Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02011 (FAD)
 5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A method is proposed for the measurement of the flux through the glycerol phosphate shuttle in pancreatic islets. Such a flux is taken as the ratio between the production of 3HOH and the specific radioactivity of L-[2-3H]glycerophosphate in islets exposed to [2-3H]glycerol. D-Glucose and non-glucidic nutrient secretagogues, such as 2-ketoisocaproate and 2-aminobicyclo[2,2,1]heptane-2-carboxylate, stimulate, in a Ca(2+)-dependent manner, circulation in the glycerol phosphate shuttle. The shuttle flux is commensurate with the fraction of pyruvate generation which is not coupled with L-lactate production. These findings support the view that a rise in D-glucose concentration leads to activation of the FAD-linked mitochondrial glycerophosphate dehydrogenase through an increase in cytosolic Ca2+ concentration.
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PMID:Hexose metabolism in pancreatic islets. Ca(2+)-dependent activation of the glycerol phosphate shuttle by nutrient secretagogues. 161 29

Glycerol-3-phosphate dehydrogenase (E. C. 1. 1. 99. 5) was solubilized from rabbit skeletal muscle mitochondria by Triton X-100 and purified through hydroxyapatite column chromatography, DEAE-Sepharose CL-6B column chromatography and sucrose density gradient ultracentrifugation. The preparation was electrophoretically pure, the total recovery was 10% and the specific activity had been increased 200-fold. The apparent molecular weight of the enzyme polypeptide was 69,000, it existed in the form of enzyme-Triton X-100 complex with a Stokes' radius of 59 A and a sedimentation coefficient of 10.7 S. There were 1.7 mg Triton X-100 and 26 micrograms phospholipid per mg protein of the preparation. The enzyme absorbed at 410 and 460 nm which could be attributed to non-haem iron and FAD respectively. Both of the absorption would be largely diminished by adding the substrate glycerol-3-phosphate.
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PMID:Purification and some properties of glycerol-3-phosphate dehydrogenase from rabbit skeletal muscle mitochondria. 357 73

Goto-Kakizaki (GK) rat, a rodent model of spontaneously occurring non-insulin dependent diabetes mellitus (NIDDM), exhibits impaired glucose-stimulated insulin secretion. To explore the background of the beta-cell dysfunction in NIDDM, we investigated whether and how the expression pattern of factors that would potentially be involved in the glucose-stimulated insulin secretion machinery is changed in GK rats. Using quantitative reverse transcription-PCR (RT-PCR) method, we found that the gene expression of CD38, a type 2 membrane protein which has ADP-ribosyl cyclase activity, is reduced by approximately 50% in islets of GK rats. Despite previous studies showing reduction in the FAD-linked mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) activity in GK rats, the mGPDH mRNA amounts were equal to those in the control Wistar rats, suggesting a difference that arose post-transcriptionally. These observations support the idea that multiple defects of the glucose-responsive insulin secreting machinery are involved in the development of diabetes in GK rats.
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PMID:Expression of CD38 gene, but not of mitochondrial glycerol-3-phosphate dehydrogenase gene, is impaired in pancreatic islets of GK rats. 766 44

A 2618-bp cDNA that encodes the human mitochondrial glycerol-3-phosphate dehydrogenase has been isolated from a HeLa cell cDNA library and the nucleotide sequence determined. An open reading frame encodes a protein of 727 amino acids that is 96% similar to the rat protein and, like the rat protein, contains sites homologous to the Ca(2+)-binding sites of calmodulin, as well as FAD- and putative glycerol-phosphate-binding sites.
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PMID:The sequence of a human mitochondrial glycerol-3-phosphate dehydrogenase-encoding cDNA. 782 23

This study aimed to compare the metabolic and secretory responses of pancreatic islets from animals with non-insulin-dependent diabetes to D-glucose with the effects of the methyl esters of succinic acid (SME) and glutamic acid (GME). The insulin secretory response to D-glucose was impaired in islets from rats with diabetes which was either inherited (Goto-Kakizaki (GK) rats) or acquired (streptozotocin-treated (STZ) rats). This coincided with a preferential alteration of oxidative relative to total glycolysis in intact islets and a selective defect of FAD-linked mitochondrial glycerophosphate dehydrogenase (m-GDH) in islet homogenates. This enzymatic defect was also found in purified B cells from STZ rats. It contrasted both with unaltered activities of glutamate dehydrogenase and succinate dehydrogenase in the islets of diabetic animals and with a normal or even increased activity of m-GDH in the livers of GK and STZ rats. The oxidation of [1,4-14C]SME and [U-14C]GME appeared decreased in islets of GK or STZ animals when compared with control rats, but no significant difference between control and diabetic rats was observed when the oxidative data were expressed relative to the rate of [U-14C]GME hydrolysis. Nevertheless, the absolute values for insulin release evoked by a non-metabolized analogue of L-leucine (BCH), by SME and by the association of BCH with either SME or GME were invariably lower in islets of GK and STZ rats than in those of control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pancreatic islet response to dicarboxylic acid esters in rats with type 2 diabetes: enzymatic, metabolic and secretory aspects. 784 32

The FAD-dependent, mitochondrial glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) is an essential component of the glycerol phosphate shuttle and is abundant in the pancreatic insulin cell, skeletal muscle, and brain. Although DNA clones for this enzyme and its homologues have been isolated from bacteria and yeast, it has never been cloned from a higher eukaryote. We have cloned and sequenced cDNAs encoding the rat mitochondrial glycerol-3-phosphate dehydrogenase. The longest cDNA (2337 base pairs) encodes a deduced protein of 727 amino acids that shows strong homology to the yeast and bacterial FAD-dependent glycerol phosphate dehydrogenases. The amino terminus of the purified mature protein was sequenced and shows identity with the deduced amino acid sequence beginning with residue 43. The 42 preceding amino acids are consistent with a mitochondrial leader peptide. A highly conserved FAD-binding domain and conserved regions possibly involved with glycerol phosphate binding are present. An unexpected finding was the homology of the deduced protein to calmodulin. Analysis of the deduced protein sequence shows a region near the carboxyl terminus containing two sequences homologous to "EF-hand" calcium-binding domains that are not present in the shorter yeast and bacterial homologues. The second of these domains appears to have features compatible with considerable affinity for calcium, whereas the first does not. The finding of a potential calcium-binding region is consistent with the known enhancement by calcium of the mammalian enzyme activity at low substrate concentrations and the lack of a requirement for calmodulin. This is the first report of EF-hands in a metabolic enzyme or in a mitochondrial protein.
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PMID:Sequence of rat mitochondrial glycerol-3-phosphate dehydrogenase cDNA. Evidence for EF-hand calcium-binding domains. 818 39

Mitochondrial glycerol phosphate dehydrogenase (mtGPD) is the rate-limiting enzyme in the glycerol phosphate shuttle, which is thought to play an important role in cells that require an active glycolytic pathway. Abnormalities in mtGPD have been proposed as a potential cause for non-insulin-dependent diabetes mellitus. To facilitate genetic studies, we have isolated genomic clones containing the coding regions of the human mtGPD-encoding gene (GPDM). The gene contains 17 exons and is estimated to span more than 80 kb. All splice junctions contain GT/AG consensus sequences. Introns interrupt the sequences encoding the leader peptide, the FAD-binding site, the calcium-binding regions, and a conserved central element postulated to play a role in glycerol phosphate binding. Fluorescence in situ hybridization was used to map this gene to chromosome 2, band q24.1. A retropseudogene was identified and mapped to chromosome 17.
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PMID:Structural organization and mapping of the human mitochondrial glycerol phosphate dehydrogenase-encoding gene and pseudogene. 868 23

The physiological regulation of nutrient catabolism in islet cells, its perturbation in non-insulin-dependent diabetes mellitus, and the tools available to compensate for such a perturbation are reviewed. In terms of physiology, emphasis is placed on the relevance of glucokinase to hexose-induced insulin release, protein-to-protein interaction and enzyme-to-enzyme channelling, and the preferential stimulation of mitochondrial oxidative events in glucose-stimulated B-cells. In terms of pathology, attention is drawn to the deficiency of FAD-linked mitochondrial glycerophosphate dehydrogenase. Last, as far as therapeutic aspects are concerned, the potential usefulness of hypoglycemic sulfonylureas and meglitinide analogs, adenosine analogs, non-glucidic nutrients, and GLP-1 is underlined.
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PMID:Regulation, perturbation, and correction of metabolic events in pancreatic islets. 890 21

The cDNA fragments coding for the FAD-, glycerophosphate- and calcium-binding domains of mitochondrial glycerophosphate dehydrogenase (mGDH) were synthetized using RNA extracted from freshly isolated pancreatic islets of a normal subject and two-non-insulin-dependent diabetic patients. Single strand conformation polymorphism analysis of the PCR products yielded the same mobility as control cDNA probes. Likewise, the nucleotide sequence and corresponding amino acid sequence were identical to the normal gene bank sequence. These findings argue against the presence, in pancreatic islets, of an mGDH isoform distinct from that previously characterized in extrapancreatic organs.
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PMID:Nucleotide sequence of cDNA fragments coding for the FAD-,glycerophosphate- and calcium-binding domains of human islet mitochondrial glycerophosphate dehydrogenase. 930 30

Recent acquisitions concerning the physiology, pathology and pharmacology of insulin secretion are reviewed. In terms of physiology, emphasis is placed on new information concerning the role of glucokinase and the identity of coupling factors in the process of glucose-stimulated insulin release. Pathological considerations concern mainly the possible participation of an inherited or acquired defect of FAD-linked mitochondrial glycerophosphate dehydrogenase in the impairment of insulin release in non-insulin-dependent diabetes. Although experimental approaches to correct such a site-specific defect have so far been unsuccessful, new therapeutic tools, especially the esters of certain nutrients, may soon be available for stimulation of proinsulin biosynthesis as well as insulin release in the diseased B cell.
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PMID:Physiology, pathology and pharmacology of insulin secretion: recent acquisitions. 934 37


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