Alternative methionine degradation via the transamination pathway: an option for therapy for homocystinuria due to cystathionine synthase deficiency.
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Animals↗
Biomedical subjects
J M Trijbels
Publications and source records attributed to J M Trijbels.
Peroxisomal oxidases and catalase in liver and kidney homogenates of normal and di(ethylhexyl)phthalate-fed rats.
1. Activities of peroxisomal oxidases and catalase were assayed at neutral and alkaline pH in liver and kidney homogenates from male rats fed a diet with or without 2% di(2-ethylhexyl)phthalate (DEHP) for 12 days. 2. All enzyme activities were higher at alkaline than at neutral pH in both groups. 3. The effect of the DEHP-diet on the peroxisomal enzymes was different in kidney and liver. Acyl-CoA oxidase activity was raised three- and sixfold in kidney and liver homogenates, respectively. The activity of D-amino acid oxidase decrease in liver, but increased in kidney homogenates. In liver homogenates, urate oxidase activity was not affected by the DEHP diet. The catalase activity was twofold induced in liver, but not in kidney. 4. The differences suggest that the changes of peroxisomal enzyme activities by DEHP treatment are not directly related to peroxisome proliferation. 5. DEHP treatment caused a marked increase of total and peroxisomal fatty acid oxidation in rat liver homogenates. 6. In the control group the rate of peroxisomal fatty acid oxidation was higher at alkaline pH than at neutral pH. 7. This rate was equal at both pH values in the DEHP-fed group, in contrast to the acyl-CoA oxidase activity. These results indicate that after DEHP treatment other parameters than acyl-CoA oxidase activity become limiting for peroxisomal beta-oxidation.
Animals↗
Immunochemical analysis of the peroxisomal beta-oxidation enzymes in rat and human heart and skeletal muscle and in skeletal muscle of Zellweger patients.
Immunoblot analyses with antibodies against the peroxisomal beta-oxidation enzymes from rat liver showed the presence of these enzymes in rat and human liver and kidney and rat adrenal gland. The bifunctional protein could not be detected in muscle tissues or cultured muscle cells. Acyl-CoA oxidase was detected in rat heart and cultured human muscle cells. 3-Ketoacyl-CoA thiolase was also detected in human and rat heart and skeletal muscle; however, this enzyme was not detectable in skeletal muscle of Zellweger patients, in agreement with the absence of peroxisomal fatty acid oxidation.
Acetyl-CoA C-Acyltransferase↗
Disturbances of cerebral purine and pyrimidine metabolism in young children with chronic renal failure.
Chronic renal failure during childhood may be associated with delayed cognitive development. From 10 children with chronic renal failure, aged 2-59 months, plasma and cerebrospinal fluid (CSF) purines and pyrimidines have been determined. A marked increase of pseudouridine and cytidine was demonstrated in CSF of 10 and 8 children, respectively. The plasma concentration of pseudouridine was increased in a varying degree to a maximal value of more than 10 times the upper limit of normal. The plasma concentration of cytidine showed only moderately elevated values. In 3 children the study of CSF and plasma was repeated 6 weeks after the start of continuous ambulatory peritoneal dialysis. The abnormal concentrations of pseudouridine and cytidine were still present in CSF and plasma. Further studies are necessary to elucidate the cause of this unknown biochemical aberration of the central nervous system.
Cerebral Cortex↗
The effect of di(ethylhexyl)phthalate on fatty acid oxidation and carnitine palmitoyltransferase in various rat tissues.
Male rats were fed a diet with or without 2% di(2-ethylhexyl)phthalate (DEHP) for 12 days. Total and peroxisomal oxidation rates of palmitic and arachidonic acid were increased in homogenates of liver and kidney after DEHP administration. The relative peroxisomal contribution to the total oxidation was only higher in liver. The activities of acyl-CoA oxidase and carnitine palmitoyltransferase were also higher in both tissues. Immunoblots showed that the increase of fatty acid oxidation was associated with a higher concentration of enzymes of peroxisomal and mitochondrial beta-oxidation. DEHP did not change total and peroxisomal fatty acid oxidation and activity of carnitine palmitoyltransferase of homogenates of heart and skeletal muscle. The cause for the tissue-specific response is discussed.
Animals↗
The involvement of fatty acid binding protein in peroxisomal fatty acid oxidation.
Rat liver fatty acid-binding protein (FABP) can function as a fatty acid donor protein for both peroxisomal and mitochondrial fatty acid oxidation, since 14C-labeled palmitic acid bound to FABP is oxidized by both organelles. FABP is, however, not detected in peroxisomes and mitochondria of rat liver by ELISA. Acyl-CoA oxidase activity of isolated peroxisomes was not changed by addition of FABP or flavaspidic acid, an inhibitor of fatty acid binding to FABP, nor by disruption of the peroxisomal membranes. These data indicate that FABP may transfer fatty acids to peroxisomes, but is not involved in the transport of acyl-CoA through the peroxisomal membrane.
Acyl Coenzyme A↗
Detection of respiratory chain dysfunction by measuring lactate and pyruvate production in cultured fibroblasts.
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Amino Acid Metabolism, Inborn Errors↗
Heterogeneous tissue expression of enzyme defects in mitochondrial myopathies.
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Energy Metabolism↗
Deficiency of the alpha and beta subunits of pyruvate dehydrogenase in a patient with lactic acidosis and unexpected sudden death.
An infant with moderate muscular hypotonia and congenital lactic acidosis died suddenly at the age of 3 months. Autopsy revealed no abnormalities responsible for this unexpected death. Measurement of mitochondrial enzymes involved in energy production indicated a severely decreased total pyruvate dehydrogenase complex (PDHC) activity in muscle tissue (0.23 nmoles x min-1 x mg protein-1, control range 2.8-8.7) and moderately decreased PDHC activity in fibroblasts (0.27 nmoles x min-1 x mg protein-1, control range 0.37-2.32). The activity of the first component E1 (pyruvate dehydrogenase) in muscle tissue was 10 times lower than that of controls (0.008 nmoles x min-1 x mg protein-1, control range 0.10-0.25). The activities of dihydrolipoyl dehydrogenase (E3) and various other mitochondrial enzymes were normal. Immunochemical analysis in skeletal muscle tissue and fibroblasts demonstrated a decrease in the amount of the alpha and beta subunits of E1. The features of this patient are compared with those of other patients reported in the literature with immunochemically confirmed combined E1 alpha and beta deficiency.
Acidosis, Lactic↗
Isolated and combined deficiencies of NADH dehydrogenase (complex I) in muscle tissue of children with mitochondrial myopathies.
We describe eight children with complex I deficiency, four of them with an isolated, the other four with an additional deficiency of complex IV. Clinical, chemical and morphological findings were compared from patients with isolated and combined deficiency. In both groups, the age of onset of symptoms was between the 1st day and the 4th month of life. Clinical and biochemical heterogeneity were observed. We found no correlation between residual activity of complex I in muscle, blood lactate level, and severity of clinical symptoms. Newborns presenting with severe lactic acidosis and children with later onset myopathy were seen in both groups. The group with combined complex I deficiency showed a more severe clinical course. By light microscopy ragged red fibres were only found in two patients with combined deficiency. However, by electron microscopy structural alterations of the mitochondria were observed in six out of seven muscle specimens.
Biopsy↗
A mitochondrial myopathy in an infant with lactic acidosis.
We describe a girl with mitochondrial myopathy, who presented with general muscle weakness, muscle hypotonia and motor retardation. The level of blood lactate and pyruvate was consistently increased. Enzymatic studies showed impairment of NADH-dehydrogenase activity (complex I of the respiratory chain) in skeletal muscle. Electron-microscopy of a muscle biopsy showed abnormalities of a mitochondrial myopathy. The girl, now aged 30 months, has been treated with riboflavine (vitamin B2) since the age of 14 months, and lactate and pyruvate levels have decreased to normal. The patient still shows mild muscle hypotonia and weakness, but good motor progress and normal cognitive development.
Acidosis, Lactic↗
Fatal neonatal cardiomyopathy associated with cataract and mitochondrial myopathy.
Three patients suffering from the neonatal form of a syndrome characterized by congenital cataract, hypertrophic cardiomyopathy, and mitochondrial myopathy are described. The patients died at 7, 10 and 18 days, respectively from cardiorespiratory failure. Mitochondrial abnormalities were observed in the heart and skeletal muscle. Despite the presence of a severe lactic acidaemia pointing to a disturbed pyruvate oxidation rate in vivo, a normal pyruvate oxidation rate was demonstrated in skeletal muscle homogenates. The activities of several enzymes of the mitochondrial respiratory chain appeared to be normal, indicating an intact respiratory chain. A myoglobinopenia could be excluded. The activities of some mitochondrial enzymes and the concentration of myoglobin increase with age.
Autopsy↗
Total and peroxisomal oxidation of various saturated and unsaturated fatty acids in rat liver, heart and m. quadriceps.
Rates of total and peroxisomal fatty acid oxidation were estimated from the production of 14C-labeled CO2 and acid-soluble products from differently labeled [14C]fatty acids, in the absence and presence of antimycinrotenone, in homogenates of liver, heart and m. quadriceps. Total and peroxisomal oxidation rates of palmitic, oleic and linoleic acid were 3-4 times higher than those of arachidonic and adrenic acid which had higher oxidation rates than those of lignoceric and erucic acid. The peroxisomal contribution to the oxidation of the last fatty acids was similar to or higher than that of palmitic acid. For all fatty acids tested in these tissues, the mitochondrial contribution to beta-oxidation was higher than the peroxisomal contribution. Production of 14CO2 and 14C-labeled, acid-soluble metabolites from [13-14]arachidonic acid indicated that polyunsaturated fatty acids can be chain-shortened beyond their double bonds in m. quadriceps and heart as well as in liver. Although 2,4-dienoyl-CoA reductase requires NADPH, addition of this coenzyme did not influence arachidonic acid oxidation. Arachidonic acid oxidation was inhibited by palmitic acid in mitochondria and peroxisomes, but arachidonic acid had only a slight effect on palmitic acid oxidation.
Animals↗
Mitochondrial myopathies: multiple enzyme defects in the respiratory chain.
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Adolescent↗
Reproducibility of urinary 3-methylhistidine excretion in human subjects consuming freely selected diets.
Eight males and six females consumed their normal diet for 9 weeks, except for weeks 3 and 9 when they followed a self-selected diet free of 3-methylhistidine (3MH) for five subsequent weekdays (days 1 to 5). Timed 24-hours urine collections were obtained on days 3, 4, and 5 of these 3MH-free dietary periods and on one day during weeks 1 and 7. At the group level, no differences in 3MH excretion (P greater than .05) between days 3, 4, and 5 in weeks 3 and 9 and between these weeks were observed. Reproducibility at the individual level was indicated by the within-subject coefficient of variation (CVw). CVw within weeks 3 and 9 was 2.5% and 5.1% for men and 4.8 and 8.0% for women. CVw between these weeks was highest when more than one measurement per week was performed. Relating 3MH to creatinine decreased the CVw between weeks. If muscle protein breakdown is to be measured at the individual level, a reasonably large biologic variation is to be taken into account and repeated measurements should be done to decrease the CVw.
Adult↗
Cystathionine-synthase-deficient patients do not use the transamination pathway of methionine to reduce hypermethioninemia and homocystinemia.
Methionine is supposed to be degraded via two known routes, the transsulfuration and the transamination pathways. In particular, patients with hypermethioninemia, due to a defect in the transsulfuration pathway, may catabolize significant amounts of methionine via the transamination pathway. In this study the relative amount of methionine degraded via the transamination pathway in 17 patients with homozygous homocystinuria, due to cystathionine synthase deficiency, was compared with 23 normal subjects, and with a patient with hypermethioninemia due to a deficiency in methionine adenosyltransferase. The homocystinuric patients and the normal subjects were studied in the fasting state as well as after methionine loading (0.1 g/kg body weight). It is concluded that in cystathionine synthase deficient patients, the transamination pathway is not quantitatively important in methionine degradation despite elevated methionine levels. This is in contrast to the patient with methionine adenosyltransferase deficiency, who catabolizes at least 20% of his dietary methionine via the transamination pathway.
Adolescent↗
[Mitochondrial defects].
Mitochondrial myopathies are characterized by structural and functional abnormalities of the mitochondria. The diseases are best classified according to the underlying biochemical defect. In this article the variability of clinical expression and mitochondrial abnormalities is illustrated. An exact diagnosis is a prerequisite for a rational therapy and genetic counseling. In exceptional cases antenatal diagnosis should be possible.
Adenosine Triphosphate↗
Acyl-CoA oxidase activity and peroxisomal fatty acid oxidation in rat tissues.
Acyl-CoA oxidase, the first enzyme of the peroxisomal beta-oxidation, was proved to be rate-limiting for this process in homogenates of rat liver, kidney, adrenal gland, heart and skeletal muscle. Acyl-CoA oxidase activity, based on H2O2-dependent leuko-dichlorofluorescein oxidation in tissue extract, was compared with radiochemically assayed peroxisomal beta-oxidation rates. Dichlorofluorescein production was a valid measure of peroxisomal fatty acid oxidation only in liver and kidney, but not in adrenal gland, heart or skeletal muscle. Production of 14C-labeled acid-soluble products from 1-14C-labeled fatty acids in the presence of antimycin-rotenone appears to be a more accurate and sensitive estimate of peroxisomal beta-oxidation than the acyl-CoA oxidase activity on base of H2O2 production. Chain-length specificity of acyl-CoA oxidase changed with the acyl-CoA concentrations used. Below 80 microM, palmitoyl-CoA showed the highest activity of the measured substrates in rat liver extract. No indications were obtained for the presence in rat liver of more forms of acyl-CoA oxidase with different chain-length specificity.
Acyl-CoA Oxidase↗