Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three brothers with diabetes mellitus, thiamine-responsive megaloblastic anemia, and sensorineural deafness are reported. Two had, in addition, congenital septal defects. The activities of thiamine-dependent enzymes were determined in one patient, revealing low alpha-ketoglutarate dehydrogenase activity, which could have caused a sideroblastic anemia with secondary megaloblastic changes. The anemia was thiamine dependent. The cause of the diabetes mellitus was not known, but it was not type 1.
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PMID:Diabetes mellitus, thiamine-dependent megaloblastic anemia, and sensorineural deafness associated with deficient alpha-ketoglutarate dehydrogenase activity. 404 2

Aluminum (Al), a known environmental pollutant, has been linked to numerous pathologies such as Alzheimer's disease and anaemia. In this study, we show that alpha-ketoglutarate (KG) mitigates the Al-mediated nuclear accumulation of hypoxia inducible factor-1alpha (HIF-1alpha) in cultured human hepatocytes (HepG2). The nuclear localization of HIF-1alpha appeared to be triggered by the Al-induced perturbation of prolyl hydroxylase 2 (PHD2). This enzyme was markedly diminished in the Al-challenged hepatocytes. The fate of PHD2 and HIF-1alpha was intricately linked to the mitochondrial dysfunction observed during Al stress. BN-PAGE, immunoblot, and HPLC revealed that the loss of alpha-ketoglutarate dehydrogenase (KGDH) and succinate dehydrogenase (SDH) activities were coupled to the accumulation of succinate. However, the treatment of the Al-stressed cells with KG recovered the activity and expression of KGDH, SDH, and PHD2 with a concomitant decrease in the levels of HIF-1alpha in the nucleus. Taken together, these data indicate that the homeostasis of KG plays a pivotal role in aerobic and anaerobic respiration.
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PMID:Alpha-ketoglutarate abrogates the nuclear localization of HIF-1alpha in aluminum-exposed hepatocytes. 1902 44

Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, increased immature progenitor and erythroblast. In erythroid cells of these mice, D-2-hydroxyglutarate (D-2HG), an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase (OGDH) activity and diminishes succinyl-CoA production. This succinyl-CoA deficiency attenuates heme biosynthesis in IDH1-mutant hematopoietic cells, thus blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells (HSC), while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 (HO-1) expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species (ROS) that induce the cell death of IDH1-mutant erythroid cells. Our results clearly demonstrate the essential role of IDH1 in normal erythropoiesis and show how its mutation leads to myeloid disorders. Our data thus have important implications for the devising of new treatments for IDH-mutant tumors.
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PMID:IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis. 3325 33