Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Multiple carboxylase deficiency has previously been characterized by deficient activity of three biotin-dependent enzymes: propionyl CoA carboxylase, pyruvate carboxylase and beta-methylcrotonyl CoA carboxylase. We have demonstrated that the activity of a fourth carboxylase, acetyl CoA carboxylase (ACC), is also deficient in fibroblasts from two patients with this disorder. Furthermore, ACC activity increased six- to eight-fold when cells from these patients were incubated in culture medium containing supplemental biotin. If the primary defect in multiple carboxylase deficiency is due to deficient activity of holocarboxylase synthetase, our results would indicate that there may be a common holocarboxylase synthetase, or at least a common subunit, for all the carboxylases. Finally, since ACC catalyzes the initial step in fatty acid biosynthesis, our results further suggest the importance of dietary supplementation with fatty acids in addition to treating these patients with pharmacologic doses of biotin.
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PMID:Deficient acetyl CoA carboxylase activity in multiple carboxylase deficiency. 611 81

Fatty liver and kidney syndrome (FLKS), a naturally occurring but experimentally reproducible disease in chickens, has several clinical, pathological, and biochemical features in common with Reye's syndrome. Because of this, it has been suggested that FLKS may serve as an animal model of Reye's syndrome. We have examined, therefore, various parameters characteristic of Reye's syndrome in chickens affected with FLKS to further delineate the similarities and differences between the two disorders. Plasma glucose concentrations were significantly lower in chickens affected with FLKS which may be caused by the significantly reduced activity of pyruvate carboxylase in all FLKS-affected animals. The activity of propionyl CoA carboxylase was low in only the most severely affected chickens, and beta-methylcrotonyl CoA carboxylase showed no difference when compared with controls. This may be due to variable sensitivities of the three carboxylases to marginal biotin deficiency which occurs with FLKS. Plasma ammonia concentrations and activities of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, however, were not elevated in the affected birds. Histological changes in the liver and kidney were noted in affected chickens, but these changes were not identical with those observed in Reye's syndrome. Although the mechanisms of nitrogen elimination in fowl differ from those in humans, failure to demonstrate hyperammonemia, elevated serum transaminase activities, or similar histological changes in tissues of affected birds indicates that FLKS is not an appropriate model for the study of Reye's syndrome.
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PMID:Fatty liver and kidney syndrome in chickens as an animal model for Reye's syndrome. 664 49

We have examined genetic complementation in pyruvate carboxylase deficiency by comparing the enzyme activity in polyethylene glycol-induced heterokaryons with that in unfused mixtures of fibroblasts from three affected children. Complementation, manifested as a three- to sevenfold increase in pyruvate carboxylase activity, was observed in fusions between a biotin-responsive multiple carboxylase (pyruvate carboxylase, propionyl CoA carboxylase, and beta-methylcrotonyl CoA carboxylase) deficient fibroblast line and two other lines deficient only in pyruvate carboxylase activity. Kinetic analysis of complementing pyruvate carboxylase deficient lines, measured by the rate of restoration of enzyme activity as a function of time, revealed that maximum restoration was achieved within 10-24 hr after fusion. This profile is similar to those oberved for fusions between the multiple carboxylase deficient line and two lines deficient in propionyl CoA carboxylase activity that are known to represent different gene mutations. Although the patients with pyruvate carboxylase deficiency had similar clinica findings, our studies indicate that pyruvate carboxylase deficiency is genetically heterogeneous, with at least two distinct, probably intergenic, complementation groups.
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PMID:Evidence for two genetic complementation groups in pyruvate carboxylase-deficient human fibroblast cell lines. 677 49

Multiple carboxylase deficiency is characterized by deficient activities of three biotin-dependent enzymes, propionyl coenzyme A carboxylase, pyruvate carboxylase, and beta-methylcrotonyl coenzyme A carboxylase. A newborn infant was seen with metabolic ketoacidosis, hyperammonemia, organic aciduria, seizures, and coma. Multiple carboxylase deficiency was subsequently confirmed by enzyme activity determinations in his peripheral blood leukocytes and cultured skin fibroblasts. The infant's neurologic and metabolic status improved markedly within a few days of administration of pharmacologic doses of oral biotin. His EEG, which was distinctly abnormal, became normal; his extensive computed tomography scan changes resolved, with the exception of ventricular dilation, over the next two months. After two weeks of biotin treatment the excretion of abnormal organic acid metabolites was reduced and his carboxylase activities increased to the normal range. However, the activities of these enzymes increased only to 30% to 55% of normal in fibroblasts incubated in supplemental biotin. This partial correction of enzyme activity differs from that observed in other individuals with multiple carboxylase deficiency and suggests biochemical heterogeneity in this disorder. Prompt diagnosis and intervention can avert some of the pathologic complications of this biotin-responsive condition.
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PMID:Multiple carboxylase deficiency: clinical and biochemical improvement following neonatal biotin treatment. 678 61

Three biotin-dependent enzymes, pyruvate carboxylase (PC), propionyl CoA carboxylase (PCC), and beta-methylcrotonyl CoA carboxylase (beta MCC), were biochemically characterized in fibroblasts from two patients with neonatal multiple carboxylase deficiency. Genetic complementation analyses indicated that both cell lines, designated lines 1 and 2, were deficient in the various carboxylase activities and belonged to the bio complementation group. The activities of the three carboxylases became normal when line 2 cells were incubated in medium supplemented with biotin (1 mg/l) for 24 hrs, whereas 4-6 days were required to achieve maximum activities of PC, PCC, and beta MCC (57%, 46%, and 29% of mean normal enzyme activity, respectively) in line 1 cells incubated in medium containing up to 10 mg/1 biotin. Furthermore, PC activity in line 2 continued to increase under apparent gluconeogenic conditions in culture, but not in line 1. Thermostability studies suggested that biotin stabilizes PC and beta MCC in both cell lines. PC in line 1 cells incubated with or without biotin was less stable than that in normal or line 2 cells, and the less than normal increase of enzyme activities in line 1, especially that of PC, may represent incomplete biotination. These results indicate that there is biochemical heterogeneity within the bio complementation group. Immunotitration with antibodies prepared against purified pig heart PCC demonstrated normal quantities of cross-reacting material in both lines and no differences in the amount of this material after incubation with supplemental biotin, despite the seven- to 20-fold increase in PCC activity. Thus, the increase in carboxylase activity in both bio lines appears to represent activation of rpe-existing apocarboxylase rather than de novo enzyme synthesis. The primary defect in this form of multiple carboxylase deficiency may be in a common holocarboxylase synthetase or in biotin transport. If the defect is in the synthetase, the differences noted between the two bio lines could be explained by a difference in the enzyme's Km for biotin.
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PMID:Biochemical characterization of biotin-responsive multiple carboxylase deficiency: heterogeneity within the bio genetic complementation group. 679 61

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

Free magnesium and MgATP2- are required for activation of the mitochondrial enzymes pyruvate carboxylase, propionyl CoA carboxylase and beta-methylcrotonyl CoA carboxylase. Previous studies have demonstrated that free Mg2+ interacts with either a Mg2+- binding site or one of the two MgATP2- sites that are required for the allosteric activation of pyruvate carboxylase. We have shown that similar Mg2+ and MgATP2- interactions occur to activate propionyl CoA carboxylase and beta-methylcrotonyl CoA carboxylase. Thus, Mg2+ and MgATP2- activation, because it is common to structurally similar carboxylases, may constitute a general mode of carboxylase activation.
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PMID:Magnesium and magnesium adenosine triphosphate activation of human propionyl CoA carboxylase and beta-methylcrotonyl CoA carboxylase. 698 5

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

Peroxidase-conjugated avidin was used to detect the endogenous avidin-binding proteins in rat tissues. By a transblot method, avidin-peroxidase interacted with proteins of mitochondrial fractions of rat liver with estimated molecular weights of 120,000 and 74,000. The proteins were identified as pyruvate carboxylase (120 kDa, pI 6.4) and methylcrotonyl-CoA carboxylase (74 kDa, pI 7.2) by two-dimensional gel electrophoresis and transblot method. The estimated molecular weight of an additional band (220,000) detected in the cytosolic fraction of rat liver was consistent with acetyl-CoA carboxylase. Intense staining also occurred with kidney, heart, ovary and adipose tissue, moderate with large and small intestine, cerebrum and cerebellum, and very faint with testis, lung and spleen. The sections of rat liver embedded in LR white were incubated with avidin-colloidal gold conjugate and examined under an electron microscope. The glutaraldehyde-perfused rat liver blocks were also incubated with streptavidin-ferritin conjugate and the ultrathin sections were cut and examined. The majority of gold and ferritin particles were found in the mitochondria of liver cells. No other cellular compartment was labeled except the cytosol which accounted for approximately 20% of the total labeling of the hepatocytes. The present procedure is a simple, rapid and inexpensive method for detecting the intracellular localization of endogenous avidin-binding proteins in the cells.
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PMID:Detection of endogenous avidin-binding proteins in rat liver cells by transblot and electron microscopy. 825 80

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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