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 have documented the presence of five mitochondrial enzymes in samples of chorionic villus tissue and measured the levels of activity. Three of the enzymes catalyse biotin-dependent reactions. These are propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase and pyruvate carboxylase. The other enzymes, 4-aminobutyric acid aminotransferase and succinic semialdehyde dehydrogenase, are involved in the degradation of the central inhibitory neurotransmitter GABA. Distinct diseases in which there is deficiency of each of these enzymes have been documented in man. Significant levels of activity were observed for all five enzymes in chorionic villus tissue. This methodology should permit early prenatal diagnosis of deficiencies of these enzymes by chorionic villus biopsy in the first trimester.
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PMID:Activity of biotin-dependent and GABA metabolizing enzymes in chorionic villus samples: potential for 1st trimester prenatal diagnosis. 372 38

Pyruvate carboxylase is the predominant anaplerotic enzyme in CNS tissues, and thus provides for net utilization of glucose to generate citric acid cycle intermediates such as alpha-ketoglutarate and malate for replenishment of the neurotransmitter pools of glutamate, GABA and aspartate. Studies reported in this paper involving immunocytochemical and biochemical techniques demonstrate: (1) the enzyme is localized in astrocytes as visualized by immunofluorescence in sections of cerebellum and (2) the enzyme activity in astrocyte-enriched populations is 3 X higher than in granule cell-enriched populations isolated from the cerebellum; similarly activity in different synaptosomal preparations parallels that for glutamine synthetase. We conclude from these results that the enzyme pyruvate carboxylase is an astrocyte-specific marker. This localization substantiates some recent hypotheses for astrocyte functions, including CO2 fixation in the CNS and the replenishment of citric acid cycle intermediates by astrocytes as precursors for amino acid neurotransmitter pools.
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PMID:Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. 388 90

We measured amino acid contents in the brains of 11 patients with dominantly inherited cerebellar disorders. Despite clinical similarities, three biochemically different disorders were found. One disorder, with demonstrated HLA linkage in one pedigree, was characterized by moderate reduction of aspartate and glutamate contents in cerebellar cortex alone. In a second disorder, aspartate and glutamate contents were reduced markedly in other brain areas as well as in cerebellar cortex. Aspartate and glutamate contents were normal in cerebellar cortex in the third disorder. GABA content in cerebellar cortex and dentate nucleus was reduced in some patients with each disorder, whereas cerebellar taurine content was normal in all patients. Aspartate deficiency in cerebellar cortex did not result from lack of aspartate aminotransferase or pyruvate carboxylase activity. These amino acid abnormalities probably imply loss of specific cerebellar neurons.
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PMID:Neurotransmitter amino acids in dominantly inherited cerebellar disorders. 611 Oct 44

In the present review evidence is presented that (1) glutamine synthesis in astrocytes is essential for synthesis of GABA in neurons; (2) alpha-ketoglutarate in the presence of alanine (as an amino group donor) can replace glutamine as a precursor for synthesis of transmitter glutamate, but maybe not as a precursor for transmitter GABA; (3) differences exist in the intraneuronal metabolic pathways for utilization of alpha-ketoglutarate plus alanine and of glutamine, and (4) alanine also functions as a substrate for oxidative metabolism in glutamatergic neurons. It should be emphasized that the supply of precursors for transmitter glutamate and GABA in glutamatergic and GABAergic neurons depends on metabolic processes in astrocytes regardless whether glutamine or alpha-ketoglutarate plus L-alanine function as the transmitter precursors. The key reason that an interaction with astrocytes is essential is that both pyruvate carboxylase, the major enzyme in the brain for net synthesis of tricarboxylic acid cycle intermediates, and glutamine synthetase, the enzyme forming glutamine from glutamate, are specifically located in astrocytes, but not in neurons.
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PMID:Utilization of glutamine and of TCA cycle constituents as precursors for transmitter glutamate and GABA. 780 91

The rates of release of the tricarboxylic acid (TCA) cycle constituents alpha-ketoglutarate (alpha-KG), malate and succinate were determined in cultured mouse cerebellar astrocytes, cerebellar granule neurons and cerebral cortical neurons. In addition, its dependence on the external HCO3- concentration was investigated together with effects of K+, glutamate and glutamine. The rate of release of these TCA cycle constituents was linear with time for at least 48 h regardless of the cell type. The release was for all 3 compounds much higher in the astrocytes (13.1, 3.8 and 1.5 nmol.h-1.mg-1 for alpha-KG, malate and succinate, respectively) than in cerebellar (6.5 and 1.5 for alpha-KG and malate) and cortical (3.5 and 1.2 for alpha-KG and malate) neurons. Release of succinate in the neurons could not be determined accurately due to the sensitivity of the assay. In the astrocytes the release of alpha-KG and malate was dependent on HCO3- in a saturable manner with Km values around 6 and 1 mM for alpha-KG and malate, respectively. The release of alpha-KG and malate from astrocytes was stimulated by glutamate (0.5 mM) whereas K+ (15 and 55 mM) and glutamine (0.5 mM) had no effect. The results clearly demonstrate that astrocytes but not neurons release appreciable amounts of TCA cycle intermediates reflecting the presence of pyruvate carboxylase in these cells. The exact functional importance of this release remains to be established but it could play some albeit a minor quantitative role for neuronal homeostasis of the neurotransmitter amino acids glutamate and GABA.
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PMID:Release of alpha-ketoglutarate, malate and succinate from cultured astrocytes: possible role in amino acid neurotransmitter homeostasis. 797 Feb 24

Net synthesis of the neurotransmitter amino acids glutamate and GABA can take place either from glutamine or from alpha-ketoglutarate or another tricarboxylic acid (TCA) cycle intermediate plus an amino acid as donor of the amino group. Since neurons lack the enzymes glutamine synthetase and pyruvate carboxylase that are expressed only in astrocytes, trafficking of these metabolites must take place between neurons and astrocytes. Moreover, it is likely that astrocytes play an important role in maintaining the energy status in neurons supplying energy substrates, e.g., in the form of lactate. The role of trafficking of glutamine, TCA cycle constituents as well as the role of lactate as an energy source in neurons is discussed. Using [U-13C] lactate and NMR spectroscopy, it is shown that lactate that can be produced in astrocytes can be taken up into neurons and metabolized through the TCA-cycle leading to labeling of TCA cycle intermediates plus amino acids derived from these. The labeling pattern of glutamate and GABA indicates that C atoms from lactate remain in the cycle for several turns and that GABA formation may involve more than one glutamate pool, i.e., that compartmentation may exist. Additionally, a possible role of citrate as a chelator of Zn++ with regard to neuronal excitation is discussed. Astrocytes produce large quantities of citrate which by chelation of Zn++ alters the excitable state of neurons via regulation of N-methyl-D-aspartate receptor activity. Thus, astrocytes may regulate neuronal activity at a number of different levels.
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PMID:Trafficking between glia and neurons of TCA cycle intermediates and related metabolites. 929 52

Glial-neuronal interactions were investigated in rats injected intraperitoneally with [1-13C]glucose and killed after 15, 30, 45, or 60 min. Brain extracts were analyzed by 13C-NMR spectroscopy and the fractional 13C-enrichment at individual carbon positions was measured for amino acids, lactate, and N-acetyl-aspartate. [1-13C]Glucose was shown to be metabolized by both neurons and glia, with the anaplerotic pathway through pyruvate carboxylase (PC) accounting for 10% of total cerebral glucose metabolism. The PC-mediated pathway accounted for 39% of the glutamine synthesis, and for 8, 6, 14% of glutamate, GABA, and aspartate synthesis, respectively. These results reflect a compartmentation of the cerebral amino acids synthesis within glial and neuronal cells. The appearance of the 13C-label in C5 of glutamate and glutamine, C1 of GABA and C2 of lactate, is suggestive of pyruvate, formation from TCA cycle intermediates and provides evidence of metabolite trafficking between astrocytes and neurons.
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PMID:The entry of [1-13C]glucose into biochemical pathways reveals a complex compartmentation and metabolite trafficking between glia and neurons: a study by 13C-NMR spectroscopy. 931 94

Using optimized administration of 13C-labeled glucose, the time course of the specific activity of glucose was measured directly by in vivo 13C-NMR in the human brain at 4 Tesla. Subsequent label incorporation was measured at the C2, C3 and C4 positions of both glutamate and the well-resolved C2, C3 and C4 resonances of glutamine and at the C2 and C3 positions of aspartate. GABA was clearly observed for the first time in vivo, suggesting a substantial GABA turnover in the normal human visual cortex. Likewise, lactate C3 labeled with an estimated active pool size on the order of 0.5 mM. A model of cerebral glutamate metabolism is proposed which predicts that glutamatergic action ('neurotransmission'), pyruvate carboxylase flux, TCA cycle activity, glucose consumption and exchange across the mitochondrial membrane can be assessed simultaneously in the human brain.
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PMID:Localized in vivo 13C-NMR of glutamate metabolism in the human brain: initial results at 4 tesla. 977 75

Carbonic anhydrase (CA) V is a mitochondrial enzyme that has been reported in several tissues of the gastrointestinal tract. In liver, it participates in ureagenesis and gluconeogenesis by providing bicarbonate ions for two other mitochondrial enzymes: carbamyl phosphate synthetase I and pyruvate carboxylase. This study presents evidence of immunohistochemical localization of CA V in the rodent nervous tissue. Polyclonal rabbit antisera against a polypeptide of 17 C-terminal amino acids of rat CA V and against purified recombinant mouse isozyme were used in western blotting and immunoperoxidase stainings. Immunohistochemistry showed that CA V is expressed in astrocytes and neurons but not in oligodendrocytes, which are rich in CA II, or capillary endothelial cells, which express CA IV on their plasma face. The specificity of the immunohistochemical results was confirmed by western blotting, which identified a major 30-kDa polypeptide band of CA V in mouse cerebral cortex, hippocampus, cerebellum, spinal cord, and sciatic nerve. The expression of CA V in astrocytes and neurons suggests that this isozyme has a cell-specific, physiological role in the nervous system. In astrocytes, CA V may play an important role in gluconeogenesis by providing bicarbonate ions for the pyruvate carboxylase. The neuronal CA V could be involved in the regulation of the intramitochondrial calcium level, thus contributing to the stability of the intracellular calcium concentration. CA V may also participate in bicarbonate ion-induced GABA responses by regulating the bicarbonate homeostasis in neurons, and its inhibition could be the basis of some neurotropic effects of carbonic anhydrase inhibitors.
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PMID:Mitochondrial carbonic anhydrase in the nervous system: expression in neuronal and glial cells. 1103 10

In order to address the question whether lactate in blood can serve as a precursor for cerebral metabolites, fully awake rats were injected intravenously with [U-(13)C]lactate or [U-(13)C]glucose followed 15 min later by decapitation. Incorporation of label from [U-(13)C]glucose was seen mainly in glutamate, GABA, glutamine, aspartate, alanine and lactate. More label was found in glutamate than glutamine, underscoring the predominantly neuronal metabolism of pyruvate from [U-(13)C]glucose. It was estimated that the neuronal metabolism of acetyl CoA from glucose accounts for at least 66% and the glial for no more than 34% of the total glucose consumption. When [U-(13)C]lactate was the precursor, label incorporation was similar to that observed from [U-(13)C]glucose, but much reduced. Plasma analysis revealed the presence of approximately equal amounts of [1,2,3-(13)C]- and [1,2-(13)C]glucose, showing gluconeogenesis from [U-(13)C]lactate. It was thus possible that the labeling seen in the cerebral amino acids originated from labeled glucose, not [U-(13)C]lactate. However, the presence of significantly more label in [U-(13)C]- than in [2,3-(13)C]alanine demonstrated that [U-(13)C]lactate did indeed cross the blood-brain barrier, and was metabolized further in the brain. Furthermore, contributions from pyruvate carboxylase (glial enzyme) were detectable in glutamine, glutamate and GABA, and were comparatively more pronounced in the glucose group. This indicated that relatively more pyruvate from lactate than glucose was metabolized in neurons. Surprisingly, the same amount of lactate was synthesized via the tricarboxylic acid cycle in both groups, indicating transfer of neurotransmitters from the neuronal to the astrocytic compartment, as previous studies have shown that this lactate is synthesized primarily in astrocytes. Taking into consideration that astrocytes take up glutamate more avidly than GABA, it is conceivable that neuronal lactate metabolism was more prominent in glutamatergic neurons.
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PMID:(13)C MR spectroscopy study of lactate as substrate for rat brain. 1111 Nov 59


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