Enzymes iron uptake

Wu J, Luther GW III (1995) Complexation of Fe(ni) by natural organic ligands in the Northwest Atlantic Ocean by a competitive ligand equilibration method and a kinetic approach. Mar Chem 50 159-177 Wu J, Boyle E, Sunda W, Wen L-S (2001) Soluble and colloidal iron in the oligotrophic North Atlantic and North Pacific. Science 293 847-849 Zivin JA, Waud DR (1982) How to analyze binding, enzyme and uptake data the simplest case, a single phase. Life Sci 30 1407-1422... 

Within the past few years, there has been considerable progress in understanding the role played by the mitochondria in the cellular homeostasis of iron. Thus, erythroid cells devoid of mitochondria do not accumulate iron (7, 8), and inhibitors of the mitochondrial respiratory chain completely inhibit iron uptake (8) and heme biosynthesis (9) by reticulocytes. Furthermore, the enzyme ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1) which catalyzes the insertion of Fe(II) into porphyrins, appears to be mainly a mitochondrial enzyme (10,11,12,13, 14) confined to the inner membrane (15, 16, 17). Finally, the importance of mitochondria in the intracellular metabolism of iron is also evident from the fact that in disorders with deranged heme biosynthesis, the mitochondria are heavily loaded with iron (see Mitochondrial Iron Pool, below). It would therefore be expected that mitochondria, of all mammalian cells, should be able to accumulate iron from the cytosol. From the permeability characteristics of the mitochondrial inner membrane (18) a specialized transport system analogous to that of the other multivalent cations (for review, see Ref. 19) may be expected. The relatively slow development of this field of study, however, mainly reflects the difficulties in studying the chemistry of iron. 

The existence of specific receptors for transferrin on the reticulocyte membrane was implied by the work of Jandl and associates, who observed that trypsin virtually abolished the ability of reticulocytes to take up iron from transferrin without affecting other metabolic functions of the cells (8). Whether the effect of the enzyme was to cleave the receptor from the cell membrane or to degrade it proteolytically was not clear. Neuraminidase treatment also depressed iron uptake by reticulocytes, but to a much lesser degree than trypsin and only at much higher concentrations than needed to abolish the hemagglutinating effects of influenza virus. Subsequent work from Morgan s laboratory has confirmed these results and has shown further that binding of transferrin to the receptor protects it from proteolytic enzymes (70). 

Copper is necessary, together with iron, for hematopoiesis, probably partly because it is needed for the synthesis of fer-roxidase (ceruloplasmin). Many enzymes require copper for activity. Examples of some of the copper-enzymes and their functions are given in Table 37-5. Mitochondrial iron uptake may be blocked by deficiency of a cuproprotein, perhaps cytochrome oxidase. Several inherited diseases involving abnormalities in copper metabolism (Wilson s disease, Menkes syndrome) or copper enzymes (X-linked cutis laxa, albinism) occur in human and in several animal species. 

Petersen, K. M. and Alderete, J. F. (1984) Iron uptake and increased intracellular enzyme activity follow host lactoferrin binding by Trichomonas vaginalis receptors. J. Exp. Med. 160 398-410. 

The rate of synthesis of erythroid ALAS, the first enzyme of the heme biosynthetic pathway, is directly dependent on the cellular iron concentration. Clinically, mutations in the ALAS2 gene are associated with XLSA. Although the cellular iron uptake systems remain completely functional in XLSA patients, this type of side-... 

If both MT-1 and HO-1 mRNA induction by heme-hemopexin involves a copper-redox enzyme in both heme transport (and consequent induction of HO-1 mRNA) and the signaling pathway for MT-1 expression, a plausible working model can be formulated by analogy with aspects of the yeast iron uptake processes and with redox reactions in transport (Figure 5-6). First, the ferric heme-iron bound to hemopexin can act as an electron acceptor, and reduction is proposed to be required for heme release. The ferrous heme and oxygen are substrates for an oxidase, possibly NADH-dependent, in the system for heme transport. Like ferrous iron, ferrous heme is more water soluble than ferric heme and thus more suitable as a transport intermediate between the heme-binding site on hemopexin and the next protein in the overall uptake process. The hemopexin system would also include a copper-redox protein in which the copper electrons would be available to produce Cu(I), either as the copper oxidase or for Cu(I) transport across the plasma membrane to cytosolic copper carrier proteins for incorporation into copper-requiring proteins [145]. The copper requirement for iron transport in yeast is detectable only under low levels of extracellular copper as occur in the serum-free experimental conditions often used. 

The blue multicopper oxidases constitute a heterogeneous family of enzymes from different sources (7). In addition to the well characterized members of this family, ascorbate oxidase (45,46), laccase (47,48), and ceruloplasmin (49,50), all from higher organisms, two other proteins have attracted much recent interest FetSp, which is involved in iron uptake in yeast (51), and CueO, which is required for copper homeostasis in Escherichia coli (52). The characteristic reactivity of these enzymes is the one-electron oxidation of four substrate equivalents coupled to the four-electron reduction of dioxygen to water (1). These processes occur at a catalytic unit constituted by four copper atoms classified according to their spectroscopic properties in... 

Several other classes of proteins have also been implicated as possible targets for lead, including other proteins in the heme biosynthetic pathway, leadbinding proteins in the kidney and brain, and heat shock proteins (342, 500-502). Lead is known to affect several steps in the heme biosynthetic pathway other than that catalyzed by ALAD Other profound effects include stimulation of 5-aminolevulinic acid synthase (ALAS) and decreased levels of iron incorporation into protoporphyrin by ferrochelatase (see Section VI.E.2 and Fig. 34) (10, 503-505). However, not all of these effects are due to direct interactions between lead and enzymes in the heme biosynthetic pathway. For instance, the widespread assertion that lead inhibits ferrochelatase is not supported by studies on the isolated enzyme (506, 507). Furthermore, increased levels of both erythrocyte protoporphyrin IX (EP) and zinc protoporphyrin (ZPP) are observed at high BLLs, suggesting that ferrochelatase is stiU competent to insert zinc into EP and that the increased levels of EP and ZPP associated with lead poisoning are most likely caused by lead interfering with iron uptake or transport (see Sections VI.C.4 and VI.E) (10, 506, 507). 

The fact that iron(ll) was clearly detected by Mossbauer spectroscopy gives a direct evidence for the iron uptake mechanism of strategy I. As the time of the iron treatment increased, the reductive capacity was decreasing because of the increased amount of iron already taken up by the root [73]. According to the Mossbauer parameters of the Fe(ll), one can see that it formed a hexaaquo complex [52] that might be the primary hydrated product of the ferric chelate reductase enzyme, accumulated in the apoplast and not attached to any of the cell wall components. At the same time, the increase in the Fe(lll)A component, representing iron both attached to the apoplast and taken up inside the cell, could be observed. The ferritin-like component (denoted by Fe(lll)B) was absolutely not detectable, which means this duration of... 

The dopamine is then concentrated in storage vesicles via an ATP-dependent process. Here the rate-limiting step appears not to be precursor uptake, under normal conditions, but tyrosine hydroxylase activity. This is regulated by protein phosphorylation and by de novo enzyme synthesis. The enzyme requites oxygen, ferrous iron, and tetrahydrobiopterin (BH. The enzymatic conversion of the precursor to the active agent and its subsequent storage in a vesicle are energy-dependent processes. 

Isolated hepatocytes incubated with ionic iron rapidly undergo lipid peroxidation. Some studies have not shown a consequent decrease in viability (as indicated by uptake of trypan blue or release of enzymes). This is probably a result of short incubation times, as changes in viability lag behind increases in lipid peroxidation, and may not occur for more than 2 h after lipid peroxidation begins (Bacon and Britton, 1990). Recent studies have shown strong correlations between increased lipid peroxidation [production of thiobarbituric acid (TBA) reactants] and loss of cell viability (trypan blue staining) (Bacon and Britton, 1989). The significance of the lag between lipid peroxidation and decreases in cell viability is as yet uncertain. 

Iron appeared to reduce the effects of orally or subcutaneously administered lead on blood enzyme and liver catalase activity (Bota et al. 1982). Treatment of pregnant hamsters with iron- or calcium-deficient diets in conjunction with orally administered lead resulted in embryonic or fetal mortality and abnormalities (ranting, edema) in the litters, while treatment with complete diets and lead did not (Carpenter 1982). Inadequate levels of iron in association with increased body burdens of lead enhanced biochemical changes associated with lead intoxication (Waxman and Rabinowitz 1966). Ferrous iron was reported to protect against the inhibition of hemoglobin synthesis and cell metabolism by lead it has been speculated that iron competes with lead uptake by the cell (Waxman and Rabinowitz 1966). In... 

In the latter case, electron uptake occurs after decarboxylation of the ketoacid via Fe3+, which is able to take up electrons in strongly oxidized regions of the black-band iron sediments. Fe-ions act catalytically on the process of thioester formation, which can then occur without the help of enzymes. Thus, it was solar UV irradiation which carried the prebiotic thioesters across the energy threshold. 

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