Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In summary, the vitamin pantothenic acid is an integral part of the acylation carriers, CoA and acyl carrier protein (ACP). The vitamin is readily available from diverse dietary sources, a fact which is underscored by the difficulty encountered in attempting to induce pantothenate deficiency. Although pantothenic acid deficiency has not been linked with any particular disease, deficiency of the vitamin results in generalized malaise clinically. In view of the fact that pantothenate is required for the synthesis of CoA, it is surprising that tissue CoA levels are not altered in pantothenate deficiency. This suggests that the cell is equipped to conserve its pantothenate content, possibly by a recycling mechanism for utilizing pantothenate obtained from degradation of pantothenate-containing molecules. Although the steps involved in the conversion of pantothenate to CoA have been characterized, much remains to be done to understand the regulation of CoA synthesis. In particular, in view of what is known about the in vitro regulation of pantothenate kinase, it is surprising that the enzyme is active in vivo, since factors that are known to inhibit the enzyme are present in excess of the concentrations known to inhibit the enzyme. Thus, other physiological regulatory factors (which are largely unknown) must counteract the effects of these inhibitors, since the pantothenate-to-CoA conversion is operative in vivo. Another step in the biosynthetic pathway that may be rate limiting is the conversion of 4'-phosphopantetheine (4'-PP) to dephospho-CoA, a step catalyzed by 4'-phosphopantetheine adenylyl-transferase. In mammalian systems, this step may occur in the mitochondria or in the cytosol. The teleological significance of these two pathways remains to be established, particularly since mitochondria are capable of transporting CoA from the cytosol. Altered homeostasis of CoA has been observed in diverse disease states including starvation, diabetes, alcoholism, Reye syndrome (RS), medium-chain acyl CoA dehydrogenase deficiency, vitamin B12 deficiency, and certain tumors. Hormones, such as glucocorticoids, insulin, and glucagon, as well as drugs, such as clofibrate, also affect tissue CoA levels. It is not known whether the abnormal metabolism observed in these conditions is the result of altered CoA metabolism or whether CoA levels change in response to hormonal or nonhormonal perturbations brought about in these conditions. In other words, a cause-effect relation remains to be elucidated. It is also not known whether the altered CoA metabolism (be it cause or result of abnormal metabolism) can be implicated in the manifestations of a disease. Besides CoA, pantothenic acid is also an integral part of the ACP molecule.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pantothenic acid in health and disease. 174 61

The metabolism of coenzyme A and control of its synthesis are reviewed. Pantothenate kinase is an important rate-controlling enzyme in the synthetic pathway of all tissues studied and appears to catalyze the flux-generating reaction of the pathway in cardiac muscle. This enzyme is strongly inhibited by coenzyme A and all of its acyl esters. The cytosolic concentrations of coenzyme A and acetyl coenzyme A in both liver and heart are high enough to totally inhibit pantothenate kinase under all conditions. Free carnitine, but not acetyl carnitine, deinhibits the coenzyme A-inhibited enzyme. Carnitine alone does not increase enzyme activity. Thus changes in the acetyl carnitine-to-carnitine ratio that occur with nutritional states provides a mechanism for regulation of coenzyme A synthetic rates. Changes in the rate of coenzyme A synthesis in liver and heart occurs with fasting, refeeding, and diabetes and in heart muscle with hypertrophy. The pathway and regulation of coenzyme A degradation are not understood.
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PMID:Coenzyme A metabolism. 298 78

1. Pantothenate kinase, which is present in cytosol, was studied in preparations from livers of rats fed normal or clofibrate-enriched diets. Effects of CoA, dephospho-CoA and different acyl-CoA derivatives on this enzyme activity were examined in vitro. 2. With partially purified pantothenate kinase or crude particle-free supernatant from the liver of normal or clofibrate-treated rats, Km for pantothenic acid was 0.016 mmol/l at the pH optimum 6.1. 3. Acetyl-CoA, propionyl-CoA, malonyl-CoA and other short-chain acyl-CoA derivatives were strong inhibitors of pantothenate kinase, with Ki in the range 0.001-0.003 mmol/l. The mechanism of inhibition appeared to be of an uncompetitive type. 4. Free CoA has been held to be the main regulator of pantothenate kinase. We found, however, that free CoASH, dephospho-CoA and long-chain acyl-CoA (with Ki 0.003-0.08 mmol/l) were less efficient inhibitors than acetyl-CoA. 5. With pantothenate kinase from clofibrate-treated animals, all inhibitors were less potent. This was most pronounced when the enzyme was assayed in a crude supernatant fraction, possibly because the inhibitors were degraded and/or protein bound. Such a reduction of normal inhibition may contribute to the increased biosynthesis of CoA previously observed during clofibrate treatment. 6. Fasting or diabetes leads to an increase of long-chain acyl-CoA and total CoA in the liver. The increase of CoA has been explained by increased acylation of CoA, and thereby reduced feed-back inhibition by free CoASH at the pantothenate kinase level. We propose another explanation. In these metabolic states, the cytosolic pool of acetyl-CoA is decreased. Since pantothenate kinase is present only in the cytosol, its activity will be released and the biosynthesis of CoA will increase. 7. Acetyl-CoA is probably a more important physiological regulator of pantothenate kinase activity than is free CoASH.
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PMID:Regulation of the biosynthesis of CoA at the level of pantothenate kinase. 708 27

The effects of fasting and diabetes on pantothenic acid (PA) metabolism were studied in rats. Tissue levels of PA and coenzyme A (CoA) and rates of [14C]PA uptake and incorporation into tissue CoA were determined. Both fasting and diabetes resulted in accelerated rates of [14C]PA uptake, higher tissue concentrations of PA, increased incorporation of [14C]PA into CoA, and elevated tissue concentrations of CoA in the liver. The concentration of PA in liver was near the Km of pantothenate kinase for PA in control animals, and increased PA uptake may, in part, account for the increased [14C]PA incorporation into CoA though an elevation in tissue PA levels. In cardiac muscle, increased [14C]PA incorporation into CoA and increased CoA levels were associated with reduced PA uptake and reduced tissue PA levels in both fasting and diabetic animals, suggesting that CoA synthesis is not controlled by substrate availability in this tissue. Uptake of [14C]PA by skeletal muscle was also reduced in diabetic animals. These data suggest that PA uptake by tissues is under metabolic or hormonal control. Decreased uptake by muscle and increased uptake by liver may represent a mechanism for shifting large body stores of PA present in muscle to the liver in which endogenous PA concentrations are normally low. In addition, both fasting and diabetes resulted in decreased urinary PA excretion, a finding that may represent a regulatory mechanism to conserve whole-body PA under these conditions.
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PMID:Effects of diabetes and fasting on pantothenic acid metabolism in rats. 724 30

Iron is essential for oxidation-reduction catalysis and bioenergetics; however, unless appropriately shielded, this metal plays a crucial role in the formation of toxic oxygen radicals that can attack all biological molecules. Organisms are equipped with specific proteins designed for iron acquisition, export and transport, and storage, as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. Despite these homeostatic mechanisms, organisms often face the threat of either iron deficiency or iron overload. This review describes several hereditary iron-overloading conditions that are confined to the brain. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich's ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron-sulfur cluster formation, and the neurologic and cardiac manifestations of Friedreich's ataxia are due to iron-mediated mitochondrial toxicity. Patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus. Finally, aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by loss-of-function mutations in ceruloplasmin gene that leads to misregulation of both systemic and central nervous system iron trafficking. Affected individuals suffer from extrapyramidal signs, cerebellar ataxia, progressive neurodegeneration of retina, and diabetes mellitus. Excessive iron depositions are found in the brain, liver, pancreas, and other parenchymal cells, but plasma iron concentrations are decreased. These conditions are not common, but awareness about them is important for differential diagnosis of various neurodegenerative disorders.
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PMID:Hereditary causes of disturbed iron homeostasis in the central nervous system. 1510 72

Neurodegenerative disorders with brain iron accumulation (NBIA) are a clinically and genetically heterogeneous group of conditions in which there is neurodegeneration accompanied by elevated levels of brain iron. NBIA is frequently of genetic etiology, but may be secondary to an acquired systemic or neurological disease. Mutations in the ferritin light chain cause an adult-onset autosomal-dominant choreiform movement disorder termed neuroferritinopathy. Homozygous mutations in the ceruloplasmin gene cause aceruloplasminemia, which is characterized by the triad of diabetes, retinopathy, and a neurological disorder in mid adulthood. Mutations in pantothenate kinase 2 (PANK2) and phospholipase A2 (PLA2G6) cause recessive, childhood-onset extrapyramidal disorders termed pantothenate kinase-associated neurodegeneration (PKAN) and infantile neuroaxonal dystrophy (INAD), respectively. There is considerable phenotypic overlap between these conditions. The most useful investigation in suspected NBIA is brain magnetic resonance imaging, which can identify pathological iron deposition and distinguish between genotypes. Iron depletion therapy has been demonstrated to be successful in aceruloplasminemia, but not neuroferritinopathy, PKAN, or INAD. The presentation of NBIA overlaps with the more common adult movement disorders and pediatric neurometabolic conditions, and a high index of suspicion is required to make a correct diagnosis.
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PMID:Neurodegeneration with brain iron accumulation. 2149 76

We developed a Drosophila model of T2D in which high sugar (HS) feeding leads to insulin resistance. In this model, adipose TG storage is protective against fatty acid toxicity and diabetes. Initial biochemical and gene expression studies suggested that deficiency in CoA might underlie reduced TG synthesis in animals during chronic HS feeding. Focusing on the Drosophila fat body (FB), which is specialized for TG storage and lipolysis, we undertook a series of experiments to test the hypothesis that CoA could protect against the deleterious effects of caloric overload. Quantitative metabolomics revealed a reduction in substrate availability for CoA synthesis in the face of an HS diet. Further reducing CoA synthetic capacity by expressing FB-specific RNAi targeting pantothenate kinase (PK orfumble) or phosphopantothenoylcysteine synthase (PPCS) exacerbated HS-diet-induced accumulation of FFAs. Dietary supplementation with pantothenic acid (vitamin B5, a precursor of CoA) was able to ameliorate HS-diet-induced FFA accumulation and hyperglycemia while increasing TG synthesis. Taken together, our data support a model where free CoA is required to support fatty acid esterification and to protect against the toxicity of HS diets.
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PMID:CoA protects against the deleterious effects of caloric overload in Drosophila. 2680 7