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3-Hydroxyacyl-CoA Dehydrogenase

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Takashi Hashimoto – One of the best experts on this subject based on the ideXlab platform.

  • Amino acid and nucleotide sequences of human peroxisomal enoyl-CoA hydratase : 3-Hydroxyacyl-CoA Dehydrogenase cDNA
    Journal of inherited metabolic disease, 1998
    Co-Authors: Seiji Fukuda, Tadao Orii, Yasuyuki Suzuki, Zhongyi Zhang, Nobuyuki Shimozawa, Toshifumi Aoyama, Takashi Hashimoto, Naomi Kondo

    Deficiency of enoyl-CoA hydratase : 3-Hydroxyacyl-CoA Dehydrogenase (peroxisomal bifunctional enzyme), one of the enzymes of the peroxisomal β-oxidation system, leads to clinical manifestations resembling Zellweger syndrome with hypotonia, psychomotor delay, hepatomegaly, typical facial appearance and accumulation of very long-chain fatty acids. The nucleotide sequence of the human peroxisomal enoyl-CoA hydratase : 3-Hydroxyacyl-CoA Dehydrogenase cDNA has been reported by Hoefler and colleagues; however, we have found some amino acid differences from our originally isolated cDNA. Contrary to the findings described in a previous paper, we report here the cDNA sequence of human peroxisomal enoyl-CoA hydratase : 3-Hydroxyacyl-CoA Dehydrogenase in which there are 9 authenticated amino acid alterations.

  • Physiological Role of D-3-Hydroxyacyl-CoA Dehydratase/D-3-Hydroxyacyl-CoA Dehydrogenase Bifunctional Protein.
    Journal of biochemistry, 1997
    Co-Authors: Ling Ling Jiang, Yasuyuki Suzuki, Takao Kurosawa, Masahiro Sato, Takashi Hashimoto

    The second and third reactions of the peroxisomal beta-oxidation spiral are thought to be catalyzed by enoyl-CoA hydratase/L-3-Hydroxyacyl-CoA Dehydrogenase bifunctional protein (L-bifunctional protein). Recently, we found the presence of D-3-Hydroxyacyl-CoA dehydratase/D-3-Hydroxyacyl-CoA Dehydrogenase bifunctional protein (D-bifunctional protein) in mammalian peroxisomes. Therefore, we studied the physiological role of the D-bifunctional protein. The contents of the L- and D-bifunctional proteins were about 0.01 and 0.5 microg/mg protein, respectively, in cultured human skin fibroblasts. The activity of conversion of hexadecenoyl-CoA to 3-ketopalmitoyl-CoA by the D-bifunctional protein was estimated to be about 0.5 milliunit/mg of fibroblast protein. This value was about 100-fold that of the L-bifunctional protein in the fibroblasts. From comparison of the activities of the bifunctional proteins with the rate of palmitate oxidation and the activities of acyl-CoA oxidase and 3-ketoacyl-CoA thiolase, it is proposed that the D-bifunctional protein plays a major role in the peroxisomal oxidation of palmitate in the fibroblasts. The contents of both the L- and D-bifunctional proteins in liver were about 2.5 microg/mg protein. Therefore, it is suggested that the D-bifunctional protein also plays a significant role in human liver peroxisomal fatty acid oxidation. Actions of the bifunctional proteins on enoyl forms of other acyl-CoA derivatives were examined. The D-bifunctional protein but not the L-bifunctional protein reacted with 2-methylhexadecenoyl-CoA and 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-2 4-enoyl-CoA. We propose that, among the reactions of the distinct group of carboxylates oxidized specifically in peroxisomes, oxidation of 2-methyl-branched fatty acids and side-chain shortening of cholesterol for bile acid formation are catalyzed by the D-bifunctional protein, but not the L-bifunctional protein.

  • Cloning and expression of cDNA for a newly identified isozyme of bovine liver 3-Hydroxyacyl-CoA Dehydrogenase and its import into mitochondria.
    Biochimica et biophysica acta, 1997
    Co-Authors: Shuichi Furuta, Shoko Miyazawa, Akio Kobayashi, Takashi Hashimoto

    cDNA for a heretofore undescribed mitochondrial 3-Hydroxyacyl-CoA Dehydrogenase, designated as the type II enzyme with different molecular and catalytic properties, compared to those of the classical mitochondrial beta-oxidation enzyme (type I enzyme), was cloned from a bovine liver cDNA library. Nucleotide sequence of the cDNA encoded 261 amino acids with a subunit molecular weight of 27,140. The deduced primary structure of the type II enzyme showed no significant homology to the reported amino acid sequence of the classical 3-Hydroxyacyl-CoA Dehydrogenases. On SDS-PAGE, no differences in subunit molecular weights were observed among the in vitro translation products, the recombinant type II enzyme produced in Escherichia coli and the purified enzyme. NH2-terminal and COOH-terminal amino acid sequence analysis of the purified type II enzyme revealed that the mature enzyme had not been proteolytically processed. The in vitro translation products of the type II enzyme were efficiently incorporated into isolated rat liver mitochondria, without changes in size, thereby suggesting that unlike other mitochondrial enzymes of fatty acid beta-oxidation, the type II enzyme had no cleavable signal peptpeptide upon import into mitochondria.

R. J. A. Wanders – One of the best experts on this subject based on the ideXlab platform.

  • Striking improvement of muscle strength under creatine therapy in a patient with long-chain 3-Hydroxyacyl-CoA Dehydrogenase deficiency.
    Journal of inherited metabolic disease, 2003
    Co-Authors: G. C. Korenke, R. J. A. Wanders, Folker Hanefeld

    Summary: Creatine monohydrate given orally led to a long-lasting improvement of muscular weakness and ataxia in a girl with long-chain 3-Hydroxyacyl-CoA Dehydrogenase deficiency

  • Secondary respiratory chain defect in a boy with long-chain 3-Hydroxyacyl-CoA Dehydrogenase deficiency: possible diagnostic pitfalls
    European journal of pediatrics, 2000
    Co-Authors: A. M. Das, R. J. A. Wanders, R. Fingerhut, Kurt Ullrich

    We report on a boy who suffered from microcephaly, growth retardation, cardiomyopathy and hepatic dysfunction. When he had his first febrile infection at the age of 3 months he showed metabolic decompensation. Laboratory parameters and clinical features were compatible with a β-oxidation defect or a respiratory chain disorder. Measurement of β-oxidation enzymes showed long-chain 3-hydroxyacyl CoA Dehydrogenase (LCHAD) deficiency; determination of respiratory chaichain complex activities revealed complete absence of complex I, II, III and IV activities in skeletal muscle and reduced activities of complexes II and IV in cultured fibroblasts, with secondary dysregulation of ATP synthase. The patient was found to be homozygous for the MTP:G1528 C mutation (LCHAD-deficiency).

  • Molecular basis of long-chain 3-Hydroxyacyl-CoA Dehydrogenase deficiency: identification of two new mutations.
    Journal of inherited metabolic disease, 1997
    Co-Authors: Lodewijk Ijlst, Jos P.n. Ruiter, W. Oostheim, R. J. A. Wanders

    Long-chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) is catalysed by the mitochondrial trifunctional protein (MTP), which also contains enoyl-CoA hydratase and 3-ketothiolase activities (Carpenter et al 1992; Uchida et al 1992). The cDNAs encoding the a and β subunits were cloned by Kamijo et al (1994a). Many patients have been described with a defect in this enzyme complex and it appears that in most patients there is an isolated deficiency of the Dehydrogenase activity of the MTP. We and others have reported a G1528C mutation in the gene coding for the α subunit of MTP, changing the codon for glutamate (510) into glutamine (IJ1st et al 1994; Sims et al 1995). In a series of 34 LCHAD-deficient patients the G1528C mutation was found to be very frequent (87%), which corresponds to the situation observed in MCAD deficiency with the frequent G985A mutation. The G1528C mutation is directly responsible for the loss of Dehydrogenase activity without changing the structure of the enzyme complex (IJ1st et al 1996). In a group of 46 LCHAD-deficient patients as studied enzymatically in our laboratory, we found 12 to be compound heterozygous for the common mutation. Here we describe two new mutations found in this compound heterozygous group.

Khalid Hussain – One of the best experts on this subject based on the ideXlab platform.

  • novel insights into fatty acid oxidation amino acid metabolism and insulin secretion from studying patients with loss of function mutations in 3 hydroxyacyl coa Dehydrogenase
    The Journal of Clinical Endocrinology and Metabolism, 2013
    Co-Authors: Amanda Heslegrave, Khalid Hussain

    Context: Mutations causing genetic defects have been described in many of the enzymes involved in mitochondrial fatty acid oxidation (FAO). Recently, mutations in the penultimate enzyme in the FAO chain have been described that result in quite different symptoms from those normally seen. Patients with mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) present with protein (leucine)-induced hyperinsulinemic hypoglycemia (HH), suggesting a link between FAO, amino acid metabolism, and insulin secretion. Evidence Acquisition and Synthesis: Peer-reviewed articles were searched in PubMed with relevance to HADH and disorders of FAO and protein sensitivity. Relevant articles were cited. Recent evidence suggests that mutations in HADH cause HH that is precipitated by protein in a similar manner to the hyperinsulinism/hyperammonemia (HI/HA) syndrome, which is caused by mutations in the GLUD1 gene, encoding the enzyme glutamate Dehydrogenase (GDH). Conclusion: Current data suggest that the HH observed in patients w…

  • Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase.
    Orphanet Journal of Rare Diseases, 2012
    Co-Authors: Amanda Heslegrave, Simon Eaton, Ritika R. Kapoor, B. Chadefaux, Teoman Akcay, Enver Simsek, Sarah E. Flanagan, Sian Ellard, Khalid Hussain

    Background: Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). HADH encodes short chain 3-hydroxacyl-CoA Dehydrogenase, an enzyme that catalyses the penultimate reaction in mitochondrial β-oxidation of fatty acids. Mutations in GLUD1 encoding glutamate Dehydrogenase, also cause protein sensitive HH (due to leucine sensitivity). Reports suggest a proteinprotein interaction between HADH and GDH. This study was undertaken in order to understand the mechanism of protein sensitivity in patients with HADH mutations. Methods: An oral leucine tolerance test was conducted in controls and nine patients with HADH mutations. Basal GDH activity and the effect of GTP were determined in lymphoblast homogenates from 4 patients and 3 controls. Immunoprecipitation was conducted in patient and control lymphoblasts to investigate protein interactions. Results: Patients demonstrated severe HH (glucose range 1.7–3.2 mmol/l; insulin range 4.8-63.8 mU/l) in response to the oral leucine load, this HH was not observed in control patients subjected to the same leucine load. Basal GDH activity and half maximal inhibitory concentration of GTP was similar in patients and controls. HADH protein could be co-immunoprecipitated with GDH protein in control samples but not in patient samples. Conclusions: We conclude that GDH and HADH have a direct proteinprotein interaction, which is lost in patients with HADH mutations causing leucine induced HH. This is not associated with loss of inhibitory effect of GTP on GDH (as in patients with GLUD1 mutations).

  • Short-chain 3-Hydroxyacyl-CoA Dehydrogenase deficiency associated with hyperinsulinism: a novel glucose-fatty acid cycle?
    Biochemical Society Transactions, 2003
    Co-Authors: Simon Eaton, I. Chatziandreou, Steve Krywawych, S. Pen, Peter E. Clayton, Khalid Hussain

    Hyperinsulinism of infancy is caused by inappropriate insulin secretion in pancreatic beta-cells, even when blood glucose is low. Several molecular defects are known to cause hyperinsulinism of infancy, such as K(ATP) channelopathies and regulatory defects of glucokinase and glutamate Dehydrogenase. Although defects of fatty acid oxidation have not previously been known to cause hyperinsulinism, patients with deficiency in SCHAD (short-chain 3-Hydroxyacyl-CoA Dehydrogenase; an enzyme of mitochondrial beta-oxidation) have hyperinsulinism. A novel link between fatty acid oxidation and insulin secretion may explain hyperinsulinism in these patients.