Transferrin turnover

STABILITY/TURNOVER ELEMENT (Transferrin Receptor mRNAs, 3 UTR)... 

Figure 7.4 (a) IREs in eukaryotic mRNAs the secondary structures of ferritin and transferrin receptor IREs. (b) The IRE localization in mRNAs the translation/ribosome binding element in the 5 -UTR of ferritin mRNA is above, that of the stability/ turnover element in the 3 -UTR of transferrin receptor mRNA is below. Adapted from Theil, 1998, by courtesy of Marcel Dekker, Inc. 

Figure 8.1 Body iron stores and daily iron exchange. The figure shows a schematic representation of the routes of iron movement in normal adult male subjects. The plasma iron pool is about 4 mg (transferrin-bound iron and non-transferrin-bound iron), although the daily turnover is over 30 mg. The iron in parenchymal tissues is largely haem (in muscle) and ferritin/haemosiderin (in hepatic parenchymal cells). Dotted arrows represent iron loss through loss of epithelial cells in the gut or through blood loss. Numbers are in mg/day. Transferrin-Tf haemosiderin - hs MPS - mononuclear phagocytic system, including macrophages in spleen and Kupffer cells in liver.

Fluxes of iron from the plasma towards BM and other tissues can be quantified by ferrokinetic studies, using 59Fe and sophisticated computer models (Ricketts et ah, 1975 Ricketts and Cavill, 1978 Barosi et ah, 1978 Stefanelli et ah, 1980). Plasma iron turnover (PIT), erythroid iron turnover (EIT), non-erythroid iron turnover (NEIT), marrow iron turnover (MIT), and tissue iron turnover (TIT) could be calculated in many disorders of iron metabolism and in all kinds of anaemias. Iron is rapidly cleared from the plasma in iron deficiency and in haemolytic anaemias. If more iron is needed for erythropoiesis, more transferrin receptors (TfR) are expressed on erythroblasts, resulting in an increased flux of iron from intestinal mucosal cells towards the plasma. In haemolytic anaemias MPS, and subsequently hepatocytes, are overloaded. In hereditary haemochromatosis too much iron is absorbed by an intrinsic defect of gut mucosal cells. As this iron is not needed for erythropoiesis,... 

The iron is transferred by the mucosal epithelium to the body and is bound to plasma transferrin in the ferric state. In the plasma, iron takes part in a dynamic transferrin-iron equilibrium and is distributed into vascular and interstitial extravascular compartment. 50 to 60% of transferrin is extravascular. The plasma iron pool in adults is about 3 mg and has an estimated turnover of 20 to 30 mg per 24 hours. Daily and obligatory losses of iron in healthy men are about 1 mg in healthy menstruating women these average 2 mg and in either case are compensated by a net absorption of 1 to 2 mg from the intestine, which enters the mobile pool of transferrin iron. 

The majority of body iron is not chelatable (iron from cytochromes and hemoglobin). There are two major pools of chelatable iron by DFO (19). The first is that delivered from the breakdown of red cells by macrophages. DFO competes with transferrin for iron released from macrophages. DFO will also compete with other plasma proteins for this iron, when transferrin becomes saturated in iron overload. The quantity of chelatable iron from this turnover is 20mg/day in healthy individuals and iron chelated from this pool is excreted in the urine (19). The second major pool of iron available to DFO is derived from the breakdown of ferritin and hemosiderin. The ferritin is catabolized every 72 hours in hepatocytes, predominantly within lysosomes (I). DFO can chelate iron that remains within lysosomes shortly after ferritin catabolism or once this iron reaches a dynamic, transiently chelatable, cytosolic low-molecular-weight iron pool (20). Cellular iron status, the rate of uptake of exogenous iron, and the rate of ferritin catabolism are influent on the level of a labile iron pool (21). Excess ferritin and... 

Schade reviewed (114) the earlier studies on the role of serum transferrin in iron transport. Various early investigators had observed that the blood serum transferrin rapidly bound iron administered either through the gastrointestinal tract or by intravenous injection. There was a rapid turnover of iron in the blood serum and the degree of saturation of the transferrin was related to the amount of iron administered. In no instances, however, was the blood serum transferrin ever saturated with iron. Jandl et al. (71) have shown that both ovotransferrin and serum transferrin can transport plasma iron into red cells and that the transport is dependent on the concentration of transferrin. Iron taken up by the blood cells could not be eluted by subsequent incubation with iron-free transferrin solutions. More recently Morgan and Laurel (99) reported that iron uptake in reticulocytes is independent of the transferrin concentration. The iron complex of serum transferrin has a higher affinity for immature red cells than does the iron-free protein (72). Both bind specifically to immature red cells and the attachment permits the cells to remove the iron. Once the iron is removed, however, the iron-free transferrin can be replaced by an iron-transferrin complex. 

The rate constants and the associated free-energy snrfaces available to the peroxide and native intermediates deserve comment since they differ overall by nearly 10 (or ca. Vkcalmol in absolnte valne). Given the relatively electronentral nature of electron transfers between the copper sites (the E° values for the three sites differ overall by only 60 mV), the differences in rate in the first instance reflect the difference in the E° value for le versus 2e reduction of dioxygen (leading to the peroxy intermediate) and peroxide (leading to the native intermediate). Second, the differences reflect the work available from the favorable 4e reduction that drives the turnover from native intermediate to fully reduced enzyme primed, now, to react with O2. This latter process, k 100 s (compare to k = 0.34s for decay of the native intermediate to fully oxidized enzyme), is functionally equivalent to the reductive release of Fe + from Fe +-transferrin catalyzed by the membrane metalloreductase, Dcytb in both cases, the lower valent metal species is more loosely coordinating. Whereas Fe + dissociates in the latter case, in MCO turnover the bound water(s) dissociate. 

In the cases of dietary heme and nonheme iron, the iron appears in the bloodstream bound to the transport protein transferrin. After its dissociation from dietary proteins by proteases, the heme is absorbed intact by the enterocyte. The heme i.s then degraded by heme oxidase. Heme oxidase catalyzes the Oj-depend-ent degradation of heme to biliverdm. Biliverdin is further degraded to bilirubin, which is excreted from the body in the bile. Heme absorption, as well as heme oxidase activity, is somewhat higher in the duodenum than in the jejunum and ileum, as determined in studies with rats. The heme catabolic pathway is shown in Figure 10,29, Most of the bilirubin in the body is not produced by the catabolism of dietary heme, but by the catabi lism of the heme present in old, or senescent, red blood cells, between 7S and 80% of the bilirubin formed in the body is derived from senescent red blood cells most of the remainder is derived from the normal turnover of the heme proteins in the liver. 

Fligh-spin iron in a nonheme environment exhibits a significant change in the thermodynamics and kinetics of protein binding on reduction from Fe " to Fe ". This is illustrated by the mammalian serum iron-transport protein, transferrin. The thermodynamic affinity for Fe " is 10 in the presence of carbonate as a synergistic anion, and is reduced to 10 on reduction to Pg2-i- 21,22 jj-on-ligand turnover is also enhanced upon reduction. The net result is a non-Nernstian spectroelectrochemical response because of an elec-trochemically driven reduction followed by a coupled equilibrium dissociation of Fe " as illustrated in eqns (2.4) and (2.5) ... 

Measurements of the levels of semm proteins such as albumin, transthyretin (also known as prealbumin), transferrin and retinol-binding protein are used as biochemical parameters in the assessment of protein energy malnutrition (Table 17-1). An ideal protein marker should have rapid turnover and present in sufficiently high concentrations in semm to be measured accurately. Transthyretin has these properties it is a sensitive indicator of protein deficiency and is effective in assessing improvement with refeeding. 

In liver, muscle and other tissues iron is taken up by the cells when transferrin saturation levels are high and deposited first in ferritin and subsequently transferred to haemosiderin. This pool of ferritin iron is most likely used within these cells to meet requirements for synthesis of haem enzymes, myoglobin and other non-haem iron proteins. The ferritin can also store iron released from the breakdown of such iron containing proteins in the course of their turnover. Mobilisation of iron from these tissues once again probably involves reduction of iron to Fe2+ and its transfer across the cell membrane to transferrin. In such tissues the level of transferrin saturation seems likely to play a major role in determining the balance between deposition of iron in ferritin and its mobilization from the storage form. 

Steady-state levels of RNA can be controlled by balancing rates of synthesis and degradation. Both endoribonucleases and exoribonucleases play a role in RNA degradation pathways. Control of transferrin-receptor mRNA levels by cytoplasmic aconitase/IRE-BP activities is a classic example of regulation of RNA turnover rates in response to physiological signals. 

Under normal conditions, almost all of the iron bound to transferrin is rapidly taken up by the marrow (35, 36, 37). The observed half-life of Fe(III)-transferrin in vivo was reported to be 1.3 hours, whereas the half-life for the protein moiety was much slower, 7 days (38). Any er) throid stimulation leads to a faster turnover of iron in vivo, and ery-throid suppression has the opposite eflFect (38). Only the reticulocytes are capable of utilizing the Fe(III) bound to transferrin although both the reticulocytes and the mature red cell can take up free Fe(III). Katz and Jandl (38) concluded that the transferrin directs the entry of iron into those cells which are still actively making hemoglobin and prevents any accumulation of iron by the mature cell. 

If iron mobilization is dependent on Cp, shouldn t there be a disturbance in iron metabolism, perhaps resembling copper deficiency, in Wilson s disease This is a disorder characterized by low plasma Cp and the accumulation of copper in the liver and brain. It is treated by eliminating copper from the diet and/or removing copper by administering penicillamine. However, the evidence to support a concomitant upset in iron utilization is tenuous. There is one recent paper by O Reilly et al. (51) in which eight patients with Wilson s disease were reported to have iron deficiency or low plasma iron or both, sometimes associated with anemia. Most of these subjects had low or low-normal levels of transferrin. One mitigating factor is that the size of the spleen in Wilson s disease is almost doubled and this may permit a more rapid turnover of plasma iron despite the low plasma ferroxidase activity. 

ESR measurements have been used to determine levels of transferrin in human plasma samples (Pocklington et al, 1977). An ESR study of the oxidation rates of iron transferrin by ceruloplasmin in the presence of ferrous ions shows that under normal conditions the transferrin appears to be able to deal readily with iron turnover (Foster et al, 1977). Since there is considerably more transferrin than ceruloplasmin in plasmas, on a competitive basis the oxidase activity of transferrin will be greater than that due to ceruloplasmin, except in cases where the total iron-binding capacity of the blood is saturated with iron. 

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