Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme metabolism and in vitro erythropoietic growth (CFU-E, BFU-E) were examined in bone marrow cells taken from two siblings with apparent familial hypochromic microcytic anemia. Bone marrow cells from both patients grew adequate numbers of CFU-E and BFU-E colonies in culture in the presence of erythropoietin. In addition, small numbers of endogenous CFU-E were seen in 7-day cultures. Assays on bone marrow cells taken from both patients revealed that baseline delta-aminolevulinic synthase activity was considerably reduced, but increased six to seven fold (to normal levels) when patients' cells were exposed to pyridoxal phosphate (PLP). In both cases, ferrochelatase and delta-aminolevulinic acid dehydratase activities were normal. Bone marrow heme oxygenase showed no significant differences in activities between normals and patients values in the absence or presence of PLP. In contrast, heme synthesis by patients' bone marrow was less than that of normals. This study demonstrates that bone marrow cells from patients with this rare disorder have some disturbances in heme metabolism, whereas erythropoiesis appeared to be normal when cultured with adequate nutrients in vitro.
 ...
PMID:Heme metabolism and in vitro erythropoiesis in anemia associated with hypochromic microcytosis. 335 54

Congenital sideroblastic anemia (CSA) is a hereditary disorder characterized by microcytic anemia and bone marrow sideroblasts. The most common form of CSA is attributed to mutations in the X-linked gene 5-aminolevulinic acid synthase 2 (ALAS2). ALAS2 is a mitochondrial enzyme, which utilizes glycine and succinyl-CoA to form 5-aminolevulinic acid (ALA), a crucial precursor in heme synthesis. Therefore, ALA supplementation could be an effective therapeutic strategy to restore heme synthesis in CSA caused by ALAS2 defects. In a preclinical study, we examined the effects of ALA in human erythroid cells, including K562 cells and human induced pluripotent stem cell-derived erythroid progenitor (HiDEP) cells. ALA treatment resulted in significant dose-dependent accumulation of heme in the K562 cell line. Concomitantly, the treatment substantially induced erythroid differentiation as assessed using benzidine staining. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis confirmed significant upregulation of heme-regulated genes, such as the globin genes [hemoglobin alpha (HBA) and hemoglobin gamma (HBG)] and the heme oxygenase 1 (HMOX1) gene, in K562 cells. Next, to investigate the mechanism by which ALA is transported into erythroid cells, quantitative RT-PCR analysis was performed on previously identified ALA transporters, including solute carrier family 15 (oligopeptide transporter), member (SLC15A) 1, SLC15A2, solute carrier family 36 (proton/amino acid symporter), member (SLC36A1), and solute carrier family 6 (neurotransmitter transporter), member 13 (SLC6A13). Our analysis revealed that SLC36A1 was abundantly expressed in erythroid cells. Thus, gamma-aminobutyric acid (GABA) was added to K562 cells to competitively inhibit SLC36A1-mediated transport. GABA treatment significantly impeded the ALA-mediated increase in the number of hemoglobinized cells as well as the induction of HBG, HBA, and HMOX1. Finally, small-interfering RNA-mediated knockdown of ALAS2 in HiDEP cells considerably decreased the expression of HBA, HBG, and HMOX1, and these expression levels were rescued with ALA treatment. In summary, ALA appears to be transported into erythroid cells mainly by SLC36A1 and is utilized to generate heme. ALA may represent a novel therapeutic option for CSA treatment, particularly for cases harboring ALAS2 mutations.
...
PMID:Effect of 5-aminolevulinic acid on erythropoiesis: a preclinical in vitro characterization for the treatment of congenital sideroblastic anemia. 2545 Mar 64