Understanding Heme Transport
http://www.100md.com
《新英格兰医药杂志》
Iron, the most abundant transition metal in the body, is an essential cofactor for proteins involved in oxygen transport, electron exchange, and the control of toxic free radicals. It is extracted from the diet in either of two forms — inorganic iron (primarily from nonanimal sources) or heme (mostly from hemoglobin and myoglobin). Over the past decade, the mechanism for the absorption of nonheme iron has been worked out in some detail,1 but specifics of the absorption of heme have remained uncertain. In a recent article, Shayeghi and colleagues reported the discovery of heme carrier protein 1 (HCP1), the first mammalian transporter that functions to bring heme into cells.2
HCP1 is a membrane protein found in the proximal intestine, where heme absorption is greatest. In support of its role in the absorption of heme iron, the investigators showed that forced expression of HCP1 in cultured cells promotes the uptake of both heme (in the form of iron protoporphyrin) and a similar molecule, zinc protoporphyrin, but not nonheme iron.
This is an important first step toward learning how heme enters the body. Available evidence suggests that heme attaches to the apical brush border of the absorptive enterocyte and enters the cell intact (Figure 1). At some point, iron must be freed from the protoporphyrin ring, although it is not certain when or where that occurs. Heme oxygenase, an enzyme that disassembles heme to liberate iron, is present in a microsomal fraction in duodenal enterocytes and has been implicated in the absorption of iron from hemoglobin.3 Free, heme-derived iron probably joins the same intracellular pathway as inorganic iron, for transport into the serum by ferroportin, the only known mammalian exporter of iron.1 However, it remains uncertain whether all heme is broken down in the intestinal epithelial cell or whether some might traverse the cell intact. If intact heme is exported from the enterocyte, it may leave the cell through the action of either of two recently characterized heme exporters, Bcrp or FLVCR.4,5 If this does occur, the subsequent disposition of plasma heme is unknown.
Figure 1. Intestinal Iron Absorption.
Mammalian iron absorption requires the transfer of iron across both the apical and the basolateral membranes of duodenal enterocytes. Divalent metal transporter 1 (DMT1), located on the apical brush-border membrane, mediates the uptake of reduced, nonheme iron (Fe2+). A portion of this iron is retained within the cell for use or for storage in ferritin; the remainder is transferred to the circulation by ferroportin, a nonheme-iron exporter. Released iron must be oxidized to bind to its plasma carrier protein, transferrin. A recent study suggests that the absorption of heme iron is mediated by HCP1,2 also expressed on the apical membrane. At least some heme is likely catabolized by heme oxygenase. This process may require the movement of heme into a membrane-bound subcellular compartment. Inorganic iron released from heme probably has the same fate as absorbed nonheme iron. The existence of two mammalian heme exporter proteins, Bcrp and FLVCR, raises the possibility that heme may transit the enterocyte intact and be exported into the serum.
Although HCP1 was consistently shown to mediate the uptake of heme in cultured cells, the amount of heme transported was small — a finding that could be explained by suboptimal experimental conditions. Alternatively, it is possible that one or more additional proteins or cofactors were lacking in the in vitro assays. Other components might, for example, be required to help supply energy for transport, since the HCP1-mediated uptake of heme is an energy-dependent process.
HCP1 is not closely related to other mammalian transporter proteins, but it bears a striking resemblance to bacterial proteins involved in the uptake of tetracycline. The three-dimensional structure of tetracycline–metal complexes is similar to that of heme: they are planar molecules carrying a metal atom at the center. Although HCP1 itself cannot transport tetracycline–metal complexes, its homology to the bacterial proteins raises the possibility that it may be able to transport other substrates similar to heme, such as cobalamin. It also suggests an approach for identifying potential pharmacologic inhibitors of HCP1 function, which may be useful in the treatment of patients with hemochromatosis and other forms of iron overload exacerbated by an increased intestinal absorption of iron.
It is not yet known whether HCP1 has physiologic roles in tissues other than the intestine. The protein is also expressed in the kidneys and the liver, suggesting that it may act at those sites. It might, for example, scavenge free heme or mediate cellular uptake of heme from its circulating carrier protein, hemopexin.
The absorption of heme is probably not necessary for survival, because the absorption of nonheme iron can be adjusted over a wide physiologic range.1 For that reason, mutations in the gene for HCP1 may turn out to be more common than the rare, disease-causing mutations reported in the genes for divalent metal transporter 1 and ferroportin. If so, mutations impairing HCP1 activity might account, in part, for the broad spectrum of clinical severity observed in patients with genetic hemochromatosis. Clinical hemochromatosis develops in only a fraction of patients homozygous for disease-associated mutations in the hemochromatosis gene (HFE), suggesting the existence of ameliorating modifier genes. Conversely, occult mutations in the gene for HCP1 might confer increased susceptibility to iron deficiency, a common condition that is likely to be influenced by the same set of genetic modifiers.
Dr. Andrews reports having received consulting fees and lecture fees from Ortho Biotech.
Source Information
From Children's Hospital and Harvard Medical School — both in Boston.
References
Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell 2004;117:285-297.
Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell 2005;122:789-801.
Raffin SB, Woo CH, Roost KT, Price DC, Schmid R. Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase. J Clin Invest 1974;54:1344-1352.
Krishnamurthy P, Ross DD, Nakanishi T, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem 2004;279:24218-24225.
Quigley JG, Yang Z, Worthington MT, et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell 2004;118:757-766.(Nancy C. Andrews, M.D., P)
HCP1 is a membrane protein found in the proximal intestine, where heme absorption is greatest. In support of its role in the absorption of heme iron, the investigators showed that forced expression of HCP1 in cultured cells promotes the uptake of both heme (in the form of iron protoporphyrin) and a similar molecule, zinc protoporphyrin, but not nonheme iron.
This is an important first step toward learning how heme enters the body. Available evidence suggests that heme attaches to the apical brush border of the absorptive enterocyte and enters the cell intact (Figure 1). At some point, iron must be freed from the protoporphyrin ring, although it is not certain when or where that occurs. Heme oxygenase, an enzyme that disassembles heme to liberate iron, is present in a microsomal fraction in duodenal enterocytes and has been implicated in the absorption of iron from hemoglobin.3 Free, heme-derived iron probably joins the same intracellular pathway as inorganic iron, for transport into the serum by ferroportin, the only known mammalian exporter of iron.1 However, it remains uncertain whether all heme is broken down in the intestinal epithelial cell or whether some might traverse the cell intact. If intact heme is exported from the enterocyte, it may leave the cell through the action of either of two recently characterized heme exporters, Bcrp or FLVCR.4,5 If this does occur, the subsequent disposition of plasma heme is unknown.
Figure 1. Intestinal Iron Absorption.
Mammalian iron absorption requires the transfer of iron across both the apical and the basolateral membranes of duodenal enterocytes. Divalent metal transporter 1 (DMT1), located on the apical brush-border membrane, mediates the uptake of reduced, nonheme iron (Fe2+). A portion of this iron is retained within the cell for use or for storage in ferritin; the remainder is transferred to the circulation by ferroportin, a nonheme-iron exporter. Released iron must be oxidized to bind to its plasma carrier protein, transferrin. A recent study suggests that the absorption of heme iron is mediated by HCP1,2 also expressed on the apical membrane. At least some heme is likely catabolized by heme oxygenase. This process may require the movement of heme into a membrane-bound subcellular compartment. Inorganic iron released from heme probably has the same fate as absorbed nonheme iron. The existence of two mammalian heme exporter proteins, Bcrp and FLVCR, raises the possibility that heme may transit the enterocyte intact and be exported into the serum.
Although HCP1 was consistently shown to mediate the uptake of heme in cultured cells, the amount of heme transported was small — a finding that could be explained by suboptimal experimental conditions. Alternatively, it is possible that one or more additional proteins or cofactors were lacking in the in vitro assays. Other components might, for example, be required to help supply energy for transport, since the HCP1-mediated uptake of heme is an energy-dependent process.
HCP1 is not closely related to other mammalian transporter proteins, but it bears a striking resemblance to bacterial proteins involved in the uptake of tetracycline. The three-dimensional structure of tetracycline–metal complexes is similar to that of heme: they are planar molecules carrying a metal atom at the center. Although HCP1 itself cannot transport tetracycline–metal complexes, its homology to the bacterial proteins raises the possibility that it may be able to transport other substrates similar to heme, such as cobalamin. It also suggests an approach for identifying potential pharmacologic inhibitors of HCP1 function, which may be useful in the treatment of patients with hemochromatosis and other forms of iron overload exacerbated by an increased intestinal absorption of iron.
It is not yet known whether HCP1 has physiologic roles in tissues other than the intestine. The protein is also expressed in the kidneys and the liver, suggesting that it may act at those sites. It might, for example, scavenge free heme or mediate cellular uptake of heme from its circulating carrier protein, hemopexin.
The absorption of heme is probably not necessary for survival, because the absorption of nonheme iron can be adjusted over a wide physiologic range.1 For that reason, mutations in the gene for HCP1 may turn out to be more common than the rare, disease-causing mutations reported in the genes for divalent metal transporter 1 and ferroportin. If so, mutations impairing HCP1 activity might account, in part, for the broad spectrum of clinical severity observed in patients with genetic hemochromatosis. Clinical hemochromatosis develops in only a fraction of patients homozygous for disease-associated mutations in the hemochromatosis gene (HFE), suggesting the existence of ameliorating modifier genes. Conversely, occult mutations in the gene for HCP1 might confer increased susceptibility to iron deficiency, a common condition that is likely to be influenced by the same set of genetic modifiers.
Dr. Andrews reports having received consulting fees and lecture fees from Ortho Biotech.
Source Information
From Children's Hospital and Harvard Medical School — both in Boston.
References
Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell 2004;117:285-297.
Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell 2005;122:789-801.
Raffin SB, Woo CH, Roost KT, Price DC, Schmid R. Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase. J Clin Invest 1974;54:1344-1352.
Krishnamurthy P, Ross DD, Nakanishi T, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem 2004;279:24218-24225.
Quigley JG, Yang Z, Worthington MT, et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell 2004;118:757-766.(Nancy C. Andrews, M.D., P)