The Role of Heme in the Release of Iron from Transferrin
in Reticulocytes

Ponka, P; Neuwirt, J; Borová, J

doi:10.1159/000459313

Cited by 29 publications

(11 citation statements)

References 9 publications

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“…It has long been recognized that haem is a feedback regulator of haem synthesis in erythroid cells (London , 1964;Ponka & Neuwirt, 1969), and although there is no doubt that haem inhibits haem synthesis in reticulocytes (Ponka et al, 1974;Schulman et al, 1974b;Morgan, 1981;Iacopetta & Morgan, 1984;Cox et al, 1985;Ponka & Schulman, 1985a), in which it can affect only post-transcriptional processes, there has been controversy conceming the mechanism involved. The original (London et al, 1964) and widely held view (Ibraham et al, 1983) is that haem feedback-inhibits the first enzyme in the haem-biosynthetic pathway, namely 6-aminolaevulinic acid synthase.…”

Section: Discussionmentioning

confidence: 99%

“…However, we have found that haem does not inhibit the activity of any of the enzymes of haem biosynthesis in rabbit reticulocytes, but rather inhibits the pathway by blocking the acquisition of iron from transferrin (Ponka & Schulman, 1985a). It was proposed that haem inhibits either iron (Ponka et al, 1974) or bicarbonate (Schulman et al, 1974b) release from transferrin; however, the release of both are probably inhibited by the same mechanism, since iron release from transferrin is accompanied by the release of bicarbonate, and vice versa (Schulman et al, 1974b;Martinez-Medellin & Schulman, 1973). More recently it has been suggested that haem inhibits the internalization of transferrin by reticulocytes (Tacopetta & Morgan, 1984;Cox et al, 1985), but the results of the present study indicate that this is probably not the primary site of haem action.…”

Section: Discussionmentioning

confidence: 99%

“…Originally it was proposed that haem inhibits either iron (Ponka et al, 1974) or bicarbonate (Schulman et al., 1 974b) release from transferrin, but more recently (lacopetta & Morgan, 1984;Cox et al, 1985) it was suggested that haem inhibits the internalization of transferrin by immature erythroid cells. In the present study we re-examined the effect of haem on Fe-transferrin interaction with reticulocytes.…”

Section: Introductionmentioning

confidence: 99%

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Haem inhibits iron uptake subsequent to endocytosis of transferrin in reticulocytes

Ponka

Schulman²,

Martinez-Medellin³

1988

Biochemical Journal

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Haem controls the rate of haem synthesis in erythroid cells by inhibiting iron incorporation from transferrin. The present results indicate that haem primarily inhibits the release of iron from transferrin subsequent to transferrin endocytosis and that the inhibition, of transferrin endocytosis caused by relatively high concentrations of haem is a secondary effect. Low concentrations of haem (10-25 ftM) significantly inhibit reticulocyte iron uptake and to a greater extent its incorporation into haem, but do not inhibit either the initial rate of transferrin uptake or its internalization by the cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Haem inhibits iron uptake subsequent to endocytosis of transferrin in reticulocytes

Ponka

Schulman²,

Martinez-Medellin³

1988

Biochemical Journal

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“…The uptake of iron by isolated mitochondria has been described, using iron-ATP [18], iron-hydroxyquinoline [19] or iron-sucrose [20] as the iron donor compound. A coherent picture, however, has not emerged.The importance of transferrin as an iron-donor directly to the mitochondria has been emphasized [14,16]. As yet, however, there are only a few studies dealing with the utilization of transferrin iron by isolated mitochondria.…”

mentioning

confidence: 99%

“…The importance of transferrin as an iron-donor directly to the mitochondria has been emphasized [14,16]. As yet, however, there are only a few studies dealing with the utilization of transferrin iron by isolated mitochondria.…”

mentioning

confidence: 99%

Uptake of Iron from Transferrin by Isolated Rat‐Liver Mitochondria Mediated by Phosphate Compounds

Konopka¹,

Romslo

1980

European Journal of Biochemistry

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1. Isolated rat-liver mitochondria accumulate iron from transferrin at neutral pH by a mechanism which is markedly stimulated by small-molecular-weight polyphosphate compounds. The efficiency of the phosphate compounds decreases in the order: pyrophosphate > ATP > GTP > 2,3-bis-(phospho)glycerate > phosphate.2. The uptake has a very low energy dependence, and it does not depend on the hydrolysis of ATP or the saturation of transferrin, but it increases in parallel to the concentration of iron to reach a saturation level of 800-1200 pmol iron/mg protein.3 . Following a chase with unlabelled transferrin, ('251)-labelled transferrin bound to the mitochondria remains constant, whereas the progressive uptake of 59Fe levels off.4. During reincubation of iron-loaded mitochondria up to 30% of the iron is mobilized in the presence of ascorbate and ATP (or apotransferrin).5. The results suggest that iron is mobilized from transferrin by the polyphosphate compounds outside the mitochondria and taken up by the mitochondria in a subsequent reaction.The ferrochelatase reaction represents the ultimate destination for the major part of iron entering the cell. Although it has been claimed that the ferrochelatase resides in part [l] or exclusively in the cytosol [2] most investigators agree that the ferrochelatase is a particulate enzyme confined to the mitochondria [3-51, tentatively on the M-side of the inner membrane [6-81 and depending on unsaturated phospholipids for full activity [9]. Hence, to reach the ferrochelatase iron has to penetrate the mitochondria1 membrane systems.The mechanism(s) by means of which iron is transported across the cytosol, from the plasma membrane to the mitochondria is largely unknown, as is the nature of the cytosol iron-binding ligands. Controversy exists as to whether iron is released from transferrin at the plasma membrane [lo, to operate on the main pathway of iron to the niitochondria in vivo. The uptake of iron by isolated mitochondria has been described, using iron-ATP [18], iron-hydroxyquinoline [19] or iron-sucrose [20] as the iron donor compound. A coherent picture, however, has not emerged.The importance of transferrin as an iron-donor directly to the mitochondria has been emphasized [14,16]. As yet, however, there are only a few studies dealing with the utilization of transferrin iron by isolated mitochondria. Barnes et al. [21] concluded from experiments with sonicated mitochondria that neither transferrin not ferritin functioned as substrate to the ferrochelatase reaction. Ulvik et al. [22] and Koller et al. [23] found that iron was mobilized from transferrin by a mechanism sensitive to uncoupler, high pH and haemin. The release process operated at a rate below that necessary to cope with the ferrochelatase and also at a pH outside that occurring in vivo. It was concluded that transferrin was not a suitable donor of iron to mitochondria. More recently, Konopka [24] and Konopka and Turska [25] reported that rat liver mitochondria accumulated iron from transferrin at a signifi...

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Increased bone marrow delta‐aminolevulinic acid synthetase activity in the acute reversible sideroblastic anemia of alcoholics

Fraser

Schacter

1980

American J Hematol

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In an effort to clarify the biochemical pathogenesis of the acute reversible siderblastic anemia of alcoholics, bone marrow delta-aminolevulinic acid (ALA) synthetase activity was measured in anemic alcoholic patients with and without pathological ring sideroblasts in their marrows and compared with the activity of this enzyme in normal subjects and in patients with idiopathic sideroblastic anemia. Mean ALA-synthetase activity measured (following addition of exogenous pyridoxal phosphate in three patients with the ring sideroblast morphologic abnormality) was 502 f 147 (SE) pmoles ALA per lo6 erythroblasts per 30 minutes, as compared with 201 f 69 in the seven alcoholic patients without pathologic sideroblastic marrow abnormalities, 169 f 32 in the six normal subjects, and 52 * 4 pmoles ALA per lo6 erythroblasts per 30 minutes in two patients with idiopathic sideroblastic anemia. Comparison of enzyme activity in the presence and absence of pyridoxal phosphate revealed that addition of this enzyme cofactor accentuated ALA-synthetase activity by an average of only 24% in the alcoholic sideroblastic group, as compared with 42% accentuation in the normal group and 8% accentuation in the idiopathic sideroblastic group. These results suggest that abnormalities in pyridoxal phosphate metabolism in alcoholics may not be of importance in the inhibition of heme biosynthesis at the level of ALA synthetase but, rather, that an enzymatic or metabolic block should be sought at a more distal site in the heme biosynthetic pathway.

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The Role of Heme in the Release of Iron from Transferrin in Reticulocytes

Cited by 29 publications

References 9 publications

Haem inhibits iron uptake subsequent to endocytosis of transferrin in reticulocytes

Haem inhibits iron uptake subsequent to endocytosis of transferrin in reticulocytes

Uptake of Iron from Transferrin by Isolated Rat‐Liver Mitochondria Mediated by Phosphate Compounds

Increased bone marrow delta‐aminolevulinic acid synthetase activity in the acute reversible sideroblastic anemia of alcoholics

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