Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new alpha chain hemoglobin variant, Hb Hobart, alpha 20(Bl)His----Arg, was detected in a 60-year-old female of British nationality. The proposita had a history of severe rheumatoid arthritis and had been treated for many years for a refractory microcytic anemia and/or iron deficiency. A hemoglobin electrophoresis screen indicated the presence of a hemoglobin variant, with electrophoretic characteristics similar to a Hb Lepore. However, the level of the variant (17.9%) and the presence of a minor variant Hb A2 band (0.4%) suggested that further investigation was indicated. The variant hemoglobin was purified by column chromatography and the alpha chain subjected to aminoethylation and tryptic digestion. Peptide mapping and amino acid analysis indicated that the histidine residue 20 had been substituted by an arginine residue. The substitution in Hb Hobart is at the first residue in the B Helix of the alpha chain of hemoglobin. As this is an externally placed amino acid in the hemoglobin molecule, a substitution at this position of the hemoglobin molecule would not be expected to cause any functional problems. A family study has shown that at least three other relatives are heterozygous for Hb Hobart. These family members have normal hematological findings.
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PMID:Hemoglobin Hobart or alpha 20(Bl)His----Arg: a new alpha chain hemoglobin variant. 365 64

It is now apparent that nutritional status has a profound impact on immune function and that the immune system may be modulated by the use of specific modes of nutritional support. In selected malnourished or severely injured patients, early nutritional support has been shown to improve outcome and decrease the incidence of infectious complications following major surgery or trauma. Enteral feedings appear to support the immune system better than parenteral feedings. TPN, although a potentially life-saving modality, should not be used indiscriminantly and should be limited to those severely malnourished or injured patients who are incapable of tolerating enteral feedings. The patient's metabolic needs should be assessed as accurately as possible, and the appropriate combination of substrates should be provided according to the patient's level of hypermetabolism. Overfeeding should be avoided. A number of nutritional substrates have been identified which may potentially modulate specific aspects of immune function. Among these, glutamine, arginine, and omega-3 fatty acids have demonstrated potential clinical usefulness. Iron deficiency appears to be a normal host defense response to infection or trauma and should not be compromised by attempts at iron replacement therapy. In summary, optimal nutritional support of the surgical patient supports the immune system and reduces the morbidity and mortality associated with severe malnutrition or injury.
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PMID:Nutrition and infection. 819 36

A cDNA clone, Ids3 (iron deficiency-specific clone 3), was isolated from an Fe-deficient-root cDNA library of Hordeum vulgare. Ids3 encodes a protein of 339 amino acids with a calculated molecular mass of 37.7 kDa, and its amino acid sequence shows a high degree of similarity with those of plant and fungal 2-oxoglutarate-dependent dioxygenases. One aspartate and two histidine residues for ferrous Fe binding (Asp-211, His-209, His-265) and arginine and serine residues for 2-oxoglutarate binding (Arg-275, Ser-277) are conserved in the predicted amino acid sequence of Ids3. Ids3 expression was rapidly induced by Fe deficiency, and was suppressed by re-supply of Fe. Among eight graminaceous species tested, Ids3 expression was observed only in Fe-deficient roots of H. vulgare and Secale cereale. which not only secrete 2'-deoxymugineic acid (DMA), but also mugineic acid (MA) and 3-epihydroxymugineic acid (epiHMA, H. vulgare), and 3-hydroxymugineic acid (HMA, S. cereale). The Ids3 gene is encoded on the long arm of chromosome 4H of H. vulgare, which also carries the hydroxylase gene that converts DMA to MA. Moreover, the Ids2 gene, which is the plant dioxygenase with the highest homology to Ids3, is encoded on the long arm of chromosome 7H of H. vulgate, which carries the hydroxylase gene that converts MA to epiHMA. The observed expression patterns of the Ids3 and Ids2 genes strongly suggest that IDS3 is an enzyme that hydroxylates the C-2' positions of DMA and epiHDMA, while IDS2 hydroxylates the C-3 positions of MA and DMA.
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PMID:Two dioxygenase genes, Ids3 and Ids2, from Hordeum vulgare are involved in the biosynthesis of mugineic acid family phytosiderophores. 1111 63

Intestinal motility disorders are more common in women of childbearing age who are prone to iron deficiency anemia. The neurotransmitters nitric oxide (NO) and acetylcholine (ACh) play a key role in ileal smooth muscle relaxation and contraction, respectively. Iron-containing heme is known to be a cofactor for nitric oxide synthase (NOS), the enzyme responsible for NO production. Therefore we tested the hypothesis that iron deficiency would downregulate ileal NOS activity without affecting the ileum's response to ACh. Twelve adult female prairie dogs were fed either an iron-supplemented (Fe+) (200 ppm) (n = 6) or an iron-deficient (Fe-) (8 ppm) (n = 6) diet for 8 weeks. Ileal circular muscle strips were harvested to measure responses to ACh and electrical field stimulation. Under nonadrenergic noncholinergic (NANC) conditions, Nomega-nitro-L-arginine (L-NNA), an NOS inhibitor, and VIP(10-28), a vasoactive intestinal peptide (VIP) inhibitor, were added prior to electrical field stimulation. NANC inhibitory responses are expressed as a percentage of optimal relaxation from EDTA. The excitatory response to ACh was similar in both groups (1.1 +/- 0.3 N/cm(2) vs. 1.5 +/- 0.3 N/cm(2), P = 0.45). The inhibitory response to electrical field stimulation under NANC conditions was greater in the Fe+ group (34.7 +/- 2.9%) compared to the Fe- group (23.9 +/- 3.2%; P<0.01). L-NNA eliminated the inhibitory response in the Fe+ group (0.02 +/- 0.02%) but not in the Fe- group (8.38 +/- 2.15%; P <0.01). VIP(10-28) led to greater relaxation in the Fe+ animals (45.8 +/- 6.6%) than in the Fe- animals (23.4 +/- 5.8%; P <0.05). Both L-NNA and VIP(10-28) had no inhibitory response (0.02 +/- 0.02%) in the Fe+ animals, whereas the Fe- animals had some residual inhibition (2.54 +/- 1.04%; P <0.05). These data suggest that ileal NANC relaxation is due to NOS and that iron deficiency results in (1) decreased NANC relaxation, (2) a compensatory relaxation due to a non-NOS, non-VIP mechanism, and (3) a normal excitatory response. We conclude that iron deficiency suppresses ileal NOS activity.
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PMID:Iron deficiency suppresses ileal nitric oxide synthase activity. 1198 81

A mutation of the iron transporter Nramp2 (DMT1, Slc11a2) causes microcytic anemia in mk mice and in Belgrade rats by impairing iron absorption in the duodenum and in erythroid cells, causing severe iron deficiency. Both mk and Belgrade animals display a glycine-to-arginine substitution at position 185 (G185R) in the fourth predicted transmembrane domain of Nramp2. To study the molecular basis for the loss of function of Nramp2(G185R), we established cell lines stably expressing extracellularly tagged versions of wild-type (WT) or mutated transporters. Like WT Nramp2, the G185R mutant was able to reach the plasmalemma and endosomal compartments, but with reduced efficiency. Instead, a large fraction of Nramp2(G185R) was detected in the endoplasmic reticulum, where it was unstable and was rapidly degraded by a proteasome-dependent mechanism. Moreover, the stability of the mutant protein that reached the plasma membrane was greatly reduced, further diminishing its surface density at steady state. Last, the specific metal transport activity of plasmalemmal Nramp2(G185R) was found to be significantly depressed, compared with its WT counterpart. Thus, a singlepoint mutation results in multiple biosynthetic and functional defects that combine to produce the impaired iron deficiency that results in microcytic anemia.
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PMID:Molecular and cellular mechanisms underlying iron transport deficiency in microcytic anemia. 1515 65

Belgrade rats exhibit microcytic, hypochromic anemia and systemic iron deficiency due to a glycine-to-arginine mutation at residue 185 in a metal ion transporter of a divalent metal transporter/divalent cation transporter/solute carrier 11 group A member 2 or 3 (DMT1/DCT1/SLC11A2), a member of the natural-resistance-associated macrophage protein (Nramp) family. By use of rabbit duodenal tissue, a calcein fluorescence assay has previously been developed to assess transport of divalent metal ions across the small-intestinal brush border membrane (BBM). The assay was readily applied here to rat BBM to learn if it detects DMT1 activity. The results demonstrate protein-mediated transport across the BBM of all tested ions: Mn(2+), Fe(2+), and Ni(2+). Transport into BBM vesicles (BBMV) from (b/b) Belgrade rats was below the detection limit. BBMV of +/b origin had substantial activity. The kinetic rate constant for Ni(2+) membrane transport for +/b BBMV was within the range for normal rabbit tissue. Vesicles from +/b basolateral membranes (BLM) showed similar activity to BBMV while b/b BLM vesicles (BLMV) lacked transport activity. Immunoblots using isoform-specific antibodies demonstrated that intestinal levels of b/b DMT1 were increased compared to +/b DMT1, reflecting iron deficiency. Immunoblots on BBMV indicated that lack of activity in b/b vesicles was not due to a failure of DMT1 to localize to the BBMV; an excess of specific isoforms was present compared to +/b BBMV or duodenal extracts. Immunoblots from BLMV also exhibited enrichment in DMT1 isoforms, despite their distinct origin. Immunofluorescent staining of thin sections of b/b and +/b proximal intestines confirmed that DMT1 localized similarly in mutant and control enterocytes and showed that DMT1 isoforms have distinct distributions within intestinal tissue.
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PMID:Transport of divalent transition-metal ions is lost in small-intestinal tissue of b/b Belgrade rats. 1573 55

Nitric oxide (NO) has been identified as a signal molecule that interplays with reactive oxygen species in response to heavy metal stresses. Roles of NO in regulating cadmium toxicity and iron deficiency have been proposed; however, the function of NO in zinc (Zn) tolerance in plants remains unclear. Here, we investigated NO accumulation and its role in plant Zn tolerance. Zn-induced NO production promoted an increase in reactive oxygen species accumulation in Solanum nigrum roots by modulating the expression and activity of antioxidative enzymes. Subsequently, programmed cell death (PCD) was observed in primary root tips. Inhibiting NO accumulation by 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (a specific NO scavenger) or N(G)-nitro-l-arginine-methyl ester (a NO synthase inhibitor) prevented the increase of superoxide radical and hydrogen peroxide as well as the subsequent cell death in the root tips, supporting the role of NO in Zn-induced PCD in the root tips. Zn-induced NO production affected the length of primary roots, the number of lateral roots, and root hair growth and thereby modulated root system architecture and activity. Investigation of metal contents in Zn-treated roots suggests that NO is required for metal (especially iron) uptake and homeostasis in plants exposed to excess Zn. Taken together, our results indicate that NO production and the subsequent PCD in root tips exposed to excess Zn are favorable for the S. nigrum seedling response to long-term Zn toxicity by modulating root system architecture and subsequent adaptation to Zn stress.
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PMID:Nitric oxide is associated with long-term zinc tolerance in Solanum nigrum. 2085 19

Transferrin receptor-2 is a transmembrane protein whose expression is restricted to hepatocytes and erythroid cells. Transferrin receptor-2 has a regulatory function in iron homeostasis, since its inactivation causes systemic iron overload. Hepatic transferrin receptor-2 participates in iron sensing and is involved in hepcidin activation, although the mechanism remains unclear. Erythroid transferrin receptor-2 associates with and stabilizes erythropoietin receptors on the erythroblast surface and is essential to control erythrocyte production in iron deficiency. We identified a soluble form of transferrin receptor-2 in the media of transfected cells and showed that cultured human erythroid cells release an endogenous soluble form. Soluble transferrin receptor-2 originates from a cleavage of the cell surface protein, which is inhibited by diferric transferrin in a dose-dependent manner. Accordingly, the shedding of the transferrin receptor-2 variant G679A, mutated in the Arginine-Glycine-Aspartic acid motif and unable to bind diferric transferrin, is not modulated by the ligand. This observation links the process of transferrin receptor-2 removal from the plasma membrane to iron homeostasis. Soluble transferrin receptor-2 does not affect the binding of erythropoietin to erythropoietin receptor or the consequent signaling and partially inhibits hepcidin promoter activation only in vitro. Whether it is a component of the signals released by erythropoiesis in iron deficiency remains to be investigated. Our results indicate that membrane transferrin receptor-2, a sensor of circulating iron, is released from the cell membrane in iron deficiency.
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PMID:Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form. 2634 29

Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. Several hematological disorders such as sickle cell disease, thalassemia and myeloproliferative diseases develop PH which worsens the prognosis. Associated oxidant injury and vascular inflammation cause endothelial damage and dysfunction. Pulmonary vascular endothelial damage/dysfunction is an early event in PH resulting in the loss of vascular reactivity, activation of proliferative and antiapoptotic pathways leading to vascular remodeling, elevated pulmonary artery pressure, right ventricular hypertrophy and premature death. Hemolysis observed in hematological disorders leads to free hemoglobin which rapidly scavenges nitric oxide (NO), limiting its bioavailability, and leading to endothelial dysfunction. In addition, hemolysis releases arginase into the circulation which converts L-arginine to ornithine, thus bypassing NO production. Furthermore, treatments for hematological disorders such as immunosuppressive therapy, splenectomy, bone marrow transplantation, and radiation have been shown to contribute to the development of PH. Recent studies have shown deregulated iron homeostasis in patients with cardiopulmonary diseases including pulmonary arterial hypertension (PAH). Several studies have reported low iron levels in patients with idiopathic PAH, and iron deficiency is an important risk factor. This article reviews PH associated with hematological disorders and its mechanism; and iron homeostasis and its relevance to PH.
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PMID:Hematological disorders and pulmonary hypertension. 2807 Feb 38

Atmospheric nitrogen fixation by photosynthetic cyanobacteria (diazotrophs) strongly influences oceanic primary production and in turn affects global biogeochemical cycles. Species of the genus Trichodesmium are major contributors to marine diazotrophy, accounting for a significant proportion of the fixed nitrogen in tropical and subtropical oceans. However, Trichodesmium spp. are metabolically constrained by the availability of iron, an essential element for both the photosynthetic apparatus and the nitrogenase enzyme. Survival strategies in low-iron environments are typically poorly characterized at the molecular level, because these bacteria are recalcitrant to genetic manipulation. Here, we studied a homolog of the iron deficiency-induced A (IdiA)/ferric uptake transporter A (FutA) protein, Tery_3377, which has been used as an in situ iron-stress biomarker. IdiA/FutA has an ambiguous function in cyanobacteria, with its homologs hypothesized to be involved in distinct processes depending on their cellular localization. Using signal sequence fusions to GFP and heterologous expression in the model cyanobacterium Synechocystis sp. PCC 6803, we show that Tery_3377 is targeted to the periplasm by the twin-arginine translocase and can complement the deletion of the native Synechocystis ferric-iron ABC transporter periplasmic binding protein (FutA2). EPR spectroscopy revealed that purified recombinant Tery_3377 has specificity for iron in the Fe3+ state, and an X-ray crystallography-determined structure uncovered a functional iron substrate-binding domain, with Fe3+ pentacoordinated by protein and buffer ligands. Our results support assignment of Tery_3377 as a functional FutA subunit of an Fe3+ ABC transporter but do not rule out dual IdiA function.
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PMID:Structural and functional characterization of IdiA/FutA (Tery_3377), an iron-binding protein from the ocean diazotroph Trichodesmium erythraeum. 3021 20


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