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)

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a recessively inherited metabolic disorder that can be due to a deficiency of electron transfer flavoprotein (ETF) or its dehydrogenase (ETF-ubiquinone oxidoreductase). ETF is a mitochondrial matrix protein consisting of alpha- (30kDa) and beta- (28kDa) subunits encoded by the ETFA and ETFB genes, respectively. In the present study, we have analysed tissue samples from 16 unrelated patients with ETF deficiency, and we report the results of ETF activity, Western blot analysis and mutation analysis. The ETF assay provides a reliable diagnostic tool to confirm ETF deficiency in patients suspected to suffer from MADD. Activity ranged from less than 1 to 16% of controls with the most severely affected patients disclosing the lowest activity values. The majority of patients had mutations in the ETFA gene while only two of them harboured mutations in the ETFB gene. Nine novel disease-causing ETF mutations are reported.
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PMID:Electron transfer flavoprotein deficiency: functional and molecular aspects. 1651 Mar 2

Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a 4Fe4S flavoprotein located in the inner mitochondrial membrane. It catalyzes ubiquinone (UQ) reduction by ETF, linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory chain. Deficiencies in ETF or ETF-QO result in multiple acyl-CoA dehydrogenase deficiency, a human metabolic disease. Crystal structures of ETF-QO with and without bound UQ were determined, and they are essentially identical. The molecule forms a single structural domain. Three functional regions bind FAD, the 4Fe4S cluster, and UQ and are closely packed and share structural elements, resulting in no discrete structural domains. The UQ-binding pocket consists mainly of hydrophobic residues, and UQ binding differs from that of other UQ-binding proteins. ETF-QO is a monotopic integral membrane protein. The putative membrane-binding surface contains an alpha-helix and a beta-hairpin, forming a hydrophobic plateau. The UQ-flavin distance (8.5 A) is shorter than the UQ-cluster distance (18.8 A), and the very similar redox potentials of FAD and the cluster strongly suggest that the flavin, not the cluster, transfers electrons to UQ. Two possible electron transfer paths can be envisioned. First, electrons from the ETF flavin semiquinone may enter the ETF-QO flavin one by one, followed by rapid equilibration with the cluster. Alternatively, electrons may enter via the cluster, followed by equilibration between centers. In both cases, when ETF-QO is reduced to a two-electron reduced state (one electron at each redox center), the enzyme is primed to reduce UQ to ubiquinol via FAD.
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PMID:Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool. 1705 Jun 91

A newborn female presented on the first day of life with clinical and biochemical findings consistent with multiple acyl-CoA dehydrogenase deficiency (MADD). Riboflavin supplementation corrected the biochemical abnormalities 24 h after commencing the vitamin. In vitro acylcarnitine profiling in intact fibroblasts both in normal and riboflavin depleted media showed normal oxidation of fatty acids excluding defects in electron transfer flavoprotein (ETF), or ETF ubiquinone oxidoreductase (ETF:QO), or a genetic abnormality in flavin metabolism. In addition, sequencing of the genes encoding ETF and ETF:QO in the proband did not reveal any pathogenic mutations. Determination of the maternal riboflavin status after delivery showed that the mother was riboflavin deficient. Repeat testing done two years after the infant's birth and while on a normal diet showed that the mother was persistently riboflavin deficient and showed a typical MADD profile on plasma acylcarnitine testing. A possible genetic defect in riboflavin transport of metabolism in the mother is postulated to be the cause of the transient MADD seen in the infant. Sequencing of the SLC16A12, RFK and FLAD1 genes encoding key enzymes in riboflavin transport of metabolism in the mother did not identify any pathogenic mutations. The underlying molecular basis of the mother's defect in riboflavin metabolism remains to be established.
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PMID:Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency. 1768 99

The intramolecular and intermolecular perturbation on the electronic state of FAD was investigated by FTIR spectroscopy by using the C=O stretching vibrations as probes in D(2)O solution. Natural and artificial FADs, i.e. 8-CN-, 8-Cl-, 8-H-, 8-OCH(3)-, and 8-NH(2)-FAD labelled by 2-(13)C, (18)O=C(2), or 4,10a-(13)C(2) were used for band assignments. The C(2)=O and C(4)=O stretching vibrations of oxidized FAD were shifted systematically by the substitution at the 8-position, i.e. the stronger the electron-donating ability (NH(2) > OCH(3) > CH(3) > H > Cl > CN) of the substituent, the lower the wavenumber region where both the C(2)=O and C(4)=O bands appear. In contrast, the C(4)=O band of anionic reduced FAD scarcely shifted. The 1,645-cm(-1) band containing C(2)=O stretching vibration shifted to 1,630 cm(-1) in the medium-chain acyl-CoA dehydrogenase (MCAD)-bound state, which can be explained by hydrogen bonds at C(2)=O of the flavin ring. The band was observed at 1,607 cm(-1) in the complex of MCAD with 3-thiaoctanoyl-CoA. The 23 cm(-1) shift was explained by the charge-transfer interaction between oxidized flavin and the anionic acyl-CoA. In the case of electron-transferring flavoprotein, two bands associated with the C(4)=O stretching vibration were obtained at 1,712 and 1,686 cm(-1), providing evidence for the multiple conformations of the protein.
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PMID:Intramolecular and intermolecular perturbation on electronic state of FAD free in solution and bound to flavoproteins: FTIR spectroscopic study by using the C = O stretching vibrations as probes. 1787 56

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive defect of the electron transfer flavoprotein or ubiquinone oxidoreductase, resulting in abnormal fatty acid, amino acid, and choline metabolism, leading to metabolic acidosis, hypoglycemia, "sweaty-feet" odor, and early neonatal deaths. This report presents a child diagnosed with this disease at birth by newborn screening using the mass spectrometer, who died suddenly at the age of 6 months. The echocardiogram revealed pericardial effusion, thickened ventricular musculature, and insufficiency of both the atrio-ventricular valves. The autopsy showed immense cardiomegaly, fatty infiltration, and hypertrophy of the ventricles. This is the first detailed case report of clinico-pathological correlation of MADD in an infant and brings into light a rare form of cardiomyopathy as a differential diagnosis in critically ill patients.
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PMID:Cardiomyopathy in multiple Acyl-CoA dehydrogenase deficiency: a clinico-pathological correlation and review of literature. 1791 79

The flavoprotein nitroalkane oxidase (NAO) catalyzes the oxidation of primary and secondary nitroalkanes to the corresponding aldehydes and ketones. The enzyme is a homologue of acyl-CoA dehydrogenase. Asp402 in NAO has been proposed to be the active site base responsible for removing the substrate proton in the first catalytic step; structurally it corresponds to the glutamate which acts as the base in medium chain acyl-CoA dehydrogenase. In the active site of NAO, the carboxylate of Asp402 forms an ionic interaction with the side chain of Arg409. The R409K enzyme has now been characterized kinetically and structurally. The mutation results in a decrease in the rate constant for proton abstraction of 100-fold. Analysis of the three-dimensional structure of the R409K enzyme, determined by X-ray crystallography to a resolution of 2.65 A, shows that the critical structural change is an increase in the distance between the carboxylate of Asp402 and the positively charged nitrogen in the side chain of the residue at position 409. The D402E mutation results in a smaller decrease in the rate constant for proton abstraction of 18-fold. The structure of the D402E enzyme, determined at 2.4 A resolution, shows that there is a smaller increase in the distance between Arg409 and the carboxylate at position 402, and the interaction of this residue with Ser276 is perturbed. These results establish the critical importance of the interaction between Asp402 and Arg409 for proton abstraction by nitroalkane oxidase.
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PMID:Mechanistic and structural analyses of the roles of Arg409 and Asp402 in the reaction of the flavoprotein nitroalkane oxidase. 1799 68

The content and distribution of body lipids are of special interest for production efficiency and meat quality in the farm animal industry. Triglycerides represent the most variable fraction of tissue lipids, and are mainly stored in adipocytes. Although several studies have reported regional differences in the expression of genes and their products in adipocytes from various species, the characteristics of i.m. adipocytes remain poorly described. To evaluate adipocyte features according to muscle and other fat locations, adipocyte proteins were isolated from trapezius skeletal muscle, and intermuscular, s.c., or perirenal adipose tissues from 6 female pigs (80 d of age). Protein extracts were labeled and analyzed by 2-dimensional, fluorescent, differential gel electrophoresis. The comparisons revealed that 149 spots were always differentially expressed (P < 0.05, ratio exceeding |2|-fold difference) between i.m. adipocytes and the fat cells derived from the 3 other adipose locations. The proteins that were downregulated in i.m. fat cells belonged to various metabolic pathways, such as lipogenesis (cytosolic malate dehydrogenase and isocitrate dehydrogenase, P < 0.01), glycolysis (enolases and aldolase, P </= 0.01), lipolysis (perilipin, P < 0.01), fatty acid oxidation (long-chain fatty-acyl CoA dehydrogenase, P < 0.01), and energy transfer (catalase, voltage-dependent anion channel 1, and electron-transfer flavoprotein, P < 0.05). In contrast, both prohibitin-1 and cell division cycle 42 homolog, with possible roles in cell growth, were up-regulated (P < 0.05) in i.m. adipocytes compared with other fat cells. Fewer differences were observed when adipocytes isolated from s.c., perirenal, and intermuscular fat tissues were compared, with a maximum of 17 spots differing significantly in abundance between perirenal and s.c. adipose tissues. The findings that proteins involved in both anabolic and energy-yielding catabolic pathways are downregulated in i.m. adipocytes compared with s.c., visceral, or intermuscular adipocytes, suggest that the metabolic activity of i.m. adipocytes is low. Thus, triggering adipogenesis rather than cell metabolism per se might be a valuable strategy to control lipid deposition in pig skeletal muscles.
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PMID:Regional differences in porcine adipocytes isolated from skeletal muscle and adipose tissues as identified by a proteomic approach. 1831 Apr 87

The biosynthetic gene cluster for the kutzneride family of hexapeptidolactones includes the four-gene cassette ktzABCD postulated to generate a nonproteinogenic amino acid. Encoded by this cassette are the nonheme FeII-dependent halogenase KtzD and the acyl-CoA dehydrogenase-like flavoprotein KtzA, proposed to work in conjunction with adenylating protein KtzB and carrier protein KtzC. In the present work, we report the in vitro reconstitution of this four-protein system and identify the final product as (1S,2R)-allocoronamic acid bound in thioester linkage to KtzC. Further analysis of KtzD and KtzA support a biosynthetic pathway that involves KtzD-mediated generation of a gamma-chloroisoleucyl intermediate which is cyclized to the final product by KtzA without redox participation of the bound flavin cofactor. This work introduces a new monomer for potential incorporation into nonribosomal peptides and validates the unique strategy for its biosynthesis.
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PMID:Biosynthesis of (-)-(1S,2R)-allocoronamic acyl thioester by an Fe(II)-dependent halogenase and a cyclopropane-forming flavoprotein. 1882 90

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a metabolic disorder due to dysfunction of electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-QO). Mutations in ETFDH, encoding ETF-QO have been associated with both riboflavin-responsive and non-responsive MADD as well as a myopathic form of CoQ(10) deficiency, although pathomechanisms responsible for these different phenotypes are not well-defined. We performed mutation analysis in four Taiwanese MADD patients. Three novel ETFDH mutations were identified in four patients and all harbored the p.A84T mutation. Muscle CoQ(10) levels and respiratory chain activities measured in two patients were normal. Three patients improved on riboflavin together with carnitine. Our results show that not all MADD patients have CoQ(10) deficiency. Based upon our data, riboflavin and carnitine may be the first-line treatment for MADD.
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PMID:ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. 1924 6

In honeybees, queens synthesize the "queen pheromone," whereas workers synthesize fatty acid components of "royal jelly" in their mandibular glands (MGs). To identify candidate proteins involved in the caste-selective MG function, we performed a proteomic analysis and identified three proteins that were expressed selectively in queen MGs (aldehyde dehydrogenase 1 [ALDH1], medium-chain acyl-CoA dehydrogenase [MCAD], and electron transfer flavoprotein alpha [ETFalpha)]), and a protein that was expressed selectively in worker MGs (fatty acid synthase [FAS)]). The quantitative reversed transcription-polymerase chain reaction demonstrated that the level of aldh1 transcription in MGs was significantly higher, whereas that of fas transcription was lower in queens than in workers. Among the eight genes encoding proteins similar to ALDH1 that are registered in the honeybee genome database, aldh6, aldh7, and aldh1 were expressed at significantly higher levels in queen MGs than in worker MGs. In situ hybridization showed that in the queen head, aldh1 was expressed in MG cells, whereas aldh6 and aldh7 were expressed in fat cells attached to the MGs. These results suggest caste- and cell type-selective aldehyde/fatty acid metabolism in honeybee MGs.
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PMID:Differential gene expression in the mandibular glands of queen and worker honeybees, Apis mellifera L.: implications for caste-selective aldehyde and fatty acid metabolism. 1966 65


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