Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.4.1.1 (pyruvate carboxylase)
 1,516 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a case of pyruvate-carboxylase deficiency (EC 6.4.1.1, McKusick 26615) with neonatal onset of lactic acidosis, hyperammonemia, and citrullinemia. The patient developed signs of severe liver damage and died at 13 days of age after increasing metabolic acidosis and severe bleedings. The pyruvate-carboxylase activity in fibroblasts was less than 1% of controls, but normal activities of propionyl-CoA carboxylase (EC 6.4.1.3) and 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) were found. To prepare for early prenatal diagnosis of pyruvate-carboxylase deficiency, the activity of the enzyme has been measured in chorionic villus samples.
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PMID:Pyruvate-carboxylase deficiency with urea cycle impairment. 393 31

Affinity chromatography on avidin-Sepharose column was used to bind the biotin-containing carboxylases from rat liver. With a biotin gradient (0-0.3 mM), peaks of activity of pyruvate, propionly CoA and beta-methylcrotonyl CoA carboxylases co-eluted. Subsequent separation of the three carboxylases was attained using DEAE-Sepharose chromatography. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis showed each of the enzymes to be pure, with pyruvate carboxylase giving a single subunit band (Mr 130 000), propionyl-CoA carboxylase giving two bands (Mr 73 000 and 56 500) and beta-methylcrotonyl-CoA carboxylase giving two bands (Mr 75 000 and 60 000). The specific activity of propionyl-CoA carboxylase (15.8 munits/mg) and beta-methylcrotonyl-CoA carboxylase (24.2 munits/mg) were comparable with reported activities for these purified enzymes, while that of pyruvate carboxylase (1.25 munits/mg) was low. This is a suitable method for the simultaneous preparation of purified carboxylases for the specific purpose of raising antisera to these enzymes.
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PMID:Simultaneous preparation of the three biotin-containing mitochondrial carboxylases from rat liver. 399 77

1. Pyruvate carboxylase (EC 6.4.1.1), purified from rat liver mitochondria to a specific activity of 14 units/mg, was used for the preparation of antibodies in rabbits. 2. Tissue distribution studies showed that pyruvate carboxylase was present in all rat tissues that were tested, with considerable activities both in gluconeogenic tissues such as liver and kidney and in tissues with high rates of lipogenesis such as white adipose tissue, brown adipose tissue, adrenal gland and lactating mammary gland. 3. Immunochemical titration experiments with the specific antibodies showed no differences between the inactivation of pyruvate carboxylase from mitochondrial or soluble fractions of liver, kidney, mammary gland, brown adipose tissue or white adipose tissue. 4. The antibodies were relatively less effective in reactions against pyruvate carboxylase from sheep liver than against the enzyme from rat tissues. 5. Pyruvate carboxylase antibodies did not inactivate either propionyl-CoA carboxylase or acetyl-CoA carboxylase from rat liver. 6. It is concluded that pyruvate carboxylase in lipogenic tissues is similar antigenically to the enzyme in gluconeogenic tissues and that the soluble activities of pyruvate carboxylase detected in many rat tissues do not represent discrete enzymes but are the result of mitochondrial damage during tissue homogenization.
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PMID:Immunochemical studies with soluble and mitochondrial pyruvate carboxylase activities from rat tissues. 549 7

Biotin containing carboxylases in cultured human skin fibroblasts were radioactively labeled by addition of [8,9-3H]biotin to biotin-depleted cell cultures. Three major bands were visualized by fluorography after sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the fibroblast proteins. These bands corresponded to pyruvate carboxylase (Mr = 125,000), the biotin-containing subunit of methyl crotonyl-CoA carboxylase (Mr = 75,000) and the biotin-containing subunit of propionyl-CoA carboxylase (Mr = 73,000) as judged by molecular weight markers, purified carboxylase protein standards, and interaction with monospecific antisera. Four out of 5 cell lines from patients with classical pyruvate carboxylase deficiency (less than 5% of normal activity) labeled with this technique displayed a normal band in the position of pyruvate carboxylase while one cell line showed complete absence of any labeled protein in this area. These results demonstrate heterogeneity in the etiology of pyruvate carboxylase deficiency.
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PMID:[3H]biotin-labeled proteins in cultured human skin fibroblasts from patients with pyruvate carboxylase deficiency. 640 85

This report concerns a patient with severe congenital lacticacidosis associated with proximal renal tubular acidosis and cystinuria. Enzyme studies with cultured skin fibroblasts obtained from the patient revealed zero pyruvate carboxylase activity, but propionyl-CoA carboxylase activity was normal. Administration of various vitamins in large amounts did not improve the clinical condition. In contrast, the patient began to thrive when her diet was supplemented with aspartic acid, asparagine, glutamic acid, and glutamine. The particular dietary treatment used and the biochemical findings merit consideration for management of future cases.
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PMID:Neonatal pyruvate carboxylase deficiency with renal tubular acidosis and cystinuria. 642 51

Oxygen uptake in skeletal muscle mitochondria respiring on pyruvate or on acetylcarnitine plus propionylcarnitine is stimulated 3--4-fold by bicarbonate. The stimulation is highly dependent on ATP. The respiration rate obtained amounts to 1/4-1/3 of the rate obtained with pyruvate-malate in the presence of ADP. With decreasing ATP/ADP ratios in the medium, a decreasing stimulation by bicarbonate is obtained. Similar results were obtained with heart mitochondria. With ATP added, a pyruvate-dependent build up of citric acid cycle intermediates takes place in incubations with skeletal muscle mitochondria amounting to about 0.5 nmol x min-1 x mg protein-1. In 14CO2-fixation experiments, the activity of pyruvate carboxylase (EC 6.4.2.1) amounts to about 3 nmol x min-1 x mg protein-1 under similar conditions. With propionylcarnitine plus acetylcarnitine a similar stimulation of respiration and fixation of bicarbonate is observed. In this case the respiration and the propionyl-CoA carboxylase (EC 6.4.1.3) is less inhibited by ADP. The results are discussed in relation to the regulation of the level of citric acid cycle intermediates in muscle tissues. It is concluded that pyruvate carboxylase is an important anaplerotic enzyme in skeletal muscle mitochondria.
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PMID:Pyruvate carboxylase and propionyl-CoA carboxylase as anaplerotic enzymes in skeletal muscle mitochondria. 677 58

Two mitochondrial biotin-dependent enzymes, propionyl-CoA carboxylase and pyruvate carboxylase, are measurable in hair roots. A third biotin-dependent enzyme, beta-methylcrotonyl-CoA carboxylase, was barely detectable in hair roots. The diagnosis of isolated propionyl-CoA carboxylase deficiency was confirmed in hair roots of a known affected patient. This method should be a rapid and accurate method for the diagnoses of the various carboxylase deficiencies, particularly isolated pyruvate carboxylase deficiency in individuals with lactic acidosis, as well as for the assessment of biotin responsiveness in these patients.
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PMID:The measurement of propionyl-CoA carboxylase and pyruvate carboxylase activity in hair roots: its use in the diagnosis of inherited biotin-dependent enzyme deficiencies. 685 Nov 81

Biotin carboxylases in mammalian cells are regulatory enzymes in lipogenesis and gluconeogenesis. In this study, endogenous biotin in skeletal and cardiac muscle was detected using avidin conjugated with alkaline phosphatase and applied in high concentrations to muscle sections. The avidin binding was subsequently visualized by histochemical demonstration of the alkaline phosphatase activity. All cardiac muscle cells showed high affinity for avidin with only the nuclei and the intercalated discs remaining unstained. In skeletal muscle a diffuse reaction could be detected in the sarcoplasm of the muscle fibres. A granular reaction was noted in the same fibres that showed activity for succinic dehydrogenase. The specificity of the coloured reaction product in the muscle sections was investigated and is suggested to be caused by avidin binding to biotin moieties in mitochondria and the cytosol. Mitochondrial and cytosolic preparations of skeletal muscle were electrophoresed in sodium dodecyl sulphate gels. After blotting and incubation with conjugated avidin, two bands with molecular weights of 75 kDa and 130 kDa respectively were evident in the mitochondrial preparation. It is suggested that the 75-kDa band represents comigration of the biotin-containing subunits of propionyl-CoA carboxylase and methylcrotonyl-CoA carboxylase. The 130-kDa band may represent the biotin-containing pyruvate carboxylase. In the cytosolic preparation a 270-kDa band was stained in blots that had been incubated with conjugated avidin; this band is suggested to represent acetyl-CoA carboxylase. A 190-kDa cytosolic band might be a cleavage product of acetyl-CoA carboxylase. We propose that using alkaline phosphatase-conjugated avidin it is possible to detect the mitochondrial and cytosolic biotin-dependent carboxylases in striated muscle.
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PMID:Biotin carboxylases in mitochondria and the cytosol from skeletal and cardiac muscle as detected by avidin binding. 816 85

We present a new case of holocarboxylase synthetase (HCS) deficiency, a rare autosomal recessive metabolic disorder, causing the "early-onset" form of multiple carboxylase deficiency. The patient was born at term of healthy consanguineous parents after an uncomplicated pregnancy. On the 2nd day of life she refused oral feeding, became tachydyspnoeic and showed excessive weight loss. Laboratory studies showed metabolic acidosis, marked lactic acidaemia, hyperammonaemia and increased urinary excretion of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxpropionic acid and methylcitric acid. Peritoneal dialysis combined with oral supplementation of biotin (10 mg/day) started on the 3rd day of life resulted in rapid clinical recovery and normalisation of biochemical parameters. HCS deficiency was established in lymphocytes and skin fibroblasts. The activities of all biotin-dependent carboxylases were severely decreased in fibroblasts grown in medium with moderate biotin concentration (10(-8) mol/l) but normal in a high biotin medium (10(-5) mol/l). Mitochondrial carboxylase activities in lymphocytes were 23%-29% of mean normal during therapy with 20 mg of biotin/day, with the higher dose of 40 mg/day they were within (3-methylcrotoryl-CoA carboxylase, pyruvate carboxylase) or slightly below (propionyl-CoA carboxylase) the normal range. At the age of 3 years the patient's physical and psychomotor development are normal. Early biotin supplementation should be considered in newborns with lactic acidosis and organoaciduria until a final diagnosis has been established. Furthermore, the required individual dose of biotin has to be carefully evaluated biochemically for the individual patient.
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PMID:Holocarboxylase synthetase deficiency: early diagnosis and management of a new case. 831 16

The enzyme activity of the mitochondrial glycerol phosphate dehydrogenase (mGPD) in the pancreatic islet has been reported to be less than one-half of normal in the Goto-Kakizaki (GK) rat, a genetic model of NIDDM. In the current study, mGPD enzyme activity and the amount of mGPD protein, as judged by Western analysis, were 35-40% of normal in the islets of these animals. With the exception of pyruvate carboxylase, the activities of other enzymes were not abnormal. The assayable activity and amount of pyruvate carboxylase protein were decreased approximately 50% in the islets of the GK rats. Because mGPD, which is the key enzyme of the glycerol phosphate shuttle, and pyruvate carboxylase, which is the key component of the pyruvate malate shuttle, have been proposed to be essential for stimulus-secretion coupling in the pancreatic beta-cell, an important question is whether the decreases in these enzymes have a causal role in the hyperglycemia or whether the diabetic syndrome caused the decreases. To attempt to differentiate between these two possibilities, GK rats were treated with insulin to normalize their blood sugars. The activities of both mGPD and pyruvate carboxylase were also normalized by insulin treatment. An incidental discovery of this study was the identification of a high level of propionyl-CoA carboxylase activity and a lesser amount of methylcrotonyl-CoA carboxylase activity in pancreatic islets. These enzymes were normal in the islets of the GK rats. This is the first report on the presence of these two carboxylases in the islet and of low pyruvate carboxylase activity in the islet in NIDDM. We conclude that the decreased mGPD and pyruvate carboxylase in the pancreatic islet of the GK rat result from the diabetic syndrome.
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PMID:Normalization by insulin treatment of low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat. 866 38


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