1
UI - 97221476
AU - Bussieres LM
AU - Pflugfelder PW
AU - Taylor AW
AU - Noble EG
AU - Kostuk WJ
IN - Department of Medicine (Division of Cardiology), University Hospital, University of Western Ontario, London, Canada.
TI - Changes in skeletal muscle morphology and biochemistry after cardiac transplantation.
SO - Am J Cardiol 1997 Mar 1;79(5):630-4
AB - Skeletal muscle biopsies (vastus lateralis) were performed in 12 patients (mean age 47 +/- 11 years) before and at 3 and 12 months after cardiac transplantation. Fiber type analysis revealed a predominance of type II fibers before cardiac transplantation (66 +/- 10%); the ratio did not change after transplantation. Fiber cross-sectional area increased by 35% to 39% in all fiber types by 12 months after cardiac transplantation. Fiber cross-sectional area, however, remained below the reported normal values. The number of capillaries surrounding each fiber did not change after cardiac transplantation. Skeletal muscle enzyme activity of phosphofructokinase, citrate synthase, and beta-hydroxyacyl coenzyme A dehydrogenase increased by 26%, 47%, and 63%, respectively, after cardiac transplantation (p < 0.05). Peak oxygen uptake also increased significantly after cardiac transplantation (19.5 +/- 8.1 ml/kg/min at 12 months vs 9.8 +/- 1.4 ml/kg/min before transplant, p < 0.01); however, uptake remained 40% below that of predicted. Thus, significant improvement in skeletal muscle morphology and biochemistry occurs in the first year after cardiac transplantation in association with improved exercise capacity. Recovery, however, may be incomplete, which could explain residual impairment of exercise capacity in these patients.
2
UI - 96405205
AU - Ding JH
AU - Yang BZ
AU - Nada MA
AU - Roe CR
IN - Kimberly H. Courtwright, Baylor University Medical Center, Dallas, Texas 75246, USA.
TI - Improved detection of the G1528C mutation in LCHAD deficiency.
SO - Biochem Mol Med 1996 Jun;58(1):46-51
AB - Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, an autosomal recessive disorder of fatty-acid oxidation, is clinically characterized by skeletal myopathy, Reye-like syndrome, or sudden unexplained infant death. A common mutation, G1528C, has recently been reported. To avoid nonspecific amplification from a "pseudogene" and potential complications, we have developed a nested PCR/PstI digestion method. Here, we report mutation studies in 11 additional unrelated patients with LCHAD deficiency. Genomic DNA fragments (117 bp) were amplified by the nested PCR, digested with PstI, and subjected to electrophoresis on 12% polyacrylamide gel. Four patients were found to be homozygous for the G1528C mutation; 7 patients were compound heterozygous, indicating significant genetic heterogeneity. The G1528C mutation has been found on at least one allele in all patients with isolated LCHAD deficiency, suggesting that it is an excellent marker for this disease. This DNA test combined with tandem mass-spectrometric in vitro probe analysis easily identifies affected individuals and carriers in families which are compound heterozygous for G1528C.
3
UI - 97093135
AU - Tyni T
AU - Majander A
AU - Kalimo H
AU - Rapola J
AU - Pihko H
IN - Department of Child Neurology, Children's Hospital, University of Helsinki, Finland. tiityn:utu.fi
TI - Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528C mutation.
SO - Neuromuscul Disord 1996 Oct;6(5):327-37
AB - Lactic acidosis and mitochondrial abnormalities have been reported in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. We studied muscle morphology and the respiratory chain function in ten patients with LCHAD deficiency and the G1528C mutation. In eight cases the light microscopy of muscle specimens showed fatty infiltration and fibre degeneration. The degenerated fibres appeared as ragged red fibres in four cases. Electron microscopy revealed enlarged mitochondria often with swollen appearance in four out of seven patients. The number of mitochondria had also increased. Complex I associated enzyme activities in muscle mitochondria were decreased in five out of seven patients, and in three of them Complex II or II + III associated activities were also affected. We suggest that the reason for respiratory chain dysfunction and structural changes of mitochondria is the accumulation of toxic intermediates of fatty acid beta-oxidation in mitochondria. Because these changes may confound the differential diagnostics between LCHAD deficiency and respiratory chain defects, awareness of their frequency is important.
4
UI - 97157568
AU - Tyni T
AU - Palotie A
AU - Viinikka L
AU - Valanne L
AU - Salo MK
AU - von Dobeln U
AU - Jackson S
AU - Wanders R
AU - Venizelos N
AU - Pihko H
IN - Department of Child Neurology, Children's Hospital, University of Helsinki, Finland.
TI - Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: clinical presentation of thirteen patients.
SO - J Pediatr 1997 Jan;130(1):67-76
AB - Long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase is one of three enzyme activities of the mitochondrial trifunctional protein. We report the clinical findings of 13 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. At presentation the patients had had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Seven patients had recurrent metabolic crises, and six patients had a steadily progressive course. Two patients had cholestatic liver disease, which is uncommon in beta-oxidation defects. One patient had peripheral neuropathy, and six patients had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. All patients were homozygous for the common mutation G1528C. However, the enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities of the mitochondrial trifunctional protein were variably decreased in skin fibroblasts. Dicarboxylic aciduria was detected in 9 of 10 patients, and most patients had lactic acidosis, increased serum creatine kinase activities, and low serum carnitine concentration. Neuroradiologically there was bilateral periventricular or focal cortical lesions in three patients, and brain atrophy in one. Only one patient, who has had dietary treatment for 9 years, is alive at the age of 14 years; all others died before they were 2 years of age. Recognition of the clinical features of long-chain 3-hydroxyacyl-CoA deficiency is important for the early institution of dietary management, which may alter the otherwise invariably poor prognosis.
5
UI - 97018658
AU - Isaacs JD Jr
AU - Sims HF
AU - Powell CK
AU - Bennett MJ
AU - Hale DE
AU - Treem WR
AU - Strauss AW
IN - Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA.
TI - Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele.
SO - Pediatr Res 1996 Sep;40(3):393-8
AB - Acute fatty liver of pregnancy (AFLP) is a devastating late gestational complication with many similarities to the inherited disorders of mitochondrial fatty acid oxidation. We report the molecular defects in a woman with AFLP and her infant who subsequently was diagnosed with trifunctional protein (TFP) deficiency. We used single-stranded conformation variance and DNA sequence analyses of the human TFP alpha-subunit gene, which encodes the long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity, to demonstrate a C to T mutation (C1678T) in exon 16 present on one allele in the mother and the affected infant. This creates a premature termination codon (R524Stop) in the LCHAD domain. Using reverse transcriptase-PCR amplification of the alpha-subunit mRNA from cultured fibroblasts, we demonstrated that transcripts containing this R524Stop mutation are present at very low levels, presumably because of rapid mRNA degradation. The affected infant also had the common E474Q mutation (nucleotide G1528C) on the second allele. Thus, he is a compound heterozygote. The father and two normal siblings are heterozygous for this E474Q mutation. This initial delineation of the R524Stop mutation provides evidence of the heterogeneity of genetic defects responsible for TFP deficiency and AFLP.
6
UI - 97085264
AU - Treem WR
AU - Shoup ME
AU - Hale DE
AU - Bennett MJ
AU - Rinaldo P
AU - Millington DS
AU - Stanley CA
AU - Riely CA
AU - Hyams JS
IN - Division of Pediatric Gastroenterology and Nutrition, Hartford Hospital, University of Connecticut School of Medicine, Farmington, USA.
TI - Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency [see comments].
SO - Am J Gastroenterol 1996 Nov;91(11):2293-300
AB - BACKGROUND: The similarity of the hepatic pathology in acute fatty liver of pregnancy (AFLP) to that seen in children with inherited disorders of intramitochondrial fatty acid oxidation (FAO) suggests that there may be a genetic basis for some cases of AFLP. OBJECTIVE: The purpose of this study was to examine patients with AFLP and their offspring to determine if there were women with AFLP who were heterozygous for the FAO defect, long chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency. METHODS: We evaluated 12 women previously diagnosed with AFLP. Provocative fasting studies and skin biopsies for examination of their cultured skin fibroblasts were performed to search for a generalized defect in FAO both in vivo and in vitro. Cultured skin fibroblasts from AFLP patients, their children, and their husbands were also examined specifically for LCHAD activity. RESULTS: Of 12 women with a previous episode of AFLP, eight had reduced LCHAD activity consistent with being heterozygous for LCHAD deficiency. The eight heterozygotes had a total of nine pregnancies complicated by AFLP. In seven of those nine pregnancies, the women developed severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Of the nine offspring delivered from these pregnancies, four were confirmed to be affected with homozygous LCHAD deficiency. Three other deceased infants were presumed to be LCHAD-deficient based on clinical findings, postmortem examination, and confirmed heterozygote parents. The remaining two infants delivered after pregnancies complicated by AFLP had LCHAD activity in the heterozygous range and are healthy at 18 and 24 months of age. Consistent with the known autosomal recessive nature of this defect, five tested husbands of LCHAD heterozygous women with a history of AFLP and affected infants also showed reduced LCHAD activity. CONCLUSIONS: These studies indicate that a significant subgroup of women with AFLP are heterozygous for LCHAD deficiency and that careful observation of their offspring for signs of this disorder is warranted. Severe preeclampsia appears to increase the risk of AFLP in LCHAD heterozygous women.
7
UI - 96422791
AU - Bennett MJ
AU - Weinberger MJ
AU - Kobori JA
AU - Rinaldo P
AU - Burlina AB
IN - Department of Pathology, University of Texas Southwestern Medical Center at Dallas, 75234, USA.
TI - Mitochondrial short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: a new defect of fatty acid oxidation.
SO - Pediatr Res 1996 Jan;39(1):185-8
AB - We describe two children with deficiency of short-chain L-3-hydroxyacyl-CoA dehydrogenase, a new disorder of the mitochondrial beta-oxidation of straight-chain fatty acids. The patients presented with fasting-induced vomiting, and ketosis and low blood glucose, features typical of ketotic hypoglycemia were documented in one. Enzyme assays were performed in cultured skin fibroblasts. In whole fibroblast preparations there was reduced enzyme activity but high residual activity due to the presence of a nonmitochondrial enzyme. In isolated fibroblast mitochondria the residual enzyme activities were 5 and 6% of the normal controls. Activity in an obligate heterozygote was intermediate, suggesting that this is an autosomal recessive disorder.
8
UI - 96338861
AU - Pons R
AU - Roig M
AU - Riudor E
AU - Ribes A
AU - Briones P
AU - Ortigosa L
AU - Baldellou A
AU - Gil-Gibernau J
AU - Olesti M
AU - Navarro C
AU - Wanders RJ
IN - Child Neurology Unit, Vall d'Hebron University Hospital, Barcelona, Spain.
TI - The clinical spectrum of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. [Review] [44 refs]
SO - Pediatr Neurol 1996 Apr;14(3):236-43
AB - Four patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency are presented. Clinical onset in the form of acute encephalopathy occurred between the ages of 9 months and 3 years. The clinical course included recurrent metabolic crises in 4 patients, cardiac involvement and retinopathy in 3, and myopathy in 2. None had signs of peripheral neuropathy. Three patients died and one is currently well. Hypoketotic hypoglycemia with C6-C14 3-hydroxy-dicarboxylic aciduria during metabolic crises associated with decreased plasma carnitine levels was the main biochemical finding. Enzymologic studies disclosed long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency in all patients. Homozygosity for a G to C mutation at position 1528 in the encoding region of the enzyme was found in 2 patients. Histologic and electron microscopic studies of liver biopsy specimens revealed steatosis in 3 patients and mitochondrial abnormalities in 2. Skeletal muscle biopsies disclosed nonspecific degenerative changes in 2 patients and were normal in the remaining 2. Ultrastructural abnormalities in mitochondria were found in 3 patients. A review of the literature combined with the data from our series (total 22 patients) disclosed acute clinical onset in 77% of cases and subacute in 23%. In the combined series, the average age at onset was 11 months, family history was positive in 32% of patients and overall mortality was 50%. We describe the clinical spectrum of this disease and emphasize that, among patients with suspected beta-oxidation defects the finding of pigmentary retinopathy should lead to the suspicion of long-chain 3-hydroxyacyl-coenzyme A-dehydrogenase deficiency. [References: 44]
9
UI - 96302264
AU - He XY
AU - Yang SY
IN - Department of Pharmacology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314, USA.
TI - Histidine-450 is the catalytic residue of L-3-hydroxyacyl coenzyme A dehydrogenase associated with the large alpha-subunit of the multienzyme complex of fatty acid oxidation from Escherichia coli.
SO - Biochemistry 1996 Jul 23;35(29):9625-30
AB - Multienzyme complexes of fatty acid oxidation from Escherichia coli with Gln or Ala substituting for His450 or with Ala in place of Gly322 in the large alpha-subunit have been purified and characterized. The alpha/Gly322-->Ala mutation did not significantly affect the catalytic efficiencies (kcat/k(m)) of different component enzymes except for a 6.1-fold decrease in the kcat/k(m) of L-3-hydroxyacyl-CoA dehydrogenase and a 10-fold increase in the k(m) for NADH. This observation confirms the prediction [Yang, X.-Y. H., Schulz, H., Elzinga, M., & Yang, S.-Y. (1991) Biochemistry 30, 6788-6795] that the E. coli dehydrogenase has an NAD-binding site at its amino-terminal domain and structurally resembles the pig heart dehydrogenase. The pH dependence of the kcat/k(m) of the E. coli dehydrogenase suggested the catalytic involvement of an amino acid residue with a pKa of 6, which is presumably a histidine residue as proposed previously on the basis of chemical modifications. Since His450 of the E. coli multifunctional protein is the only histidine conserved in all known L-3-hydroxyacyl-CoA dehydrogenases, and since its counterpart in pig heart enzyme appeared to be close to the 3-keto group of the fatty acyl moiety of the substrate, His450 was replaced by either Gln or Ala. The catalytic properties of 3-ketoacyl-CoA thiolase, enoyl-CoA hydratase, and delta 3-cis-delta 2-trans-enoyl-CoA isomerase of the alpha/His450-->Gln mutant complex were virtually unchanged except for a small decrease in the kcat values of the latter two enzymes. In contrast, the dehydrogenase of this mutant complex was almost inactive due to a greater than 3000-fold decrease in its kcat and a 6-fold increase in the k(m) for NADH. The alpha/His450-->Ala mutant complex showed similar catalytic behaviors. Taken together, several lines of evidence lead to the conclusion that His450 is the catalytic residue of L-3-hydroxyacyl-CoA dehydrogenase of the E. coli multifunctional fatty acid oxidation protein.
10
UI - 96366737
AU - IJlst L
AU - Ruiter JP
AU - Hoovers JM
AU - Jakobs ME
AU - Wanders RJ
IN - Department of Pediatrics, Institute of Human Genetics, University Hospital Amsterdam, The Netherlands.
TI - Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.
SO - J Clin Invest 1996 Aug 15;98(4):1028-33
AB - Mitochondrial trifunctional protein (MTP) is a recently identified enzyme involved in mitochondrial beta-oxidation, harboring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain 3-ketothiolase activity. A deficiency of this protein is associated with impaired oxidation of long-chain fatty acids which can lead to sudden infant death. Furthermore, it is clear that this inborn error of fatty acid oxidation is very frequent, second to medium chain acyl-CoA dehydrogenase deficiency. In most patients only the LCHAD activity of MTP is deficient with near normal activity of the two other enzyme activities of the complex. We recently described the occurrence of a frequent G1528C mutation in the cDNA coding for the a subunit of MTP. Using S. cerevisiae for expression of wild type and mutant protein we show that the G1528C mutation is directly responsible for the loss of LCHAD activity. Furthermore, we describe a newly developed method allowing identification of the G1528C mutation in genomic DNA. The finding of an 87% allele frequency of the G1528C mutation in 34 LCHAD deficient patients makes this a valuable test for prenatal diagnosis. Finally, we show that the gene encoding the alpha subunit of MTP is located on chromosome 2p24.1-23.3.
11
UI - 96189988
AU - Dani R
AU - Mendes GS
AU - Medeiros J de L
AU - Peret FJ
AU - Nunes A
IN - Gastroenterology Service, Hospital Israel Pinheiro of the Instituto de Previdencia, Belo Horizonte, Brazil.
TI - Study of the liver changes occurring in preeclampsia and their possible pathogenetic connection with acute fatty liver of pregnancy.
SO - Am J Gastroenterol 1996 Feb;91(2):292-4
AB - OBJECTIVE: The objective of the present study was to investigate liver involvement in preeclampsia on the basis of clinical, laboratory, and histological data and to detect a possible connection with fatty liver of pregnancy by the determination of microvesicular fatty infiltration of the liver. METHODS: The authors studied the liver changes in 10 patients with preeclampsia, observing the clinical and laboratory alterations, the macroscopic liver surface features by laparoscopy, and the presence of microvesicular fatty infiltration by specific lipid staining of hepatic tissue collected by needle biopsy. RESULTS: Macroscopy of the liver surface disclosed some degree of subcapsular liver hemorrhage in all cases; however, the hemorrhage was not related to the clinical and histological severity of the disease. Microvesicular fat droplets were observed in all patients, and the intensity of the fat deposition was not related to pressor levels, laboratory alterations, or the evolution of preeclampsia. CONCLUSIONS: The presence of fatty liver infiltration in all patients studied supports the idea that preeclampsia and acute fatty liver of pregnancy could be components of the same pathologic spectrum, with a probable, but still unproved, pathogenetic connection. The deficiency of the long chain 3-hydroxyacyl-coenzyme A dehydrogenase activity may be the determining factor in the evolution of the disease.
12
UI - 96157720
AU - Furuta S
AU - Hashimoto T
IN - Department of Biochemistry, Shinshu University School of Medicine, Nagano. sfuruta:gipac.shinshu-u.ac.jp
TI - Purification and properties of 3-hydroxyacyl coenzyme A dehydrogenase-binding protein from rat liver mitochondria.
SO - J Biochem (Tokyo) 1995 Oct;118(4):810-8
AB - Mitochondria isolated from rat liver were freeze-thawed and washed with 0.1 M potassium phosphate, pH 7.4. Most of the 3-hydroxyacyl coenzyme A (CoA) dehydrogenase activities were removed and this mitochondrial membrane fraction could bind exogenous 3-hydroxyacyl-CoA dehydrogenase. 3-Hydroxyacyl-CoA dehydrogenase-binding protein was extracted from the washed membrane fraction with a buffer containing 2% Triton X-100 and 2% sodium taurodeoxycholate. The binding protein was purified by Ultrogel AcA 34 gel chromatography, calcium phosphate gel-cellulose chromatography and 3-hydroxyacyl-CoA dehydrogenase affinity chromatography. The molecular mass of the purified binding protein was estimated to be 140 kDa by gel filtration and its subunit molecular mass was determined as 60 kDa by SDS-PAGE suggesting that the protein is a homodimer. The binding protein and 3-hydroxyacyl-CoA dehydrogenase formed a complex at low ionic strength and the stoichiometry revealed that 1 mol of the binding protein bound 2 mol of 3-hydroxyacyl-CoA dehydrogenase. Purified 3-hydroxyacyl-CoA dehydrogenase-binding protein interacted with 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase but did not bind other mitochondrial beta-oxidation enzymes. The pH optimum of the binding activity was from pH 6 to 7 and the binding activity was diminished by increasing the concentration of salt in the medium.
13
UI - 96090045
AU - Conjard A
AU - Ferrier B
AU - Martin M
AU - Caillette A
AU - Carrier H
AU - Baverel G
IN - Laboratoire de Physiopathologie Metabolique et Renale (INSERM C.R.I. 95-02-01), Faculte de Medecine Alexis Carrel, Lyon, France.
TI - Effects of chronic renal failure on enzymes of energy metabolism in individual human muscle fibers.
SO - J Am Soc Nephrol 1995 Jul;6(1):68-74
AB - In order to improve knowledge about the mechanisms underlying the alterations of energy metabolism recently observed in the skeletal muscle of patients suffering from chronic renal failure, this study was designed to test (1) whether changes in the activity of key enzymes of energy metabolism occur in the muscle of these patients, and if so (2) whether the different muscle fiber types are equally altered in their metabolic machinery. For this, the maximum activities of 14 enzymes were measured in individual muscle fibers microdissected from biopsies of rectus abdominis muscle obtained from seven normal subjects and seven patients with end-stage renal failure before renal replacement therapy. A large decrease in the activities of beta-hydroxyacyl-coenzyme A dehydrogenase, a key enzyme of the beta-oxidation pathway, of citrate synthase, which initiates the tricarboxylic acid cycle, and of fructose-1,6-bisphosphatase, which contributes to the synthesis of glycogen from lactate, was observed in the three fiber types (slow-twitch oxidative, fast-twitch oxidative-glycolytic, and fast-twitch glycolytic). A smaller reduction of the activities of phosphofructokinase and/or pyruvate kinase, two key enzymes of glycolysis, was also observed in slow-twitch oxidative and/or fast-twitch oxidative-glycolytic fibers. These results demonstrate that the abnormalities of muscle energy metabolism observed in patients with chronic renal failure are due, at least in part, to intrinsic changes in the key enzymes of major energy-providing pathways; they also offer a satisfactory explanation for the defect of oxidative metabolism recently demonstrated in the muscle of these patients.
14
UI - 96006279
AU - Hicks P
AU - Bennett MJ
AU - Squires J
AU - Ramilo O
IN - Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas 75235, USA.
TI - Heterozygosity for long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and deterioration in liver function in a newborn infant infected with human immunodeficiency virus.
SO - J Pediatr 1995 Oct;127(4):599-602
AB - A child with perinatally acquired human immunodeficiency virus infection had rapidly progressive hepatic dysfunction, as had her older sibling who died. Urinary organic acid studies revealed 3-hydroxydicarboxylic aciduria, and cultured skin fibroblasts had reduced activity of 3-hydroxy-coenzyme A dehydrogenase. The introduction of a low fat diet resulted in marked improvement in clinical status and reversal of the liver disease. This case illustrates the necessity of metabolic evaluation in patients with liver dysfunction, even when other causes of liver dysfunction are present.
15
UI - 95330502
AU - Mygind E
IN - Danish State Institute of Physical Education, Copenhagen.
TI - Fibre characteristics and enzyme levels of arm and leg muscles in elite cross-country skiers.
SO - Scand J Med Sci Sports 1995 Apr;5(2):76-80
AB - Performance tests and measurements of maximal aerobic capacity were performed during the competition period in elite cross-country skiers. Muscle biopsies were taken in the middle of January. Histochemical fibre typing, determination of fibre areas and number of capillaries as well as assays for citrate synthetase (CS), 3-hydroxyacyl coenzyme A dehydrogenase (HAD), lactate dehydrogenase (LDHtot and LDH1-2) were performed on biopsies from the triceps brachii (TRI) and vastus lateralis muscles (VAS). The relative percentage of slow-twitch fibres was 51.3 and 68.6 in TRI and VAS, respectively. The FTa fibre area in TRI was significantly larger than in VAS. No differences were found in the number of capillaries per fibre in TRI (2.7) and VAS (2.5). The number of capillaries per area was significantly lower in TRI (373) as compared to VAS (422). The LDHtot enzyme level was significantly higher in TRI than VAS, while the oxidative enzyme activities (CS and HAD) were significantly lower in TRI as compared with VAS. From all independent variables, only the maximal aerobic power was related significantly to performance time. The difference in maximal aerobic power between the skiers could explain 45% of the total variance in performance.
16
UI - 95148633
AU - Sims HF
AU - Brackett JC
AU - Powell CK
AU - Treem WR
AU - Hale DE
AU - Bennett MJ
AU - Gibson B
AU - Shapiro S
AU - Strauss AW
IN - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.
TI - The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy.
SO - Proc Natl Acad Sci U S A 1995 Jan 31;92(3):841-5
AB - Mitochondrial long chain fatty acid beta-oxidation provides the major source of energy in the heart. Deficiencies of human beta-oxidation enzymes produce sudden, unexplained death in childhood, acute hepatic encephalopathy, skeletal myopathy, or cardiomyopathy. Long chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxidoreductase, EC 1.1.1.211] catalyzes the third step in beta-oxidation, and this activity is present on the C-terminal portion of the alpha subunit of mitochondrial trifunctional protein. We used single-stranded conformation variance analysis of the exons of the human LCHAD (alpha subunit) gene to determine the molecular basis of LCHAD deficiency in three families with children presenting with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mothers had acute fatty liver and associated sever complications during pregnancies with the affected infants. The analysis in two affected children revealed a G to C mutation at position 1528 (G1528C) of the alpha subunit of the trifunctional protein on both alleles. This is in the LCHAD domain and substitutes glutamine for glutamic acid at position 474 of mature alpha subunit. The third child had this G1528C mutation on one allele and a different mutation (C1132T) creating a premature termination codon (residue 342) on the second allele. Our results demonstrate that mutations in the LCHAD domain of the trifunctional protein alpha subunit in affected offspring are associated with maternal acute fatty liver of pregnancy. This is the initial delineation of the molecular basis of isolated LCHAD deficiency.
17
UI - 94215159
AU - Alvares K
AU - Fan C
AU - Dadras SS
AU - Yeldandi AV
AU - Rachubinski RA
AU - Capone JP
AU - Subramani S
AU - Iannaccone PM
AU - Rao MS
AU - Reddy JK
IN - Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611.
TI - An upstream region of the enoyl-coenzyme A hydratase/3-hydroxyacyl-coenzyme A dehydrogenase gene directs luciferase expression in liver in response to peroxisome proliferators in transgenic mice.
SO - Cancer Res 1994 May 1;54(9):2303-6
AB - Peroxisome proliferators, which are structurally diverse nonmutagenic agents, induce hepatocarcinogenesis in rats and mice. Exposure to these xenobiotics leads to a rapid and coordinated transcriptional activation of the genes for the peroxisomal beta-oxidation enzyme system pathway in the liver. We have previously identified a peroxisome proliferator-responsive element in the 5'-flanking region of the rat peroxisomal hydratase/dehydrogenase (PBE) gene, the second enzyme in the beta-oxidation pathway. The peroxisome proliferator-responsive element in the PBE gene was shown to direct the induction of a luciferase reporter gene in vitro. We have now used this 3.2-kilobase 5'-flanking region of the PBE gene fused to the coding region of luciferase to generate transgenic mice. Three independent lines of transgenic mice expressed luciferase in response to ciprofibrate, a peroxisome proliferator. The induction of luciferase is specific to the liver; this agrees with the tissue-specific induction of PBE. Two other hypolipidemic drugs, nafenopin and Wy-14,643, were also capable of inducing luciferase activity in the liver. This study suggests that the PBE upstream element can be used to direct and modulate the expression of cloned genes by changing the levels of peroxisome proliferators. Also, the PBE-luciferase transgenic mouse should be an excellent model system for screening xenobiotics for potential peroxisome proliferator property.
18
UI - 95068080
AU - Fryburg JS
AU - Pelegano JP
AU - Bennett MJ
AU - Bebin EM
IN - Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville 22908.
TI - Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (L-CHAD) deficiency in a patient with the Bannayan-Riley-Ruvalcaba syndrome.
SO - Am J Med Genet 1994 Aug 1;52(1):97-102
AB - Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas, hypotonia, developmental delay, and a lipid myopathy. The etiology of the lipid storage myopathy has been unclear. We describe a black boy with findings of BRRS who also has a defect in long-chain fatty acid oxidation expressed in cultured skin fibroblasts as a deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (L-CHAD). He also has an abnormal brain MRI and increased size of both lower limbs. We present this child because of his unusual combination of findings, and postulate that L-CHAD deficiency may be the cause of the lipid myopathy in BRRS.
19
UI - 94301213
AU - Tremblay A
AU - Simoneau JA
AU - Bouchard C
IN - Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Quebec, Canada.
TI - Impact of exercise intensity on body fatness and skeletal muscle metabolism.
SO - Metabolism 1994 Jul;43(7):814-8
AB - The impact of two different modes of training on body fatness and skeletal muscle metabolism was investigated in young adults who were subjected to either a 20-week endurance-training (ET) program (eight men and nine women) or a 15-week high-intensity intermittent-training (HIIT) program (five men and five women). The mean estimated total energy cost of the ET program was 120.4 MJ, whereas the corresponding value for the HIIT program was 57.9 MJ. Despite its lower energy cost, the HIIT program induced a more pronounced reduction in subcutaneous adiposity compared with the ET program. When corrected for the energy cost of training, the decrease in the sum of six subcutaneous skinfolds induced by the HIIT program was ninefold greater than by the ET program. Muscle biopsies obtained in the vastus lateralis before and after training showed that both training programs increased similarly the level of the citric acid cycle enzymatic marker. On the other hand, the activity of muscle glycolytic enzymes was increased by the HIIT program, whereas a decrease was observed following the ET program. The enhancing effect of training on muscle 3-hydroxyacyl coenzyme A dehydrogenase (HADH) enzyme activity, a marker of the activity of beta-oxidation, was significantly greater after the HIIT program. In conclusion, these results reinforce the notion that for a given level of energy expenditure, vigorous exercise favors negative energy and lipid balance to a greater extent than exercise of low to moderate intensity. Moreover, the metabolic adaptations taking place in the skeletal muscle in response to the HIIT program appear to favor the process of lipid oxidation.
20
UI - 94124113
AU - Treem WR
AU - Rinaldo P
AU - Hale DE
AU - Stanley CA
AU - Millington DS
AU - Hyams JS
AU - Jackson S
AU - Turnbull DM
IN - Division of Pediatric Gastroenterology, Hartford Hospital, Farmington, Connecticut 06115.
TI - Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.
SO - Hepatology 1994 Feb;19(2):339-45
AB - The pathogenesis of acute fatty liver of pregnancy is unknown, but similarities in the clinical presentation and the histological appearance of the liver with those found in children with metabolic defects in the intramitochondrial beta-oxidation pathway of the liver suggest that a disturbance in hepatic fatty acid oxidation may play a role. We report a woman with acute fatty liver of pregnancy who gave birth to a seemingly normal full-term infant who was seen at 4 mo of age with hypoglycemia, coma and profound hepatic steatosis. The infant had a defect in fatty acid oxidation, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, and the mother proved to be heterozygous for this metabolic condition. We hypothesize that the interaction of an affected fetus with a female heterozygous for this defect in fatty acid oxidation in the late third trimester accounts for some cases of acute fatty liver of pregnancy.
21
UI - 93156506
AU - Wilcken B
AU - Leung KC
AU - Hammond J
AU - Kamath R
AU - Leonard JV
IN - Oliver Latham Laboratory, New South Wales Health Department, Sydney, Australia.
TI - Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency.
SO - Lancet 1993 Feb 13;341(8842):407-8
AB - We report on eleven pregnancies in 5 mothers. 6 of the babies had long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency, and each of the pregnancies was complicated by features such as fatty liver and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome. By contrast, 3 of the mothers also gave birth to unaffected babies, and these pregnancies were largely uncomplicated. We conclude that there may be adverse effects on maternal liver function from a fetus with LCHAD deficiency. Heterozygosity in the mother cannot alone account for the adverse effects because of the segregation of these effects with fetal LCHAD status.
22
UI - 94109389
AU - Hartmann CM
AU - Gehring H
AU - Christen P
IN - Biochemisches Institut der Universitat Zurich, Switzerland.
TI - The mature form of imported mitochondrial proteins undergoes conformational changes upon binding to isolated mitochondria.
SO - Eur J Biochem 1993 Dec 15;218(3):905-10
AB - Mature mitochondrial proteins (aspartate aminotransferase, malate dehydrogenase, hydroxyacyl coenzyme A dehydrogenase, creatine kinase) and cytosolic proteins (aldolase, glyceraldehyde-3-phosphate dehydrogenase) with a basic pI were found to bind to isolated mitochondria, electrostatic interactions being mainly responsible for their binding. Mitochondrial aspartate aminotransferase bound with a Kd' of 30 nM in 0.6 M sorbitol, 20 mM Hepes/KOH, pH 7.4, at 25 degrees C. Cytosolic aspartate aminotransferase and glutamate dehydrogenase (a protein located in the mitochondrial matrix) both with an acidic pI, did not bind to mitochondria. Treatment of mitochondria with proteinases did not affect the subsequent binding of imported mitochondrial proteins. Their association with both intact and proteinase-treated mitochondria resulted in a marked increase in their susceptibility toward proteinase K. In contrast, the basic cytosolic proteins tested bound only to intact mitochondria and thereby did not become more susceptible toward proteolytic attack. Treatment of mitochondria with adriamycin, a drug binding to acidic phospholipids, prevented the subsequent association of mitochondrial aspartate aminotransferase with mitochondria and the ensuing conformational labilization. Apparently, the mature moiety of imported mitochondrial proteins is partially unfolded upon interaction with the lipid component of the mitochondrial envelope. Both the binding of the mitochondrial proteins and their conformational labilization is independent of ATP and the electrochemical potential across the inner membrane.
23
UI - 93307328
AU - Moore R
AU - Glasgow JF
AU - Bingham MA
AU - Dodge JA
AU - Pollitt RJ
AU - Olpin SE
AU - Middleton B
AU - Carpenter K
IN - Department of Child Health, Queen's University of Belfast, Northern Ireland.
TI - Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency--diagnosis, plasma carnitine fractions and management in a further patient.
SO - Eur J Pediatr 1993 May;152(5):433-6
AB - Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD), the third enzyme of the mitochondrial beta-oxidation pathway, carries out the dehydrogenation of 3-hydroxyacyl-CoA compounds of 12-18 carbon length. To date only nine cases of LCHAD deficiency have been documented. We report a further patient who as a neonate developed non-specific gastrointestinal symptoms and at 5 months of age cardiomyopathy, recurrent hypoketotic hypoglycaemia and gross alterations of plasma carnitine fractions. Dietary management with medium chain triglycerides led rapidly to clinical improvement. There was a close correlation between the clinical condition, plasma carnitine fractions and cardiac function. At 2 years of age she is developing normally.
24
UI - 92276165
AU - Bangsbo J
AU - Jacobsen K
AU - Nordberg N
AU - Christensen NJ
AU - Graham T
IN - August Krogh Institute, Copenhagen, Denmark.
TI - Acute and habitual caffeine ingestion and metabolic responses to steady-state exercise [published erratum appears in J Appl Physiol 1992 Aug;73(2):following table of contents].
SO - J Appl Physiol 1992 Apr;72(4):1297-303
AB - This study compared the exercise catecholamine and metabolic responses to a caffeine challenge in trained subjects before and after a 6-wk period of increased caffeine ingestion. Trained subjects (n = 6) were challenged with 500 mg of caffeine followed by prolonged exercise before and after 6 wk of increased caffeine ingestion (500 mg ingested before each daily run). A control group (n = 6) of trained subjects followed the same protocol except for caffeine ingestion. Acute caffeine ingestion resulted in increased plasma epinephrine and decreased respiratory exchange ratio (RER) during exercise. After 6 wk of caffeine supplementation, the epinephrine response to exercise or caffeine plus exercise was decreased, although the latter still resulted in a lower RER value compared with exercise without caffeine ingestion. Activity of key metabolic enzymes (hexokinase, citrate synthase, phosphorylase, and 3-hydroxyacyl-coenzyme A dehydrogenase) from biopsies of the gastrocnemius showed no response to 6 wk of this increased adrenergic receptor stimulation and, on the basis of the lower RER, enhanced fat metabolism. This study suggests that caffeine ingestion by trained subjects causes increases in plasma epinephrine and reduces the RER during exercise. However, habitual stimulation results in a general dampening of the epinephrine response to caffeine or exercise. There was no indication that increased adrenergic stimulation and fat oxidation caused any adaptation in the activity of metabolic enzymes.
25
UI - 92198421
AU - Carpenter K
AU - Pollitt RJ
AU - Middleton B
IN - Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, England, U.K.
TI - Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria.
SO - Biochem Biophys Res Commun 1992 Mar 16;183(2):443-8
AB - We have purified to homogeneity the long-chain specific 3-hydroxyacyl-CoA dehydrogenase from mitochondrial membranes of human infant liver. The enzyme is composed of non-identical subunits of 71 kDa and 47 kDa within a native structure of 230 kDa. The pure enzyme is active with 3-ketohexanoyl-CoA and gives maximum activity with 3-ketoacyl-CoA substrates of C10 to C16 acyl-chain length but is inactive with acetoacetyl-CoA. In addition to 3-hydroxyacyl-CoA dehydrogenase activity, the enzyme possesses 2-enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities which cannot be separated from the dehydrogenase. None of these enzymes show activity with C4 substrates but all are active with C6 and longer acyl-chain length substrates. They are thus distinct from any described previously. This human liver mitochondrial membrane-bound enzyme catalyses the conversion of medium- and long-chain 2-enoyl-CoA compounds to: 1) 3-ketoacyl-CoA in the presence of NAD alone and 2) to acetyl-CoA (plus the corresponding acyl-CoA derivatives) in the presence of NAD and CoASH. It is therefore a multifunctional enzyme, resembling the beta-oxidation enzyme of E. coli, but unique in its membrane location and substrate specificity. We propose that its existence explains the repeated failure to detect any intermediates of mitochondrial beta-oxidation.
26
UI - 92128031
AU - Rinaldo D
AU - Le Dividich J
IN - Institut National de la Recherche Agronomique, Station de Recherches Porcines, L'Hermitage, France.
TI - Effects of warm exposure on adipose tissue and muscle metabolism in growing pigs.
SO - Comp Biochem Physiol A 1991;100(4):995-1002
AB - 1. Forty-eight pigs weaned at 3 weeks old and acclimated to the experimental temperatures for 2 weeks before the start of the experiment, were fed ad lib and used between 9 and 33 kg live weight to determine the effects of warm exposure (31.5 vs 18.5 degrees C) on adipose tissue and muscle metabolism. 2. Warm exposure induced a decline in the lipid content (P less than 0.01) of backfat whereas degree of saturation (P less than 0.05) and adipocytes size were increased (P less than 0.05). 3. At 31.5 degrees C, as compared to 18.5 degrees C, activities of malic enzyme and glucose-6-phosphate dehydrogenase were depressed by an average 33% in backfat (P less than 0.01) and 23% in leaf fat (P less than 0.05) while lipoprotein-lipase activity was stimulated by 60% (P less than 0.01) in leaf fat. 4. In warm conditions, the activities of the enzymes indicative of oxidative and glycolytic metabolism in muscle, i.e. lactate dehydrogenase, beta-hydroxyacyl coenzyme-A dehydrogenase, citrate synthase and cytochrome oxidase, were reduced in the longissimus dorsi muscle (P less than 0.05) and to a lesser extent in the trapezius muscle. 5. At 31.5 degrees C, pigs exhibit lower average plasma levels of insulin, T3 and T4 than those maintained at 18.5 degrees C.
27
UI - 92104132
AU - Desplanches D
AU - Mayet MH
AU - Ilyina-Kakueva EI
AU - Frutoso J
AU - Flandrois R
IN - Unite Associee Centre National de la Recherche Scientifique 1341, Faculte de Medecine Lyon Grange-Blanche, Universite Claude Bernard Lyon, France.
TI - Structural and metabolic properties of rat muscle exposed to weightlessness aboard Cosmos 1887.
SO - Eur J Appl Physiol 1991;63(3-4):288-92
AB - Male Wistar rats were subjected to 12.5 days of weightlessness aboard Cosmos 1887. Histomorphometric and biochemical analyses were investigated in soleus (SOL), plantaris (PL) and extensor digitorum longus (EDL) muscles of flight rats (group F) and compared with data from two groups of terrestrial controls: one group living free in a vivarium (group V) and another subjected to a flight simulation except for the state of weightlessness (group S). Relative to groups V and S, no alteration in the percentage distribution of fibres had occurred in SOL, PL or EDL, after the flight. In SOL muscles from group F animals, cross-sectional areas of all fibre types were reduced to a greater extent (-40%) than capillary to fibre ratio (-24%) leading to a higher capillary density (+33%) than in V and S groups. In PL, type I, IIA and IIB fibre cross-sectional areas were less decreased (-25%). In EDL, only fast-twitch fibre cross-sectional areas showed an average decrease of 30%. Capillary per fibre ratio was reduced by 15% and 28% respectively in PT and EDL muscles from group F rats compared to control groups V and S. Citrate synthase and 3-hydroxyacyl-coenzyme A dehydrogenase activities remained unchanged in SOL, PL and EDL following spaceflight. These findings indicate greater atrophy and functional alterations (capillarity) compared to those observed after 7 days of microgravity on Cosmos 1667.
28
UI - 91257064
AU - Duran M
AU - Wanders RJ
AU - de Jager JP
AU - Dorland L
AU - Bruinvis L
AU - Ketting D
AU - Ijlst L
AU - van Sprang FJ
IN - University Children's Hospital, Het Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands.
TI - 3-Hydroxydicarboxylic aciduria due to long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency associated with sudden neonatal death: protective effect of medium-chain triglyceride treatment.
SO - Eur J Pediatr 1991 Jan;150(3):190-5
AB - Two siblings were found to be affected by long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, one of which died suddenly and unexpectedly on the 3rd day of life suffering from extreme hypoketotic hypoglycaemia. The younger sibling started to have feeding problems, lowered consciousness, and liver dysfunction at the age of 5 months. Her urine contained large amounts of C6-C14 3-hydroxydicarboxylic acids and conjugated 3-hydroxyoctanoic acid, as verified by gas chromatography/mass spectrometry. Plasma long-chain acylcarnitine was increased. A clue to the diagnosis was given by the results of a phenylpropionic acid loading test. This revealed small, but significant amounts of conjugated 3-hydroxyphenylpropionic acid (phenylhydracrylic acid) in the patient's urine. Subsequently, the activity of long-chain 3-hydroxyacyl-CoA dehydrogenase was found to be deficient in cultured skin fibroblasts. Based on the findings obtained by a medium-chain triglyceride load, a diet enriched in this type of fat was prescribed. On this regimen the patient started to thrive, signs of cardiomyopathy disappeared, and her liver function normalized.
29
UI - 91224462
AU - John-Alder HB
AU - Joos B
IN - Department of Biological Sciences, Rutgers University, Piscataway, New Jersey 08854.
TI - Interactive effects of thyroxine and experimental location on running endurance, tissue masses, and enzyme activities in captive versus field-active lizards (Sceloporus undulatus).
SO - Gen Comp Endocrinol 1991 Jan;81(1):120-32
AB - This study investigates the effects of exogenous thyroxine (T4) on running endurance, tissue masses, and the activities of citrate synthase (CS), pyruvate kinase (PK), cytosolic alpha-glycerophosphate dehydrogenase (alpha-GPDH), and beta-hydroxyacyl Coenzyme A dehydrogenase (HOAD) in Sceloporus undulatus (eastern fence lizard). The enzymes were assayed to indicate maximal catabolic activities that support exercise. Parallel experiments were done on captive and field-active groups to determine whether responses in captive studies adequately predict responses in nature. Exogenous T4 was administered via intraperitoneal pellets. The effect of T4 on running endurance was dependent on the location of the experiment (P = 0.040) such that stamina was increased by T4 only in field-active lizards. At lower levels of biological organization, interactivity between T4 and experimental location was evident but less prevalent than at the level of the whole animal, and some location effects occurred independent of T4 treatment. Heart and kidney masses were significantly greater and total hind leg muscle mass was less in captive than in field-active lizards. Thyroxine reduced liver mass in both locations and kidney mass only in captive lizards. Mass-specific CS and alpha-GPDH in gastrocnemius muscle (mixed fiber type) and HOAD in heart were lower in captive than in field-active lizards; PK in heart and liver and alpha-GPDH in heart were higher in captive lizards. Thyroxine increased CS in liver and HOAD in heart, decreased alpha-GPDH in liver in both locations, and decreased alpha-GPDH in gastrocnemius only in captive lizards. The effects of T4 differed significantly between experimental locations in gastrocnemius muscle (T4 decreased PK only in captive lizards) and in liver (T4 increased PK in field-active lizards and decreased PK in captive lizards). The mechanistic basis of differences in stamina between captive and field-active and between placebo and T4-treated lizards is largely unexplained by the factors measured here, thus illustrating the uncertainty of predicting organismal performance from lower level measurements. Nonetheless, T4 has now been shown to have greater physiological activity in field-active than in captive Sceloporus with regard to resting and total daily metabolic rates and running endurance. The results of this study further confirm that endocrine experiments on captive animals may not predict responses in nature. Further efforts to clarify the physiological significance of seasonal variations in levels of thyroid hormones will have to involve, at least in part, invasive studies on field-active lizards.
30
UI - 91210970
AU - Vici CD
AU - Burlina AB
AU - Bertini E
AU - Bachmann C
AU - Mazziotta MR
AU - Zacchello F
AU - Sabetta G
AU - Hale DE
IN - Department of Metabolism, Bambino Gesu Children's Hospital, Rome, Italy.
TI - Progressive neuropathy and recurrent myoglobinuria in a child with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.
SO - J Pediatr 1991 May;118(5):744-6
31
UI - 91035260
AU - DiRusso CC
IN - Department of Biochemistry, University of Tennessee, Memphis 38163.
TI - Primary sequence of the Escherichia coli fadBA operon, encoding the fatty acid-oxidizing multienzyme complex, indicates a high degree of homology to eucaryotic enzymes.
SO - J Bacteriol 1990 Nov;172(11):6459-68
AB - In Escherichia coli at least five enzyme activities required for the beta-oxidation of fatty acids are associated with a multienzyme complex composed of two subunits in alpha 2 beta 2 conformation (A. Pramanik et al., J. Bacteriol. 137:469-473, 1979). In the present work, the DNA sequence of the genes encoding these two subunits, fadB and fadA, has been determined. The direction of transcription was from fadB to fadA rather than from fadA to fadB, as suggested previously (S. K. Spratt et al., J. Bacteriol. 158:535-542, 1984). Only 10 nucleotides separated the coding sequences for the two peptides, confirming the suggestion that these genes form an operon. The peptides encoded by fadB and fadA were 729 amino acids and 387 amino acids, respectively, in length. The larger and smaller peptides had predicted molecular masses of 79,678 and 40,876 Da, respectively. Recently, the sequence of the fadA gene was published in a separate report (Yang et al., J. Biol. Chem. 265:10424-10429, 1990). In this work, most of the DNA sequence for fadA was confirmed, and 10 errors were corrected. Three of these nucleotide changes resulted in five amino acid residue changes predicted in the carboxy terminus of the fadA-encoded peptide. By comparison to other peptide sequences, the alpha subunit encoded within fadB had 31% perfect identity with the rat peroxisomal enoyl-coenzyme A:hydratase-3-hydroxyacyl-coenzyme A dehydrogenase trifunctional enzyme over the entire length of the two peptides. In agreement with the work of Yang et al., the beta subunit encoded within fadA had 35 to 45% perfect identity with five thiolase genes from different eucaryotic sources over the entire length of the peptide.
32
UI - 90078130
AU - Youngleson JS
AU - Jones DT
AU - Woods DR
IN - Department of Microbiology, University of Cape Town, South Africa.
TI - Homology between hydroxybutyryl and hydroxyacyl coenzyme A dehydrogenase enzymes from Clostridium acetobutylicum fermentation and vertebrate fatty acid beta-oxidation pathways.
SO - J Bacteriol 1989 Dec;171(12):6800-7
AB - The enzymes NAD-dependent beta-hydroxybutyryl coenzyme A dehydrogenase (BHBD) and 3-hydroxyacetyl coenzyme A (3-hydroxyacyl-CoA) dehydrogenase are part of the central fermentation pathways for butyrate and butanol production in the gram-positive anaerobic bacterium Clostridium acetobutylicum and for the beta oxidation of fatty acids in eucaryotes, respectively. The C. acetobutylicum hbd gene encoding a bacterial BHBD was cloned, expressed, and sequenced in Escherichia coli. The deduced primary amino acid sequence of the C. acetobutylicum BHBD showed 45.9% similarity with the equivalent mitochondrial fatty acid beta-oxidation enzyme and 38.4% similarity with the 3-hydroxyacyl-CoA dehydrogenase part of the bifunctional enoyl-CoA hydratase:3-hydroxyacyl-CoA dehydrogenase from rat peroxisomes. The pig mitochondrial 3-hydroxyacyl-CoA dehydrogenase showed 31.7% similarity with the 3-hydroxyacyl-CoA dehydrogenase part of the bifunctional enzyme from rat peroxisomes. The phylogenetic relationship between these enzymes supports a common evolutionary origin for the fatty acid beta-oxidation pathways of vertebrate mitochondria and peroxisomes and the bacterial fermentation pathway.
33
UI - 90054226
AU - He XY
AU - Yang SY
AU - Schulz H
IN - Department of Chemistry, City College of The City University of New York, New York 10031.
TI - Assay of L-3-hydroxyacyl-coenzyme A dehydrogenase with substrates of different chain lengths.
SO - Anal Biochem 1989 Jul;180(1):105-9
AB - A method for assaying L-3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) which permits rate measurements with L-3-hydroxyacyl-CoA substrates of various chain lengths at physiological pH is described. The method is based on a coupled assay system in which 3-ketoacyl-CoA compounds formed by the dehydrogenase are cleaved by 3-ketoacyl-CoA thiolase (EC 2.3.1.16) in the presence of CoASH. The advantages of this assay method are its irreversibility and elimination of product inhibition. The assay procedure was used to determine the kinetic parameters (Km, Vmax) of pig heart L-3-hydroxyacyl-CoA dehydrogenase with several substrates of various chain lengths. The data obtained show the enzyme to be most active with medium-chain substrates whereas Km values for medium-chain and long-chain substrates are almost equal but much lower than those previously reported.
34
UI - 88068574
AU - Birktoft JJ
AU - Holden HM
AU - Hamlin R
AU - Xuong NH
AU - Banaszak LJ
IN - Department of Biological Chemistry, Washington University School of Medicine, St. Louis, MO 63110.
TI - Structure of L-3-hydroxyacyl-coenzyme A dehydrogenase: preliminary chain tracing at 2.8-A resolution.
SO - Proc Natl Acad Sci U S A 1987 Dec;84(23):8262-6
AB - The conformation of L-3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) has been derived from electron-density maps calculated at 2.8-A resolution with phases obtained from two heavy-atom derivatives and the bound coenzyme, NAD. Like other dehydrogenases, 3-hydroxyacyl-CoA dehydrogenase is a double-domain structure, but the bilobal nature of this enzyme is more pronounced than has been previously observed. The amino-terminal domain, which comprises approximately the first 200 residues, is responsible for binding the NAD cofactor and displays considerable structural homology with the dinucleotide binding domains observed in other NAD-, NADP-, and FAD-dependent enzymes. The carboxyl-terminal domain, comprising the remaining 107 residues, appears to be all alpha-helical and bears little homology to other known dehydrogenases. The subunit-subunit interface in the 3-hydroxyacyl-CoA dehydrogenase dimer is formed almost exclusively by residues in the smaller helical domain. A difference map between the apo and holo forms of the crystalline enzyme has been interpreted in terms of the NAD molecule being bound in a typically extended conformation. The location of the coenzyme binding site, along with the structural homology to other dehydrogenases, makes it possible to speculate about the location of the binding site for the fatty acyl-CoA substrate.
35
UI - 86304943
AU - Ji LL
AU - Lennon DL
AU - Kochan RG
AU - Nagle FJ
AU - Lardy HA
TI - Enzymatic adaptation to physical training under beta-blockade in the rat. Evidence of a beta 2-adrenergic mechanism in skeletal muscle.
SO - J Clin Invest 1986 Sep;78(3):771-8
AB - Nonselective and beta 1-selective adrenergic antagonists were tested for their effects on enzymatic adaptation to exercise training in rats as follows: trained + placebo (TC); trained + propranolol (TP); trained + atenolol (TA); and corresponding sedentary groups, SC and SP. Trained rats ran 1 h/d at 26.8 m/min, 15% grade, 5 d/wk, 10 wk. Both beta-antagonists were given at doses that decreased exercise heart rates by 25%. Training increased skeletal muscle citrate synthase, cytochrome c oxidase (Cyt-Ox), carnitine palmitoyltransferase (CPT), beta-hydroxyacyl coenzyme A dehydrogenase, mitochondrial malate dehydrogenase (MDH), and alanine aminotransferase (ALT) activities significantly in the TC group, but not in TP. These enzyme activities, except Cyt-Ox and CPT, were also significantly increased in TA. Hepatic phosphoenolpyruvate carboxykinase activity did not alter with training or beta-blockade. Fructose 1,6-bisphosphatase activity was lower in TC than in SC, but unchanged in TP or TA. Hepatic mitochondrial MDH and ALT activities increased with training only in TC. It is concluded that beta 2-adrenergic mechanisms play an essential role in the training-induced enzymatic adaptation in skeletal muscle.
36
UI - 87033610
AU - Kispal G
AU - Sumegi B
AU - Alkonyi I
TI - Isolation and characterization of 3-hydroxyacyl coenzyme A dehydrogenase-binding protein from pig heart inner mitochondrial membrane.
SO - J Biol Chem 1986 Oct 25;261(30):14209-13
AB - 3-Hydroxyacyl coenzyme A (CoA) dehydrogenase-binding protein was solubilized from inner mitochondrial membrane by using taurodeoxycholate at high ionic strength. The binding protein was isolated from the suspension using 3-hydroxyacyl-CoA dehydrogenase affinity chromatography. The protein eluted from the affinity column had a molecular weight of approximately 150,000, as determined by gel filtration. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the protein is a dimer consisting of 69,000 and 71,000 molecular weight subunits. The enzyme binding capacity of this protein was tested with a polyethylene glycol precipitation method: 0.5 mg of enzyme could be precipitated together with 1 mg of binding protein, showing that 1 mol of binding protein binds 1 mol of enzyme. This protein had no affinity toward malic dehydrogenase, citrate synthase, and fumarase. The approximately 2-fold increase in the 3-hydroxyacyl-CoA dehydrogenase activity when it was measured in the presence of the binding protein is additional evidence of enzyme-binding protein interaction. When incorporated into liposomes, the binding protein retained its ability to bind 3-hydroxyacyl-CoA dehydrogenase, but did not bind malic dehydrogenase, citrate synthase, and fumarase. These results suggest that the protein isolated by us has a specific function in anchoring a beta-oxidation enzyme to the matrix surface of the mitochondrial membrane.
37
UI - 84212217
AU - Spratt SK
AU - Black PN
AU - Ragozzino MM
AU - Nunn WD
TI - Cloning, mapping, and expression of genes involved in the fatty acid-degradative multienzyme complex of Escherichia coli.
SO - J Bacteriol 1984 May;158(2):535-42
AB - Two protein subunits (42,000 and 78,000 daltons) encoded by the fadAB genes form a multifunctional enzyme complex containing thiolase, 3-hydroxyacyl-coenzyme A dehydrogenase, crotonase , epimerase, and isomerase activities (S. Pawar and H. Schulz, J. Biol. Chem. 256:3894-3899, 1981). In an attempt to characterize the structural organization and regulatory properties of these genes, a 5.2-kilobase pair fragment containing the fadAB genes has been isolated. Plasmids containing this fragment (i) complement mutations in the fadAB genes; (ii) overproduce by 10- to 50-fold thiolase, 3-hydroxyacyl-coenzyme A dehydrogenase and crotonase ; and (iii) specify a 42,000- and a 78,000-dalton protein. The fadA gene, which encodes the 42,000-dalton protein, has been localized within the original clone to a 3.3-kilobase pair fragment. Thiolase activity, which is encoded by the 42,000-dalton protein, was not observed in the absence of the 78,000-dalton protein, suggesting that an intact complex is required for function. Transposon Tn5 insertional mutagenesis of the cloned fadAB genes has demonstrated that both fadA and fadB are transcribed as a single transcriptional unit with the direction of transcription from fadA to fadB . The molecular cloning and characterization of the fadAB region confirm the original genetic contention that the genes encoding the proteins for the multifunctional complex form an operon.
38
UI - 84276423
AU - Gottesmann P
AU - Hamm R
TI - [Lipoamide dehydrogenase, citrate synthase and beta-hydroxyacyl-CoA-dehydrogenase of skeletal muscle. II. Compartmentalization of the enzymes in muscle mitochondria and their relative binding capacity]. [German]
OT - Lipoamiddehydrogenase, Citratsynthase. und beta-Hydroxyacyl-CoA-dehydrogenase des Skelettmuskels. II. Kompartimentierung der Enzyme im Muskel-Mitochondrion und Ermittlung ihrer relativen Bindungsfestigkeit.
SO - Z Lebensm Unters Forsch 1984 May;178(5):371-5
AB - The compartimentation and the relative strength of binding of the enzymes lipoamide dehydrogenase (LIPDH), citrate synthase (CS), and beta-hydroxyacyl-coenzyme A-dehydrogenase (HADH) in mitochondria isolated from bovine muscle (M. sternomandibularis) were studied using the following methods: Availability of the enzymes for proteases before and after opening of the intracrystal line space and after disintegration of the mitochondrial membranes; release of the enzymes after different treatments of the mitochondria: homogenization with phosphate buffer plus Triton X-100; suspension in dest. water and saccharose-tris buffer with and without added digitonin; ultrasonic treatment; freezing and thawing. From the results it can be concluded that the three enzymes are bound to the inner surface of the inner membrane of the mitochondrion, and that the binding strength increases according to the series CS less than HADH less than LIPDH.
39
UI - 85044391
AU - Stern JS
AU - Inokuchi T
AU - Castonguay TW
AU - Wickler SJ
AU - Horwitz BA
TI - Scapular brown fat removal enhances development of adiposity in cold-exposed obese Zucker rats.
SO - Am J Physiol 1984 Nov;247(5 Pt 2):R918-26
AB - To investigate the contribution of brown fat (BAT) to the development of obesity in genetically obese Zucker rats (fa/fa), scapular brown fat (SBAT) was removed from obese and lean 4-wk-old females. Eight weeks after surgery there was no regrowth of SBAT. Lipectomy had no effect on body weight gain, food intake, and body composition when rats were housed at 25 degrees C. Lean rats completely compensated for the lipectomy by increasing BAT mass, protein, cellularity, and activity of citrate synthase (CS) in axillary, perirenal, and thoracic depots. beta-Hydroxyacyl-coenzyme A dehydrogenase (HOAD) activity was increased, but compensation was incomplete. In lipectomized obese rats, only BAT protein and cell number were increased sufficiently for complete compensation. In a second experiment SBAT was removed from obese and lean rats, but rats were housed in the cold (10 degrees C) for 8 wk. In lean rats, although compensation was incomplete, it was sufficient to maintain a weight gain and body composition comparable with sham-operated lean rats. In obese rats, where there was little or no compensation for lipectomy, weight gain and fat deposition were greater than observed in sham-operated obese controls. These data support the hypothesis that reducing the amount of functional BAT contributes to the development of increased adiposity.
40
UI - 85031692
AU - Nemeth PM
AU - Lowry OH
TI - Myoglobin levels in individual human skeletal muscle fibers of different types.
SO - J Histochem Cytochem 1984 Nov;32(11):1211-6
AB - An attempt was made to determine the relationship of myoglobin content to specific fiber types in human muscle. Biopsies were obtained from biceps brachii, vastus lateralis, and gastrocnemius muscles of untrained subjects and from the vastus lateralis muscle of a highly trained athlete at peak training and at intervals of no training (detraining). Individual muscle fibers were assayed, by quantitative microanalytical methods, for myoglobin, lactate dehydrogenase, malate dehydrogenase, citrate synthase, beta-hydroxyacyl-coenzyme A dehydrogenase, and adenylokinase activities all on the same fiber. The enzyme levels were used to classify the fibers into type I or II. The results show that the content of myoglobin in human muscle does not differ greatly between fiber types in contrast to other species. The type II fibers contained, on the average, at least two-thirds as much myoglobin as type I fibers. The concentration of myoglobin did not change in either fiber type during detraining (84 days), despite marked changes in lactate dehydrogenase, adenylokinase and the three oxidative enzymes.
41
UI - 83127471
AU - Pramanik A
AU - Schulz H
TI - Multienzyme complexes of fatty acid oxidation from Escherichia coli K12 and from a mutant with a defective L-3-hydroxyacyl coenzyme A dehydrogenase.
SO - Biochim Biophys Acta 1983 Jan 7;750(1):41-6
AB - An Escherichia coli mutant (fadB64), with a defective L-3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) which is unable to grow on long-chain fatty acids as the sole carbon source, was shown to possess a fatty acid oxidation complex that contains five beta-oxidation enzymes, including L-3-hydroxyacyl-CoA dehydrogenase. A comparative study of the complexes from the mutant, from its parental strain and from wild-type E. coli B demonstrated the immunological and gross structural identity of all three fatty acid oxidation complexes. A kinetic evaluation of the complexes led to the suggestion that the mutation may have affected the active site of L-3-hydroxyacyl-CoA dehydrogenase so that it is inactive with acetoacetyl-CoA as a substrate, but exhibits an increasing percentage of the parental dehydrogenase activity with increasing chain length of the substrate.
42
UI - 83082626
AU - Moncla BJ
AU - Hillier SL
AU - Charnetzky WT
TI - Constitutive uptake and degradation of fatty acids by Yersinia pestis.
SO - J Bacteriol 1983 Jan;153(1):340-4
AB - Yersinia pestis was found to utilize palmitic acid as a primary carbon and energy source. No inhibition of growth by palmitic acid was observed. Comparison of palmitic acid uptake by cells pregrown either with or without palmitic acid demonstrated that fatty acid uptake was constitutive. High basal levels of two enzymes of beta-oxidation, beta-hydroxyacyl-coenzyme A dehydrogenase and thiolase, and the two enzymes of the glyoxylate shunt, isocitrate lyase and malate synthase, were found in cells grown in defined medium with glucose. Elevated levels of all four enzymes were found when cells were grown with acetate as a primary carbon and energy source, and even higher levels were observed when palmitic acid was provided as a primary carbon and energy source. High-pressure liquid chromatography was used to demonstrate that, in the presence of glucose, uniformly labeled [14C]palmitic acid was converted to intermediates of the tricarboxylic acid cycle and glyoxylate shunt. Pregrowth with palmitic acid was not required for this conversion. Strains lacking the 6- or the 47-megadalton plasmid did not take up [3H]palmitic acid but did possess levels of enzyme activity comparable to those observed in the wild-type strain.
43
UI - 84009825
AU - Lowry OH
AU - Berger SJ
AU - Carter JG
AU - Chi MM
AU - Manchester JK
AU - Knor J
AU - Pusateri ME
TI - Diversity of metabolic patterns in human brain tumors: enzymes of energy metabolism and related metabolites and cofactors.
SO - J Neurochem 1983 Oct;41(4):994-1010
AB - Biopsies from 15 human gliomas, five meningiomas, four Schwannomas, one medulloblastoma, and four normal brain areas were analyzed for 12 enzymes of energy metabolism and 12 related metabolites and cofactors. Samples, 0.01-0.25 microgram dry weight, were dissected from freeze-dried microtome sections to permit all the assays on a given specimen to be made, as far as possible, on nonnecrotic pure tumor tissue from the same region. Great diversity was found with regard to both enzyme activities and metabolite levels among individual tumors, but the following generalities can be made. Activities of hexokinase, phosphorylase, phosphofructokinase, glycerophosphate dehydrogenase, citrate synthase, and malate dehydrogenase levels were usually lower than in brain; glycogen synthase and glucose-6-phosphate dehydrogenase were usually higher; and the averages for pyruvate kinase, lactate dehydrogenase, 6-phosphogluconate dehydrogenase, and beta-hydroxyacyl coenzyme A dehydrogenase were not greatly different from brain. Levels of eight of the 12 enzymes were distinctly lower among the Schwannomas than in the other two groups. Average levels of glucose-6-phosphate, lactate, pyruvate, and uridine diphosphoglucose were more than twice those of brain; 6-phosphogluconate and citrate were about 70% higher than in brain; glucose, glycogen, glycerol-1-phosphate, and malate averages ranged from 104% to 127% of brain; and fructose-1,6-bisphosphate and glucose-1,6-bisphosphate levels were on the average 50% and 70% those of brain, respectively.
44
UI - 83109075
AU - Holden HM
AU - Banaszak LJ
TI - L-3-hydroxyacyl coenzyme A dehydrogenase. The location of NAD binding sites and the bilobal subunit structure.
SO - J Biol Chem 1983 Feb 25;258(4):2383-9
AB - 3-Hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) is a mitochondrial enzyme involved in the beta-oxidation of long chain fatty acids. The determination of its molecular structure at 5.25-A resolution by x-ray diffraction techniques is described. Three isomorphous derivatives, K2PtCl6, methyl mercuric chloride, and IrCl3, were prepared using crystals previously soaked in an NAD-containing solution. The positions of the heavy atom sites were determined by inspection of Patterson maps and confirmed by cross-difference Fourier maps. After refinement of the heavy atom positions, electron density maps at 5.25-A resolution were calculated. Careful study of these electron density maps revealed a unique crystalline packing arrangement in which the asymmetric unit contained 1.5 dimers of L-3-hydroxyacyl coenzyme A dehydrogenase. With this packing motif, one L-3-hydroxyacyl coenzyme A dehydrogenase dimer lies in a general position in the asymmetric unit, while the other dimer is located such that its molecular 2-fold axis is coincident with a crystallographic dyad. At 5.25-A resolution, each L-3-hydroxyacyl coenzyme A dehydrogenase subunit displays a bilobal structure. The larger lobe, which binds NAD, has approximate dimensions of 37 X 45 X 35 A. The size of the smaller lobe is approximately 30 X 23 X 20 A. Difference Fourier maps between the crystalline apo- and holoenzyme have also been calculated at 5.25-A resolution, and preliminary model fitting studies show that NAD binds to L-3-hydroxyacyl coenzyme A dehydrogenase in an open conformation similar to that found in other dehydrogenases.
45
UI - 82167210
AU - Hii V
AU - Courtright JB
TI - Induction of acyl coenzyme A synthetase and hydroxyacyl coenzyme A dehydrogenase during fatty acid degradation in Neurospora crassa.
SO - J Bacteriol 1982 May;150(2):981-3
AB - Neurospora crassa is able to use long-chain fatty acids as the sole carbon and energy source. After growth on oleate there was nearly a 10-fold induction of the acyl coenzyme A (CoA) synthetase and a fivefold increase in the activity of the 3-hydroxyacyl-CoA dehydrogenase. There was a slight induction of the enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase, but no apparent induction of the flavin-linked acyl-CoA dehydrogenase. These noncoordinate changes in the fatty acid degradation enzymes suggest that they are not organized into a multienzyme complex as is found in bacteria.
46
UI - 82190911
AU - Le Hir M
AU - Dubach UC
TI - Peroxisomal and mitochondrial beta-oxidation in the rat kidney: distribution of fatty acyl-coenzyme A oxidase and 3-hydroxyacyl-coenzyme A dehydrogenase activities along the nephron.
SO - J Histochem Cytochem 1982 May;30(5):441-4
AB - In order to determine the localization of the peroxisomal and the mitochondrial pathways of beta-oxidation in the rat kidney, fatty acyl-coenzyme A (CoA) oxidase and 3-hydroxyacyl-CoA dehydrogenase activities were measured in glomeruli and in eight proximal and distal segments of the nephron. Structurally defined segments were dissected and analyzed with microchemical assays. The peroxisomal fatty acyl-CoA oxidase is restricted to the proximal tubule. The 3-hydroxyacyl-CoA dehydrogenase activity represents mainly the mitochondrial pathway and is similarly distributed in all cortical proximal and distal segments. It is much lower in glomeruli and collecting ducts. The distribution patterns of the two enzymes remain the same after 48 hr of starvation, although the activity of fatty acyl-CoA oxidase increases in glomeruli, proximal convolution, and collecting ducts. It is concluded that the capacity for mitochondrial beta-oxidation of fatty acids is similar in the proximal and the distal nephron. The proximal tubule possesses, additionally, a peroxisomal pathway for beta-oxidation with a capacity of the same order of magnitude as in liver cells.
47
UI - 82107093
AU - Guy PS
AU - Snow DH
TI - Skeletal muscle fibre composition in the dog and its relationship to athletic ability.
SO - Res Vet Sci 1981 Sep;31(2):244-8
AB - Skeletal limb muscles of the dog could generally be differentiated into three fibre types according to myosin adenosine triphosphatase (ATPase) (pH 9.4) and succinic dehydrogenase activities. However, because this was not always possible, for comparative purposes only, division into low myosin ATPase (slow twitch) type I and high myosin ATPase (fast twitch) type II fibres was used. The percentage of these fibre types in m deltoideus, m triceps brachii caput longum, m vastus lateralis, m gluteus medius, m biceps femoris and m semitendinosus was examined in the greyhound, crossbred and foxhound. In all muscles the greyhound had a significantly higher percentage of fibres with high myosin ATPase activity at pH 9.4 than the other breeds, with almost 100 per cent in most muscles examined. The activities of nine enzymes and glycogen concentration were determined in m gluteus medius and m semitendinosus of the greyhound and crossbred. Significantly higher levels of creatine kinase, aldolase, alanine aminotransferase and citrate synthase and significantly lower activities of 3-hydroxyacyl coenzyme A dehydrogenase and hexokinase were found in both muscles of the greyhound. The implications of these findings are discussed.
48
UI - 82050826
AU - Holden HM
AU - Banaszak LJ
AU - Frieden C
AU - McLoughlin DJ
TI - Differences in the binding of coenzyme to L-3-hydroxyacyl-coenzyme A dehydrogenase in the crystalline state and in solution.
SO - FEBS Lett 1981 Sep 14;132(1):15-8
49
UI - 81182223
AU - Belman MJ
AU - Kendregan BA
TI - Exercise training fails to increase skeletal muscle enzymes in patients with chronic obstructive pulmonary disease.
SO - Am Rev Respir Dis 1981 Mar;123(3):256-61
AB - We examined the effect of a 6-wk exercise training program on several skeletal enzymes in patients with chronic obstructive pulmonary disease. Eight trained their arms and 7 trained their legs. In all patients, muscle biopsy specimens were taken from the trained limbs, and in 7 patients, additional biopsy specimens were taken from the untrained limbs. The enzymes examined were citrate synthase, 3-beta-hydroxyacyl coenzyme A dehydrogenase, and pyruvate kinase. Also examined were cardiac frequency responses to incremental and endurance cycle ergometry; these responses were evaluated for arm and leg exercise, respectively. Despite the patient's increased exercise endurance, we were unable to document a significant increase in the enzyme concentrations in the trained limbs. Similarly, analyses of the cardiac frequency failed to show the evolution of the typical cardiovascular training response. This pattern is in marked contrast to that seen in normal subjects after endurance training. We conclude that patients with chronic obstructive pulmonary disease are incapable of exercising at an intensity high enough to induce the classic training response and associated changes in muscle enzymes. Therefore, other mechanisms must be important in explaining the increased endurance for submaximal exercise.
50
UI - 78234488
AU - Roberts CM
AU - Conrad RS
AU - Sokatch JR
TI - The role of enoyl-coa hydratase in the metabolism of isoleucine by Pseudomonas putida.
SO - Arch Microbiol 1978 Apr 27;117(1):99-108
AB - The purpose of the present study was to determine if the enoyl coenzyme A hydratase formed by Pseudomonas putida during growth on isoleucine was a unique enzyme specific for isoleucine metabolism. The highest levels of the hydratase were formed during growth on isoleucine intermediates and the lowest levels during growth on glutamate and glucose. Data from growth experiments revealed that 2-methyl-3-hydroxybutyryl coenzyme A hydratase, an enzyme unique to isoleucine metabolism and enoyl coenzyme A hydratase were coordinately induced, but that 3-hydroxyacyl coenzyme A dehydrogenase was under separate control. The hydratase was purified 180-fold from isoleucine cells, and its physical and catalytic properties reported. The highest activity was with crotonyl coenzyme A,Vmax = 1100 x 10(3) moles/min mole enzyme, next was tiglyl coenzyme A, Vmax = 61 x 10(3) moles/min mole enzyme, and last was 3-methyl-crotonyl coenzyme A, Vmax = 2.3 x 10(3) moles/min mole enzyme. Enzyme purified from butyrate cells had the same elution patterns during column chromatography and catalytic properties as the enzyme from isoleucine cells. These data support the conclusion that a single enzyme in P. putida is responsible for the hydration of both tiglyl coenzyme A and crotonyl coenzyme A.
51
UI - 77158485
AU - Craig I
AU - Tolley E
AU - Bobrow M
TI - A preliminary analysis of the segregation of human hydroxyacyl coenzyme A dehydrogenase in human-mouse somatic cell hybrids.
SO - Birth Defects 1976;12(7):114-7
52
UI - 77025150
AU - Craig I
AU - Tolley E
AU - Bobrow M
TI - A preliminary analysis of the segregation of human hydroxyacyl coenzyme A dehydrogenase in human-mouse somatic cell hybrids.
SO - Cytogenet Cell Genet 1976;16(1-5):114-7
53
UI - 75137458
AU - Bradshaw RA
AU - Noyes BE
TI - L-3-hydroxyacyl coenzyme A dehydrogenase from pig heart muscle. EC 1.1.1.35 L-3-hydroxyacyl-CoA: NAD oxidoreductase.
SO - Methods Enzymol 1975;35:122-8
54
UI - 75116759
AU - Weininger M
AU - Noyes BE
AU - Bradshaw RA
AU - Banaszak LJ
TI - Letter: L-3-hydroxyacyl coenzyme A dehydrogenase: crystallographic properties of the pig heart enzyme.
SO - J Mol Biol 1974 Dec 5;90(2):409-13
55
UI - 73166546
AU - Noyes BE
AU - Bradshaw RA
TI - L-3-hydroxyacyl coenzyme A dehydrogenase from pig heart muscle. II. Subunit structure.
SO - J Biol Chem 1973 May 10;248(9):3061-6
56
UI - 73166545
AU - Noyes BE
AU - Bradshaw RA
TI - L-3-hydroxyacyl coenzyme A dehydrogenase from pig heart muscle. I. Purification and properties.
SO - J Biol Chem 1973 May 10;248(9):3052-9
1
UI - 97018658
AU - Isaacs JD Jr
AU - Sims HF
AU - Powell CK
AU - Bennett MJ
AU - Hale DE
AU - Treem WR
AU - Strauss AW
IN - Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA.
TI - Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele.
SO - Pediatr Res 1996 Sep;40(3):393-8
AB - Acute fatty liver of pregnancy (AFLP) is a devastating late gestational complication with many similarities to the inherited disorders of mitochondrial fatty acid oxidation. We report the molecular defects in a woman with AFLP and her infant who subsequently was diagnosed with trifunctional protein (TFP) deficiency. We used single-stranded conformation variance and DNA sequence analyses of the human TFP alpha-subunit gene, which encodes the long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity, to demonstrate a C to T mutation (C1678T) in exon 16 present on one allele in the mother and the affected infant. This creates a premature termination codon (R524Stop) in the LCHAD domain. Using reverse transcriptase-PCR amplification of the alpha-subunit mRNA from cultured fibroblasts, we demonstrated that transcripts containing this R524Stop mutation are present at very low levels, presumably because of rapid mRNA degradation. The affected infant also had the common E474Q mutation (nucleotide G1528C) on the second allele. Thus, he is a compound heterozygote. The father and two normal siblings are heterozygous for this E474Q mutation. This initial delineation of the R524Stop mutation provides evidence of the heterogeneity of genetic defects responsible for TFP deficiency and AFLP.
2
UI - 97085264
AU - Treem WR
AU - Shoup ME
AU - Hale DE
AU - Bennett MJ
AU - Rinaldo P
AU - Millington DS
AU - Stanley CA
AU - Riely CA
AU - Hyams JS
IN - Division of Pediatric Gastroenterology and Nutrition, Hartford Hospital, University of Connecticut School of Medicine, Farmington, USA.
TI - Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency [see comments].
SO - Am J Gastroenterol 1996 Nov;91(11):2293-300
AB - BACKGROUND: The similarity of the hepatic pathology in acute fatty liver of pregnancy (AFLP) to that seen in children with inherited disorders of intramitochondrial fatty acid oxidation (FAO) suggests that there may be a genetic basis for some cases of AFLP. OBJECTIVE: The purpose of this study was to examine patients with AFLP and their offspring to determine if there were women with AFLP who were heterozygous for the FAO defect, long chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency. METHODS: We evaluated 12 women previously diagnosed with AFLP. Provocative fasting studies and skin biopsies for examination of their cultured skin fibroblasts were performed to search for a generalized defect in FAO both in vivo and in vitro. Cultured skin fibroblasts from AFLP patients, their children, and their husbands were also examined specifically for LCHAD activity. RESULTS: Of 12 women with a previous episode of AFLP, eight had reduced LCHAD activity consistent with being heterozygous for LCHAD deficiency. The eight heterozygotes had a total of nine pregnancies complicated by AFLP. In seven of those nine pregnancies, the women developed severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Of the nine offspring delivered from these pregnancies, four were confirmed to be affected with homozygous LCHAD deficiency. Three other deceased infants were presumed to be LCHAD-deficient based on clinical findings, postmortem examination, and confirmed heterozygote parents. The remaining two infants delivered after pregnancies complicated by AFLP had LCHAD activity in the heterozygous range and are healthy at 18 and 24 months of age. Consistent with the known autosomal recessive nature of this defect, five tested husbands of LCHAD heterozygous women with a history of AFLP and affected infants also showed reduced LCHAD activity. CONCLUSIONS: These studies indicate that a significant subgroup of women with AFLP are heterozygous for LCHAD deficiency and that careful observation of their offspring for signs of this disorder is warranted. Severe preeclampsia appears to increase the risk of AFLP in LCHAD heterozygous women.
3
UI - 95148633
AU - Sims HF
AU - Brackett JC
AU - Powell CK
AU - Treem WR
AU - Hale DE
AU - Bennett MJ
AU - Gibson B
AU - Shapiro S
AU - Strauss AW
IN - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.
TI - The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy.
SO - Proc Natl Acad Sci U S A 1995 Jan 31;92(3):841-5
AB - Mitochondrial long chain fatty acid beta-oxidation provides the major source of energy in the heart. Deficiencies of human beta-oxidation enzymes produce sudden, unexplained death in childhood, acute hepatic encephalopathy, skeletal myopathy, or cardiomyopathy. Long chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxidoreductase, EC 1.1.1.211] catalyzes the third step in beta-oxidation, and this activity is present on the C-terminal portion of the alpha subunit of mitochondrial trifunctional protein. We used single-stranded conformation variance analysis of the exons of the human LCHAD (alpha subunit) gene to determine the molecular basis of LCHAD deficiency in three families with children presenting with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mothers had acute fatty liver and associated sever complications during pregnancies with the affected infants. The analysis in two affected children revealed a G to C mutation at position 1528 (G1528C) of the alpha subunit of the trifunctional protein on both alleles. This is in the LCHAD domain and substitutes glutamine for glutamic acid at position 474 of mature alpha subunit. The third child had this G1528C mutation on one allele and a different mutation (C1132T) creating a premature termination codon (residue 342) on the second allele. Our results demonstrate that mutations in the LCHAD domain of the trifunctional protein alpha subunit in affected offspring are associated with maternal acute fatty liver of pregnancy. This is the initial delineation of the molecular basis of isolated LCHAD deficiency.
4
UI - 94124113
AU - Treem WR
AU - Rinaldo P
AU - Hale DE
AU - Stanley CA
AU - Millington DS
AU - Hyams JS
AU - Jackson S
AU - Turnbull DM
IN - Division of Pediatric Gastroenterology, Hartford Hospital, Farmington, Connecticut 06115.
TI - Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.
SO - Hepatology 1994 Feb;19(2):339-45
AB - The pathogenesis of acute fatty liver of pregnancy is unknown, but similarities in the clinical presentation and the histological appearance of the liver with those found in children with metabolic defects in the intramitochondrial beta-oxidation pathway of the liver suggest that a disturbance in hepatic fatty acid oxidation may play a role. We report a woman with acute fatty liver of pregnancy who gave birth to a seemingly normal full-term infant who was seen at 4 mo of age with hypoglycemia, coma and profound hepatic steatosis. The infant had a defect in fatty acid oxidation, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, and the mother proved to be heterozygous for this metabolic condition. We hypothesize that the interaction of an affected fetus with a female heterozygous for this defect in fatty acid oxidation in the late third trimester accounts for some cases of acute fatty liver of pregnancy.
5
UI - 93239114
AU - Grimbert S
AU - Fromenty B
AU - Fisch C
AU - Letteron P
AU - Berson A
AU - Durand-Schneider AM
AU - Feldmann G
AU - Pessayre D
IN - Unite de Recherches de Physiopathologie Hepatique (Institut National de la Sante et de la Recherche Medicale Unite 24, Hopital Beaujon, Clichy, France.
TI - Decreased mitochondrial oxidation of fatty acids in pregnant mice: possible relevance to development of acute fatty liver of pregnancy.
SO - Hepatology 1993 Apr;17(4):628-37
AB - Severe impairment of the beta-oxidation of fatty acids, as a consequence of a single factor or a combination of different causes, leads to microvesicular steatosis of the liver. In an effort to understand the mechanism(s) leading to the development of acute fatty liver of pregnancy in some women, we determined the effects of pregnancy on the mitochondrial oxidation of fatty acids in mice. In vivo, the rate of oxidation of the whole fatty-acid chain length was determined by measuring the rate of exhalation of [14C]CO2 after intragastric administration of a tracer dose of [U-14C]palmitic acid. [14C]CO2 exhalation was not significantly decreased at 14 days of gestation, but it had declined by 40% at 18 days of gestation (i.e., 24 to 48 hr before delivery). The rate of first beta-oxidation cycle was assessed by measuring the rate of [14C]CO2 exhalation after administration of [1-14C]octanoic acid, [1-14C]butyric acid or [1-14C]palmitic acid. [14C]CO2 exhalation had declined by 60%, 46%, and 24% after administration of [1-14C]octanoic acid, [1-14C]butyric acid and [1-14C]palmitic acid, respectively, in 18-day-pregnant mice. Total hepatic lipids and triglycerides, expressed per gram of liver, remained unchanged in 18-day-pregnant mice. In vitro, the rate of mitochondrial beta-oxidation (expressed per milligram of protein) had decreased by 47% at 18 days' gestation with [U-14C]palmitic acid as substrate and by 33% with [1-14C]octanoic acid but remained unchanged with [1-14C]palmitic acid. The activity of the tricarboxylic acid cycle, assessed by the formation of [14C]CO2 from [1-14C]acetic acid, had decreased by 24%. We conclude that the mitochondrial oxidation of fatty acids decreased during late-term pregnancy in mice as a consequence of both decreased mitochondrial beta-oxidation of medium-chain fatty acids, and decreased activity of the tricarboxylic acid cycle. We suggest that this effect, in combination with other factors, may contribute to the development of fatty liver of pregnancy in some pregnant women.
6
UI - 91085814
AU - Schoeman MN
AU - Batey RG
AU - Wilcken B
IN - Department of Medicine, Westmead Hospital, Australia.
TI - Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring.
SO - Gastroenterology 1991 Feb;100(2):544-8
AB - A case of a 29-year-old woman who has had two episodes both clinically and biochemically consistent with acute fatty liver of pregnancy is described. These episodes occurred in two successive pregnancies, and liver biopsy confirmed the diagnosis in the second pregnancy. Both pregnancies were managed by prompt fetal delivery; on both occasions this led to a complete biochemical resolution of the liver function abnormalities. Two healthy babies were delivered by ceasarian sections. This case is of particular importance because a rapidly progressive and devastating illness developed in both infants, leading to death at 6 1/2 and 6 months, respectively. The illness in both babies was characterized by wide-spread fatty infiltration of several vital organs and a failure of any treatment to influence the outcome of that illness. Studies suggested that the illness in the children was caused by a still ill-defined disorder of fatty acid oxidation. The biochemical disorder evidenced in this family is discussed, in an attempt to shed light on the etiology of acute fatty liver of pregnancy.
7
UI - 91112270
AU - Hautekeete ML
AU - Degott C
AU - Benhamou JP
IN - Service d'Hepatologie, Hopital Beaujon, Clichy, France.
TI - Microvesicular steatosis of the liver. [Review] [80 refs]
SO - Acta Clin Belg 1990;45(5):311-26
AB - The term "microvesicular steatosis of the liver" refers to a variant form of hepatic fat accumulation whose histologic features contrast with the much more common macrovesicular steatosis. Microvesicular steatosis of the liver was originally described in association with conditions who share a number of biochemical and a limited number of clinical features: acute fatty liver of pregnancy, Reye's syndrome, Jamaican vomiting sickness, sodium valproate toxicity, high-dose tetracycline toxicity and certain congenital defects of urea cycle enzymes; they were thought to constitute an entity of "microvesicular fat diseases". In recent years the disease has been described in a wide variety of conditions: alcoholism, toxicity of several medications, delta hepatitis in South America and Central Africa, sudden childhood death, congenital defects of fatty acid beta oxidation, cholesterol ester storage disease, Wolman disease and Alpers syndrome. Not much is known regarding the pathogenesis of microvesicular steatosis but in many instances the primary defect could be a mitochondrial lesion, and inhibition of the mitochondrial beta oxidation of fatty acids has been the most frequently implicated defect. The different conditions associated with microvesicular steatosis are heterogenous in many aspects. Maintaining the concept of "microvesicular fat diseases" as a unique entity seems no longer justified. [References: 80]