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)

Complementary DNAs encoding the precursor of human placental short chain acyl-coenzyme A (CoA) dehydrogenase (SCAD) (EC 1.3.99.2) were cloned and sequenced. The cDNA inserts in these clones were 1,852 bases in length combined, and encoded the entire 412-amino acid precursor SCAD (mol wt 44,303). This sequence included the 24-amino acid leader peptide moiety (mol wt 2,576) and 388 amino acids corresponding to the mature protein (mol wt 41,727). The comparison of SCAD and medium chain acyl-CoA dehydrogenase sequences revealed a high degree of homology, suggesting that these enzymes evolved from a common ancestral gene and belong to a gene family. We also studied mutant human SCAD in cultured skin fibroblasts from three patients with hereditary SCAD deficiency. Labeling fibroblast cultures with [35S]-methionine followed by immunoprecipitation with anti-SCAD antibody revealed that a normal size variant SCAD protein was synthesized. In all of the three SCAD-deficient cell lines, the size of variant SCAD mRNA as determined by Northern blotting using one of the normal SCAD cDNA as a probe was also normal, and no difference was observed on Southern blots in the restriction patterns of mutant genomic DNA using EcoRI, TaqI, HincII, and BamHI. These results suggest that the defects in SCAD in these cell lines are caused by a point mutation.
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PMID:Molecular cloning and nucleotide sequence of complementary DNAs encoding human short chain acyl-coenzyme A dehydrogenase and the study of the molecular basis of human short chain acyl-coenzyme A dehydrogenase deficiency. 256 44

A catalytic intermediate, the so-called "purple complex," of acyl-CoA dehydrogenase is produced on its reaction with the substrate, acyl-CoA. The purple complex is a charge-transfer complex between the reduced enzyme and the product, enoyl-CoA. Resonance Raman spectra of the purple complexes of three acyl-CoA dehydrogenases [short-chain acyl-CoA (SCAD), medium-chain acyl-CoA (MCAD), and isovaleryl-CoA (IVD) dehydrogenases] were measured with excitation at 632.8 nm within charge-transfer absorption bands. The 1,577 cm-1 band of the SCAD purple complex formed in the reaction with butyryl-CoA is mainly associated with the C(1) = O stretching of crotonyl-CoA, judging from the isotopic frequency shifts upon 13C or 18O substitution of butyryl-CoA. The 1,627 cm-1 band of the C(1) = O moiety of crotonyl-CoA in solution shifted downward by 50 cm-1 on complexation with reduced SCAD. This large frequency shift indicates a substantial interaction between C(1) = O and the enzyme, and is further evidence for an appreciable contribution of a polarized form of the C(1) = O moiety in the enzyme-bound enoyl-CoA. This frequency shift can be explained by the hydrogen bond of C(1) = O. The 1,577 cm-1 band of the MCAD purple complex remained constant, regardless of the acyl carbon-chain length (from C4 to C16 of the substrate, acyl-CoA); the alky chain scarcely affected the interaction of the C(1) = O moiety in the active site.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structural modulation of 2-enoyl-CoA bound to reduced acyl-CoA dehydrogenases: a resonance Raman study of a catalytic intermediate. 759 42

We studied the effect of riboflavin treatment on the clinical status and on the activities of beta-oxidation and respiratory chain enzymes in a 69-year-old patient with late-onset myopathy. Before treatment, she was very weak and wasted in the limbs and trunk muscles; also, she could not walk or attend to daily activities. Marked lipid storage was present in the muscle biopsy. The activities of short-chain acyl coenzyme A (acyl-CoA) dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD) in isolated muscle mitochondria were reduced to less than 10% of control values. This defect in fatty acid oxidation was associated with a marked deficiency of two flavin-dependent respiratory chain complexes: complex I activity was 20% and complex II activity was 25% of control values. By contrast, the activities of the nonflavin-dependent complex III and complex IV were normal. Western blot analysis of the patient's muscle mitochondrial extracts with antibodies raised against purified SCAD, MCAD, and the alpha- and beta-subunits of the electron transfer flavoprotein (ETF) showed absence of SCAD cross-reacting material (CRM), markedly decreased MCAD-CRM, and normal amounts of both alpha- and beta-ETF-CRM. After riboflavin treatment, the patient's clinical status dramatically improved and morphologic changes in muscle disappeared. SCAD activity increased to 55% of control values, whereas MCAD, LCAD, and complex I and complex II activities normalized. SCAD and MCAD immunoreactivity was restored to normal. On the basis of our experience and the data in the literature, we concluded that some lipid storage myopathies can show dramatic response to riboflavin.
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PMID:Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme A dehydrogenase and respiratory chain deficiency. 796 76

Short chain (SCAD), medium chain (MCAD), and long chain acyl-CoA dehydrogenases (LCAD) catalyze the first step of fatty acid oxidation, while isovaleryl-CoA dehydrogenase (IVD) is involved in leucine oxidation. They are homologous flavoproteins belonging to the acyl-CoA dehydrogenase (ACD) family. Electron transfer flavoprotein (ETF) serves as an obligatory electron acceptor for these reactions. We demonstrated that the expression of SCAD, MCAD, and LCAD and the alpha-subunit of ETF (alpha-ETF) showed a similar developmental pattern, while that of IVD was distinctly different from others. The ontogenic pattern of each enzyme in the liver differed distinctly from that in the heart. The degree of glucagon-enhanced ACD expression in vivo and in vitro in both the liver and heart was especially high in fasted rats. Dexamethasone induced all ACD mRNAs in the heart. In contrast, it strongly suppressed mRNAs of all ACDs and alpha-ETF mRNA in the liver, except IVD mRNA. Dexamethasone induced IVD mRNA in both the liver and heart. Starvation strongly stimulated expression of all five genes in various tissues, with the highest in the heart, except the IVD gene which was down-regulated. The degree of induction by 3-day starvation differed in different age groups of rats. Feeding the rats a fat-free diet for 7 days caused a marked increase of IVD mRNA in the heart, whereas the high fat diet for the same period resulted in a severe decrease of the same degree, suggesting a protein-sparing mechanism. However, these manipulations of dietary fat content had little effect on the expression of other ACD genes.
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PMID:Developmental, nutritional, and hormonal regulation of tissue-specific expression of the genes encoding various acyl-CoA dehydrogenases and alpha-subunit of electron transfer flavoprotein in rat. 822 58

We have shown previously that acetoacetyl-CoA bound to medium-chain acyl-CoA dehydrogenase from pig kidney is transformed into an enolate form, O = C(3)-C(2)H = C(1)-O-, and that the interaction between the C(4a) = N(5) moiety of flavin and the O = C(3)-C(2)H = C(1)-O- moiety of acetoacetyl-CoA is important for the charge-transfer interaction [Nishina, Y. et al. (1992) J. Biochem. 111, 699-706]. In this study, we examined four kinds of acyl-CoA dehydrogenases [short-chain acyl-CoA (SCAD), medium-chain acyl-CoA (MCAD), long-chain acyl-CoA (LCAD), and isovaleryl-CoA (IVD) dehydrogenases] from bovine liver. The Raman spectra of non-labeled and isotopically labeled acetoacetyl-CoA in keto-form revealed that the 1,716-cm-1 and 1,650-cm-1 bands were derived from the C(3) = O and the C(1) = O stretching mode, respectively. In the charge-transfer complexes of acetoacetyl-CoA with the four kinds of dehydrogenases, the resonance Raman (RR) bands corresponding to the C(3) = O and the C(1) = O of acetoacetyl-CoA were observed at around 1,643-1,622 and 1,506-1,476 cm-1, respectively, indicating that acetoacetyl-CoA was transformed into the enolate form as the result of the complexation with the enzymes. Further, in RR spectra with excitation at 632.8 nm, within the charge-transfer band of the complexes of acetoacetyl-CoA with the four acyl-CoA dehydrogenases, both bands associated with the C(4a) = N(5) moiety of oxidized flavin and the O = C(3)-C(2)H = C(1)-O- moiety of acetoacetyl-CoA were enhanced, but the benzene portion of oxidized flavin was not. These results indicate that the substrate activating mechanism is common to all four kinds of dehydrogenases, i.e., the interaction between the C(1) = O of acetoacetyl-CoA and the positively polarized atoms of the enzymes located in close proximity to the oxygen atom of C(1) = O is important, and the C(4a) = N(5) moiety of flavin participates in the interaction. Some kinds of 3-ketoacyl-CoAs were tested instead of acetoacetyl-CoA and essentially similar results were obtained. The positions of the bands derived from the C(1)-O- moiety of 3-ketoacyl-CoAs were different by ca. 30 cm-1 in two groups, i.e., ca. 1,475 cm-1 for SCAD and MCAD and ca. 1,505 cm-1 for LCAD and IVD, that is, RR spectra can classify the four dehydrogenases into two groups.
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PMID:Substrate activating mechanism of short-chain acyl-CoA, medium-chain acyl-CoA, long-chain acyl-CoA, and isovaleryl-CoA dehydrogenases from bovine liver: a resonance Raman study on the 3-ketoacyl-CoA complexes. 874 5

Long-chain acyl-CoA dehydrogenase (LCAD) is one of four enzymes involved in the initial step of mitochondrial beta-oxidation of straight-chain fatty acids. It is a member of the acyl-CoA dehydrogenase (Acad or ACAD) gene family of enzymes, which also includes very-long-chain (VLCAD), medium-chain (MCAD), and short-chain (SCAD) acyl-CoA dehydrogenases. These enzymes all have similar activity but differ only in the chain length specificity for their substrate. Mitochondrial beta-oxidation provides an important source of energy especially during times of fasting. In order to understand the role of LCAD in this pathway, we have cloned and characterized the entire mouse (Mus musculus) gene encoding LCAD (Acadl). Acadl is a single-copy, nuclear encoded gene approximately 35 kb in size. We have sequenced the entire coding region, all intron/exon boundaries, 1.7 kb of its 5' regulatory region, and mapped the transcription start site. The gene contains 11 coding exons ranging in size from 67 bp to 275 bp, interrupted by 10 introns ranging in size from 1.0 kb to 6.6 kb in size. The Acadl 5' regulatory region, like other members of the Acad family, lacks a TATA or CAAT box and is GC rich. This region does contain multiple, putative cis-acting DNA elements recognized by either SP1 or members of the steroid-thyroid family of nuclear receptors, which has been shown with other members of the ACAD gene family to be important in regulated expression. The characterization of the mouse Acadl gene will allow further study of LCAD in an in vivo model, and how its expression may be coordinated with other members of the Acad gene family.
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PMID:Structural characterization of the mouse long-chain acyl-CoA dehydrogenase gene and 5' regulatory region. 954 92

A novel hexyl-substituted methylenecyclopropyl acetyl-CoA was tested as an enzyme-specific acyl-CoA dehydrogenase inhibitor. Its CoA ester generated in situ from the carboxylic acid and CoASH, displayed marked differences in inhibition specificity as compared to methylenecyclopropyl acetyl-CoA, consistent with the substrate specificities of the target enzymes. Thus methylenecyclopropyl acetyl-CoA inactivated short-chain-specific acyl-CoA dehydrogenase rapidly, medium-chain-specific acyl-CoA dehydrogenase much more slowly and had no effect on long-chain- or very long-chain-specific acyl-CoA dehydrogenases. The hexyl-substituent on the methylenecyclopropyl ring gave an inhibitor which rapidly inactivated MCAD and LCAD whilst VLCAD was inhibited more slowly and SCAD was essentially unaffected. In some cases (e.g. SCAD and MCPA-CoA) inhibition was accompanied by flavin bleaching. In other cases (e.g. LCAD and C6MCPA) less pronounced bleaching suggests a different chemistry of inhibition.
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PMID:Novel methylenecyclopropyl-based acyl-CoA dehydrogenase inhibitor. 980 84

A 2-year-old female was well until 12 months of age when she was found to be anemic and had dilated cardiomyopathy. Total plasma carnitine was 6 microM and acylcarnitine analysis while receiving carnitine supplement revealed an increase in the four-carbon species. Urine organic acids were normal. In vitro analysis of the mitochondrial pathways for beta oxidation, and leucine, valine, and isoleucine metabolism was performed in fibroblasts using stable isotope-labeled precursors to these pathways followed by acylcarnitine analysis by tandem mass spectrometry. 16-2H3-palmitate was metabolized normally down to the level of butyryl-CoA thus excluding SCAD deficiency. 13C6-leucine and 13C6-isoleucine were also metabolized normally. 13C5-valine incubation revealed a significant increase in 13C4-isobutyrylcarnitine without any incorporation into propionylcarnitine as is observed normally. These same precursors were also evaluated in fibroblasts with proven ETF-QO deficiency in which acyl-CoA dehydrogenase deficiencies in each of these pathways was clearly identified. These results indicate that in the human, there is an isobutyryl-CoA dehydrogenase which exists as a separate enzyme serving only the valine pathway in addition to the 2-methyl branched-chain dehydrogenase which serves both the valine and the isoleucine pathways in both rat and human.
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PMID:Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. 988 13

The SCAD deficient mouse model has been useful to investigate mechanisms of deficient fatty acid oxidation disease in human patients. This mouse model has been thoroughly characterized and is readily available from the Jackson Laboratory. Using the new technologies of gene-knockout mouse modeling, we envisage developing additional members of the acyl-CoA dehydrogenase family of enzyme deficiencies in mice and furthering our understanding of fatty acid metabolism in health and disease.
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PMID:Lessons learned from the mouse model of short-chain acyl-CoA dehydrogenase deficiency. 1070 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


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