Biochemistry of nonheme iron in man. II. Absorption of iron

The currently accepted concept of iron absorption proposes first the entry of iron into the intestinal mucosal cell through the brush border membrane. It is a relatively slow process. In the cell, the iron may be transferred to plasma or become sequestered by ferritin. The latter becomes unavailable for transfer to plasma and is exfoliated and excreted. In iron deficiency and idiopathic hemochromatosis, the rate of iron uptake into the intestinal mucosal cell is increased and entry into ferritin is decreased, whereas the rate of transfer to plasma remains constant. The reverse occurs in case of secondary iron overload. It is currently accepted that a transferrin, whose levels increase in iron deficiency, enters the intestinal lumen from the liver via bile, where it may sequester iron and bring it into the cells by the process of endocytosis. Iron presented as inorganic ferric or ferrous salts may also be absorbed, though the more soluble ferrous salts are adsorbed much more rapidly. Heme iron is absorbed very effectively, though it is not subject to regulation by the individual's iron status to the same extent as is inorganic iron absorption. Brush border membranes apparently contain saturable iron receptors for inorganic iron, but whether or not the absorption process requires energy is an open question. Absorption of iron may also be affected by its availability; different food components affect iron absorbability to a different extent.     

Brain iron homeostasis.

The anatomical and cellular distribution of non-haem iron, ferritin, transferrin, and the transferrin receptor have been studied in postmortem human brain and these studies, together with data on the uptake and transport of labeled iron, by the rat brain, have been used to elucidate the role of iron and other metal ions in certain neurological disorders. High levels of non-haem iron, mainly in the form of ferritin, are found in the extrapyramidal system, associated predominantly with glial cells. In contrast to non-haem iron, the density of transferrin receptors is highest in cortical and brainstem structures and appears to relate to the iron requirement of neurones for mitochondrial respiratory activity. Transferrin is synthesized within the brain by oligodendrocytes and the choroid plexus, and is present in neurones, consistent with receptor mediated uptake. The uptake of iron into the brain appears to be by a two-stage process involving initial deposition of iron in the brain capillary endothelium by serum transferrin, and subsequent transfer of iron to brain-derived transferrin and transport within the brain to sites with a high transferrin receptor density. A second, as yet unidentified mechanism, may be involved in the transfer of iron from neurones possessing transferrin receptors to sites of storage in glial cells in the extrapyramidal system. The distribution of iron and the transferrin receptor may be of relevance to iron-induced free radical formation and selective neuronal vulnerability in neurodegenerative disorders.     

Ferric iron reduction and iron assimilation in Saccharomyces cerevisiae.

We have used the yeast Saccharomyces cerevisiae as a model organism to study the role of ferric iron reduction in eucaryotic iron uptake. S. cerevisiae is able to utilize ferric chelates as an iron source by reducing the ferric iron to the ferrous form, which is subsequently internalized by the cells. A gene (FRE1) was identified which encodes a protein required for both ferric iron reduction and efficient ferric iron assimilation, thus linking these two activities. The predicted FRE1 protein appears to be a membrane protein and shows homology to the beta-subunit of the human respiratory burst oxidase. These data suggest that FRE1 is a structural component of the ferric reductase. Subcellular fractionation studies showed that the ferric reductase activity of isolated plasma membranes did not reflect the activity of the intact cells, implying that cellular integrity was necessary for function of the major S. cerevisiae ferric reductase. An NADPH-dependent plasma membrane ferric reductase was partially purified from plasma membranes. Preliminary evidence suggests that the cell surface ferric reductase may, in addition to mediating cellular iron uptake, help modulate the intracellular redox potential of the yeast cell.     

Studies on air-ion-enhanced iron chlorosis I. Active and residual iron

The effects of positive and negative air ions on the active and residual iron fractions of barley seedlings were studied during the course of iron chlorosis. Active iron is that fraction localized in the chloroplasts which dissolves in 1.0 N HC1 and participates in the biosynthesis of chlorophyll. Residual iron is not soluble in 1.0 N HC1 and is not concerned with the biosynthesis of chlorophyll. Air ions of either charge induced a significant decrease in active iron content which was associated with a decrease in chlorophyll content. Concomitantly there occurred an increase in both the residual iron and the cytochrome c fractions of the seedlings. There is evidence that the rise in residual iron content may involve not only cytochrome c but also other cytochromes and iron-containing enzymes as well. We have theorized that the site of air ion action in the experiments reported may be the regulatory systems controlling iron metabolism in the seed and young seedling. Through this action air ions apparently divert endogenous free-state iron from conversion to active iron and make it available for the production of a number of ironcontaining compounds which are components of the residual iron fraction.

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Zusammenfassung Die Wirkung von positiven und negativen Luftionen auf die Aktiv- und Rest-EisenfraktÏon in Gerstenkeimlingen wurde im Verlauf der Eisenchlorose untersucht. Aktiv-Eisen ist die Fraktion in dem FarbstofftrÄger, die in 1.0 N HC1 lösbar und an der Chlorophyllsynthese beteiligt ist. Rest-Eisen istnicht löslich in 1.0 N HC1 und an der Chlorophyllsynthese unbeteiligt. Positive und negative Luftionen bewirkten eine signifikante Verminderung des Gehalts an Aktiv-Fe und Chlorophyll. Gleichzeitig wurden höhere Anteile an Rest-Fe und Cytochrom c gefunden. Es sind Hinweise dafür vorhanden, dass die Zunahme des Rest-Fe nicht nur das Cytochrom c,sondern auch andere Fe-haltige Enzyme betrifft. Die Autoren nehmen an, dass die Luftionen an dem Regulationssystem angreifen, das den Eisenstoffwechsel der Samen und Keimlinge kontrolliert. Luftionen verhindern scheinbar die Umbildung von endogenem Fe-freier Form zu Aktiv-Fe und machen es für die Bildung einer Reihe von Fe-haltigen Verbindungen zugÄnglich, die in der Rest-Fe Fraktion enthalten sind.

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Resume Les effets de l'ionisation positive ou négative de l'air ont été étudiés fraction active et sur la fraction résiduelle du Fer contenu dans des germes d'orge au cours de la sidérochlorose. Le Fer actif est la fraction des chloroplastes soluble dans l'Acide Chlorhydrique 1,0 N et participant à la biosynthèse de la chlorophylle. Le Fer résiduel n'est pas soluble dans H C1 1,0 N et n'entre pas dans la biosynthèse de la chlorophylle. Les ions positifs et négatifs de l'air ont provoqué une réduction significative de la teneur en Fer actif et en chlorophylle. Simultanément, il est apparu un accroissement de Fer résiduel et du Cytochrome c. Certains indices suggèrent que l'accroissement du Fer actif porte non seulement sur le Cytochrome c mais aussi sur d'autres enzymes contenant du Fer. Les auteurs pensent que les ions de l'air agissent au niveau des systèmes de régulation du métabolisme du Fer dans les graines et dans les germes. Les ions de l'air détournent apparemment le Fer libre endogène de la conversion en Fer actif et le rendent disponible pour la formation d'un certain nombre de composés contenant du Fer qui entrent dans la fraction du Fer résiduel.

     

Biochemistry of nonheme iron in man. I. Iron proteins and cellular iron metabolism

Total plasma iron turnover in man is about 36 mg/day. Transferrin is the iron transport protein of plasma, which can bind 2 atoms of iron per protein molecule, and which interacts with various cell types to provide them with the iron required for their metabolic and proliferative processes. All tissues contain transferrin receptors on their plasma membrane surfaces, which interact preferentially with diferric transferrin. In erythroid cells as well as certain laboratory cell lines, the removal of iron from transferrin apparently proceeds via the receptor-mediated endocytosis process. Transferrin and its receptor are recycled to the cell surface, whereas the iron remains in the cell. The mode of iron uptake in the hepatocyte, the main iron storage tissue, is less certain. The release of iron by hepatocytes, as well as by the reticuloendothelial cells, apparently proceeds nonspecifically. All tissues contain the iron storage protein ferritin, which stores iron in the ferric state, though iron must be in the ferrous state to enter and exit the ferritin molecule. Cellular cytosol also contains a small-molecular-weight ferrous iron pool, which may interact with protoporphyrin to form heme, and which apparently is the form of iron exported by hepatocytes and macrophages. In plasma, the ferrous iron is converted into the ferric form via the action of ceruloplasmin.     

Nitric oxide and iron proteins.

Nitric oxide interactions with iron are the most important biological reactions in which NO participates. Reversible binding to ferrous haem iron is responsible for the observed activation of guanylate cyclase and inhibition of cytochrome oxidase. Unlike carbon monoxide or oxygen, NO can also bind reversibly to ferric iron. The latter reaction is responsible for the inhibition of catalase by NO. NO reacts with the oxygen adduct of ferrous haem proteins (e.g. oxyhaemoglobin) to generate nitrate and ferric haem; this reaction is responsible for the majority of NO metabolism in the vasculature. NO can also interact with iron-sulphur enzymes (e.g. aconitase, NADH dehydrogenase). This review describes the underlying kinetics, thermodynamics, mechanisms and biological role of the interactions of NO with iron species (protein and non-protein bound). The possible significance of iron reactions with reactive NO metabolites, in particular peroxynitrite and nitroxyl anion, is also discussed.     

Ochratoxin A-induced iron deficiency anemia.

Ochratoxin A at 8 micrograms per g of diet, but not at lower doses, fed to chickens from 1 day to 3 weeks of age resulted in significantly (P less than 0.05) decreased packed blood cell volume and hemoglobin concentration without altering the number of circulating erythrocytes. Serum iron and percentage of transferrin saturation were lowered at 4 and 8 micrograms/g. Therefore, anemia was characteristic of severe ochratoxicosis of young chickens, and the anemia was categorized as a hypochromic-microcytic anemia of the iron deficiency type. These data indicate that ochratoxin A by itself does not cause hemorrhagic anemia syndrome of chickens and that an anemia caused by a nutritional deficiency can be elicited by a mycotoxin.     

Tetrahymena. Adaptation to high iron

Fe-starved ciliates Tetrahymena thermophila cease to multiply at Fe(III) concentrations above 10 microM in a synthetic nutrient medium lacking a good iron chelator such as citrate. If, however, the Fe(III) concentration is gradually increased over a series of subcultivations the cells will tolerate up to 300 microM Fe(III). Our experiments rule out the possibility of genetic selection of Fe-tolerant clones and suggest a physiological type of adaptation.