA expression of enzymes of fatty acid metabolism relative to age-matched WT mice. However, both protein expression of fatty acid oxidation enzymes and the rate of fatty acid oxidation remain unchanged unless heart failure occurs, suggesting the involvement of posttranscriptional mechanisms in the metabolic changes associated with heart failure.
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PMID:Overexpression of angiotensinogen in the myocardium induces downregulation of the fatty acid oxidation pathway. 1687 18


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