Ascorbate is a cofactor in numerous metabolic reactions. Humans can not synthesize ascorbate due to inactivation of the gene which encodes the essential enzyme for ascorbate synthesis, l-gulono-γ-lactone oxidase.
There is strong evidence that ascorbate, in addition to the known dietary ascorbate ability to enhance non-heme iron absorption in the gut, can regulate cellular iron uptake and metabolism in mammalian systems. Ascorbate modulates iron metabolism by stimulating ferritin synthesis, inhibiting lysosomal ferritin degradation, and reducing cellular iron outflow. In addition, the ascorbate cycle through the plasma membrane is responsible for ascorbate-stimulated iron uptake from low molecular weight iron-citrate complexes, which play a prominent role in the plasma of individuals with iron overload disorders. Importantly, this iron uptake pathway is of particular importance for iron metabolism in the brain of astrocytes and iron loading of the tissue in diseases such as hereditary hemochromatosis and β-thalassemia. Recent evidence also suggests that ascorbate is a novel modulator of the classical transferrin-iron uptake pathway, which under physiological conditions provides almost all the iron for cellular demand and erythropoiesis. Ascorbate stimulates transferrin-dependent iron uptake by an intracellular reduction mechanism, strongly suggesting that it stimulates iron mobilization by the endosome. The ability of ascorbate to regulate the iron uptake of transferrin may be helpful in explaining the metabolic defect contributing to ascorbate deficiency-induced anemia.
Asc - ascorbateCGcytbchromaffin granules cytochrome b561Dcytbduodenal cytochrome b561DHAdehydroascorbateDMT1divalent metal transporter isoform 1FBXL5F box and leucine-rich repeat protein 5FIHfactor inhibition HIFFPN1ferroportin 1FTH1H-ferritinFTLL-ferritinGULOl-gulono-γ-lactone oxidaseGLUTfacilitative glucose transporterHIFhypoxia-inducible factorholo-Tfmono- or diferric TfIREiron-responsive elementIRPiron Regulatory proteinISCiron low-sulfur clusterLcytblysosomal cytochrome b561NTBInon-Tf-linked ironPHDprolyl-4-hydroxylase domains containing iron-dependent prolyl hydroxylase SDR2 stromal cells stem receptor 2Steap3six transmembrane epithelial prostate 3SVCTsodium vitamin C cotransporter tftransferrinTfRTf receptorUTRuntranslated region
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