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Role of Transferrin in Iron Metabolism

Written By

Nitai Charan Giri

Submitted: 23 August 2021 Reviewed: 16 September 2021 Published: 05 October 2022

DOI: 10.5772/intechopen.100488

Iron Metabolism IntechOpen
Iron Metabolism A Double-Edged Sword Edited by Marwa Zakaria

From the Edited Volume

Iron Metabolism - A Double-Edged Sword

Edited by Marwa Zakaria and Tamer Hassan

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Abstract

Transferrin plays a vital role in iron metabolism. Transferrin is a glycoprotein and has a molecular weight of ~80 kDa. It contains two homologous iron-binding domains, each of which binds one Fe (III). Transferrin delivers the iron to various cells after binding to the transferrin receptor on the cell surface. The transferrin-transferrin receptor complex is then transported into the cell by receptor-mediated endocytosis. The iron is released from transferrin at low pH (e.g., endosomal pH). The transferrin-transferrin receptor complex will then be transported back to the cell surface, ready for another round of Fe uptake and release. Thus, transferrin plays a vital role in iron homeostasis and in iron-related diseases such as anemia. In the case of anemia, an increased level of plasma transferrin is often observed. On the other hand, low plasma transferrin level or transferrin malfunction is observed during the iron overdose. This chapter will focus on the role of transferrin in iron metabolism and diseases related to transferrin.

Keywords

  • Transferrin
  • metabolism
  • transferrin receptor
  • homeostasis
  • endocytosis
  • intestine
  • divalent metal transporter (DMT1)
  • Steap3
  • endosome

1. Introduction

Iron metabolism is one of the most intricate processes involving many organs and tissues, such as the intestine, the bone marrow, the spleen, the liver, etc. [1, 2]. Various proteins are also involved in maintaining iron homeostasis. Transferrin is a glycoprotein that plays a central role in iron metabolism [3]. It is present at a concentration of 30-60 μM in blood [4]. Transferrin can be divided into several sub-groups – serum transferrin, lactoferrin, and ovotransferrin. Hepatocytes produce serum transferrin found in serum, CSF, etc. Mucosal epithelial cells produce lactoferrin found in milk [5]. Lactoferrin is also found in secretions such as tear and saliva and cells such as neutrophils and leukocytes. Ovotransferrin is an iron-binding protein found in avian egg white. Together transferrins form the most important iron regulation system by transporting iron from the intestine or the sites of heme degradation to proliferating cells [6, 7]. This chapter will focus on the role of transferrin in iron metabolism.

Unlike ferritin, transferrin is a relatively new protein and is found only in phylum Chordata. Transferrin contains ~680 amino acid residues and two subdomain (N-and C-terminal domains) or lobes (Figure 1) [8]. It has a molecular weight of 80 kDa. The N-terminal lobe consists of residues 1-330 (approx.), while the C-terminal lobe consists of residues 340-680 (approx.) [9]. The two subunits are connected by a small hinge (residues 330-340). Transferrins show high sequence similarity - ~70% identity among lactoferrins while 50-60% identity between lactoferrin and transferrin [10]. The N- and C-terminal halves of these molecules show ~40% sequence identity. It has been suggested that the transferrin molecule may have evolved from the structural gene of an ancestral protein possessing only one metal-binding site and about 340 amino acids by gene duplication [11, 12]. This gene duplication might have led to an increase in its Fe(III) binding capacity and affinity [13]. Although transferrin contains many cysteine residues, it does not have any free sulfhydryl groups (present as disulfide).

Figure 1.

Structure of human transferrin (top) and two of its iron (brown sphere)-binding sites (bottom).

Transferrins show greater species variability in carbohydrate composition than in their amino acid composition. The total carbohydrate content varies from 3–12% weight of protein. The number of carbohydrate chains per protein molecule varies from 1 to 4. Human serum transferrin contains about 6% carbohydrate. This carbohydrate moiety has two identical, branched hetero-saccharide chains attached to the amide group of Asn residues via N-glycosidic linkages. However, a minor population of transferrin contains only tri-branched glycans. These carbohydrate groups affect the recognition and conformation of the native protein. The carbohydrate groups can also influence the solubility of the protein.

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2. Iron binding to transferrin

Transferrins are bilobal where each lobe reversibly binds a ferric iron (logK = 22.5 for C-site and 21.4 for N-site). Although two iron sites can be distinguished by kinetic and few other studies, their coordination environments are similar (Figure 1, bottom). X-ray crystallography indicates that the iron-binding site involves two phenolate oxygen from Tyr, two oxygen from bidentate bicarbonate, nitrogen from His, and oxygen from the carboxylate group of an Asp. Although transferrin binds Fe(III), iron is absorbed as Fe(II) in the intestine. Ceruloplasmin may catalyze the oxidation of Fe(II) to Fe(III) so that it may be bound to transferrin. However, there is some evidence that transferrin binds Fe(II), although with a much lower affinity. The resulting Fe(II)-transferrin-bicarbonate (or carbonate) will be oxidized by molecular oxygen to Fe(III)-transferrin-bicarbonate (or carbonate) [14, 15]. Thus, transferrin binds two Fe(III) in the presence of carbonate or bicarbonate to form a pink-colored complex with an absorption maximum of 465-470 nm. This iron-binding is pH-dependent, where the efficiency of iron-binding is maximum at pH between 7.5 and 10. This iron-binding efficiency decreases upon lowering the pH, and partial dissociation occurs at pH 6.5. Complete dissociation of iron occurs at pH 4.5. This decrease in iron-binding efficiency is useful for preparing apo-transferrin in vitro. For every Fe(III) bound to the protein, three protons are released. Considering that two Tyr residues are bound to Fe(III), these two ligands may be responsible for two protons. The third proton may come from bicarbonate.

Superimposition of the apo-transferrin (no iron) structure with the holo form (diferric) indicates the presence of open and closed forms, respectively (Figure 2). It has been suggested that apo-transferrin can exist both in an open and closed formation. However, the closed conformation exists less than 10% of the time [16]. Differential scanning calorimetry experiment performed by titrating Fe(III) into apo-transferrin indicated cooperativity between the two lobes in transferrin. During this process, Fe(III) first binds to the C-lobe and then to the N-lobe. It was also observed that the binding of Fe(III) in the C-lobe helps strengthen the binding of Fe(III) in N- lobe. It is worth noting that the interface of the lobes contains hydrophobic patches. The hydrophobic interaction may cause the movement in one lobe as the other one closes due to Fe(III) binding. Also, Fe(III) binding to transferrin alters the surface charge (Figure 3). The surface charge in holo-transferrin is more negative than apo-transferrin. Thus, electrostatics may drive the onset of endocytosis.

Figure 2.

Superimposition of the structures of apo-transferrin (cyan) and holo(diferric)-transferrin (green).

Figure 3.

Distribution of surface charge in apo-transferrin (left) and holo-transferrin (right).

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3. Transfer of iron from transferrin to cells

Under physiological conditions, Fe(III) is tightly bound to transferrin. Considering the Ka of the reaction between transferrin and iron, iron will take thousands of years to dissociate spontaneously from transferrin to blood. Thus, there must be some unique mechanism for transferring iron from transferrin to cells. Now it is established that transferrin receptors on the cell surface play an important role in transferring iron from transferrin to cells. Transferrin receptor is a 180 kDa homodimer type II transmembrane glycoprotein [17]. Two monomers of ~769 amino acids are linked by two disulfide bridges [18]. Each monomer contains three major domains – a C-terminal extracellular domain, a transmembrane domain, and an N-terminal intracellular domain. The C-terminal extracellular domain comprises ~671 amino acids and has two main subunits – domain head and a stock of ~37 amino acids that separate the head from the transmembrane domain. The transmembrane domain consists of ~20-28 residues that create a hydrophobic region. This region contains palmitoylation sites (Cys62 and Cys67) that help the transferrin receptor cling to the cell membrane. The intracellular N-terminal domain is made up of ~61-66 residues. Due to the dimeric nature of the transferrin receptor, it binds two transferrin molecules.

3.1 Conformational change in the transferrin receptor due to transferrin binding

X-ray crystal structure of iron-bound transferrin in complex with transferrin receptor provides the molecular details of the interaction between transferrin and transferrin receptor (Figure 4) [19]. Conformation changes in the C-terminal domain of transferrin receptor occurs when transferrin receptor binds iron-bound transferrin. These conformation changes have been suggested to be responsible for initiating endocytosis for Fe(III) uptake by the cells. The most dramatic change in the transferrin receptor structure is observed in the loop containing Asn317 (one of the three glycosylation sites, Figure 5A). Also, Phe316 is shifted by ~8 Å while His318 is shifted by ~12.5 Å. These movements bring these residues closer to the C-terminus of other transferrin receptor monomer (Figure 5B). The binding of transferrin to transferrin receptor leads to a rotation along transferrin receptor dimeric interface bringing four His (His475 and His684 from each monomer) into proximity (Figure 5C). The binding of transferrin to transferrin receptor also causes two Trp residues (Trp641 and Trp740) to undergo significant changes (Figure 5D).

Figure 4.

Interaction of transferrin (cyan: The brown sphere is transferrin-bound iron) with C-terminal extracellular domain of transferrin receptor (green).

Figure 5.

Conformational change of transferrin receptor (cyan) due to the formation of transferrin-transferrin receptor complex (green): Structural change of the loop containing Asn317 (A), movements of Phe316 and His318 from one monomer (indicated by ‘) to the other monomer (B) four his residues of transferrin receptor come to close proximity due to transferrin binding (C) and movements of Trp641 and Trp740 from one monomer (indicated by ‘) to the other monomer (D).

The interaction of the transferrin receptor with transferrin also depends on pH. For these interactions, the important pH values are 7.4 (blood pH) and 5.5 (endosomal pH). It has been reported that at blood pH diiron bound transferrin exclusively formed saturated transferrin-transferrin receptor complex [20]. However, monomeric transferrin (N-lobe or C-lobe) with one iron as well as apo-transferrin could not saturate the transferrin receptor. It was shown that the diiron-containing transferrin has the maximum affinity for the transferrin receptor, while the apo-transferrin had the lowest affinity for the transferrin receptor. However, this trend is reversed at endosomal pH. Here, apo-transferrin has the highest affinity for the transferrin receptor. This strong interaction is necessary for transferrin to return to the cell surface and repeat further Fe(III) uptake.

Thus, the recognition of diiron bound transferrin is essential for initiating endocytosis (Figure 6). This transferrin-mediated endocytosis involves the clathrin coating of the ensuing endosome to protect it from proteolytic degradation. Thus, the enclosed transferrin and transferrin receptor are protected so that they can be recycled. The adaptor protein complex mediates the formation of a proton-pumping endosome that includes other membrane proteins such as Steap3, a ferrireductase [21, 22]. Once the endosome enters the cell, it is acidified to a pH of 5.5. This acidification may enable the chelator to penetrate the metal-binding site and induce a semi-open conformation that ultimately leads to metal release. It has been reported that the sulfate binding to Fe(III) prevents His and Asp from binding to Fe(III) and thus leads to a semi-open conformation of the transferrin (Figure 7). During the metal release and its delivery to the cytosol via the divalent metal transporter 1 (DMT1), the reduction of Fe(III) to Fe(II) occurs. However, there is some debate about the order of chelation and reduction. One group of researchers think that acidification coupled with chelation by an intracellular chelator (e.g., citrate, ATP) results in the dissociation of Fe(III) from transferrin [23]. This Fe(III) is then reduced to Fe(II) by Steap3. DMT1 then transports Fe(II) into the cytosol, forming a labile iron pool [24, 25]. However, this Fe(II) is quickly stored in ferritin and inserted into various iron-dependent proteins [26, 27]. Another group of researchers believes that the interaction between diiron bound transferrin and transferrin receptor alters the redox potential of Fe(III) from −0.53 V to −0.3 V (vs. SHE) [28, 29]. Then Steap3 will reduce Fe(III) to Fe(II), which will weaken the metal affinity of transferrin (logβ value of diFe(III) bound transferrin is 43.5 while that of diFe(II) bound transferrin is 13) [30, 31]. Fe(II) will then undergo facile dissociation, possibly with the help of a chelator, and be transported out of the endosome by DMT1. Some researchers also believe that ascorbate is the likely reducing agent [32]. Recently, Fe(III) bound to citrate near the transferrin metal-binding site has been reported (Figure 8). However, in this structure, Fe(III) is not ligated to any protein-derived ligand. This citrate-bound iron (without protein-derived ligand) can be considered citrate scavenging of Fe(III) from transferrin.

Figure 6.

Proposed pathway of transferrin receptor mediated endocytosis and iron release into the cytosol.

Figure 7.

Sulfate binding to iron (brown sphere) leads to semi-open conformation by preventing the ligation of his and asp to iron.

Figure 8.

Structure of citrate bound iron (brown sphere) near the metal binding site in transferrin.

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4. Significance of bilobal transferrin

Since no eukaryotic single-lobed transferrin is known [33], it is reasonable to think that the emergence and persistence of a bilobal structure offer substantial advantages to the organism that uses transferrin for iron transport. However, the nature of the advantages has not been confirmed. One hypothesis is that the bilobal protein resists loss through glomerular filtration in the kidney [34]. However, this hypothesis has been questioned since the bilobal structure may have evolved before the filtration kidney appeared [35]. It has been reported that the C-lobe of full-length transferrin binds iron with four times higher affinity than the isolated C-lobe at pH 7.4 [36]. This affinity becomes 25 times at pH 6.7. Iron release from the N-terminal lobe occurs in the pH range from 6 to 4 compared with 4 to 2.5 for native lactoferrin. These results also support the idea that the more facile iron release from the half-molecule (N-terminal lobe only) compared to the full-length protein is due to the absence of stabilizing interactions between N-terminal and C-terminal halves [10]. It appears that the efficiency of iron release from the C-lobe of native transferrin is impaired by stabilizing interactions of the lobes with each other that retard the release of iron. However, the binding of the transferrin receptor will overcome this problem. Thus, the bilobal structure is favored during evolution so that iron will be released from transferrin when it is complexed with the transferrin receptor.

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5. Kinetics of iron release from bilobal transferrin

Although the members of the transferrin family have essentially the same fold due to the high degree of sequence identity, individual transferrin differs in their iron-binding property [37, 38]. Mechanism of iron release from each lobe differs mainly due to the differences in second shell residues [23]. In vitro studies with purified transferrin have shown that the iron-loaded protein releases iron as the pH is lowered [39]. Iron-loaded human serum transferrin releases iron over a pH range of 6.5 to 4, whereas the iron release from lactoferrin occurs in the pH range of 4 to 2.5 [40]. Hen serum transferrin releases the first iron in the pH range of 6.5 to 5.2 [41]. Under similar conditions, human serum transferrin 6.0 to 5.5. The loss of the remaining iron from hen serum transferrin C-lobe occurs over a pH range of 5.2 to 4. Studies performed in the absence of transferrin receptor indicate that 96% of the time, iron is released from N-lobe followed by slow release from C-lobe [42]. Also, there is cooperativity among the two lobes in the absence of transferrin receptors [43]. Thus, the iron release from the N-lobe is sensitive to the C-lobe. On the other hand, iron is released from the C-lobe 65% of the time in the presence of the transferrin receptor.

5.1 Iron release from C-lobe

Iron release from the C-lobe of transferrin is very slow and unaffected by N-lobe [44]. C-lobe has a triad of Lys534-Arg632-Asp634 that controls the iron release in the absence of the transferrin receptor [45, 46]. Lys534 and Arg632 in the C-lobe may share a H-bond that is stabilized by Asp634. Thus, the protonation of Asp634 will trigger the iron release. However, in the structure of pig transferrin, the Lys and Arg are too far away (~4.1 Å apart) to share a H-bond [47]. However, mutation of Lys/Arg to Ala severely retards iron release from C-lobe [48]. Iron release from the C-lobe in the presence of transferrin receptor proceeds via a different mechanism and is 7-10 fold faster than that in the absence of transferrin receptor. Recent studies have shown that the iron release from the C-lobe is dictated by His349 [49]. Based on the cryo-EM, it was suggested that a pair of hydrophobic residues (Trp641 and Phe760) interact with His349 and stimulates iron release by stabilizing the apo-transferrin/transferrin receptor complex [50]. The role of His349 in the iron release has been demonstrated by mutating His349 to Ala. In this H349A mutant, the iron release from C-love is reduced by 12 fold.

5.2 Iron release from N-lobe

In the absence of transferrin receptors, the iron release from N-lobe is controlled by the protonation of a pair of Lys. These two Lys residues are 3 Å apart and share a H-bond [51]. When the pH is reduced, protonation of one of the Lys residues causes the positively charged Lys residues to repeal each other (moving at least 9 Å apart) [52]. This repulsion triggers a cleft opening as well as the release of iron [53]. Mutations of any of these to two Lys to either Glu or Ala drastically slowed the rate of iron release [54]. The release of iron from the N-lobe is further facilitated by the binding of anions to Arg143 [55].

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6. Stabilization of apo-transferrin/transferrin receptor complex

The return of apo-transferrin to the cell surface is a distinctive feature of the endocytic cycle. As revealed by the apo-transferrin structure, the N-lobe is stabilized by a salt bridge between Asp240 and Arg678 [56]. Additionally, the PRKP loop (residues 142-145) is connected to the bridge by a disulfide bond (between Cys137 and Cys331). In the apo-transferrin structure, the movement of the PRKP loop and the disulfide bond brings the bridge closer to the protease-like domain of the transferrin receptor to possibly further stabilize the apo-conformation in a pH-dependent manner.

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7. Biological function of transferrin

Transferrin delivers the iron to various cells after binding to the transferrin receptor on the cell surface. The transferrin-transferrin receptor complex is then transported into the cell by receptor-mediated endocytosis. The iron is released from transferrin at low pH (e.g., endosomal pH). The transferrin-transferrin receptor complex will then be transported back to the cell surface, ready for another round of Fe uptake and release. This process can turn over roughly a million atoms of iron per cell per minute in active reticulocytes [57]. It is well known that Fe(III) salts are highly susceptible to hydrolysis at neutral pH to produce insoluble ferric hydroxide. Thus, the concentration of free Fe(III) in physiological fluids will be very low (~10−18 M). However, the daily turnover of hemoglobin iron is ~30 mg (~10−4 M). Thus, there is a need for a high-affinity iron-binding protein, like transferrin. By binding iron upon its release into the bloodstream, serum transferrin prevents the hydrolysis and precipitation of iron [58]. Thus, it increases the solubility of iron in the blood to the micromolar level and consequently increases its bioavailability [59]. Transferrin is usually ~30% saturated with iron with ~27% diferric transferrin, 23% monoferric transferrin (N-lobe), 11% monoferric transferrin (C-lobe), and 40% apo-transferrin [60, 61]. During increasing iron overload, the empty iron binding sites in transferrin are occupied, and thus, iron toxicity is not overserved until transferrin has been saturated with iron. Serum transferrin also inhibits the reduction of Fe(III) to Fe(II), which may lead to iron toxicity via the formation of reactive oxygen species. By having a very high affinity for Fe(III), transferrin can prevent the uptake of Fe(III) by pathogenic microorganisms. The most important role of transferrin is in the transport of iron among the site of absorption (intestinal mucosal cells), utilization (immature erythroid cells), storage (liver), and hemoglobin degradation. Thus, transferrin plays a vital and central role in iron metabolism (Figure 9). Although transferrin has a high molecular weight and binds only two iron ions, it is relatively efficient since it is used in many cycles of iron transport. Transferrin is recycled more than 10 times a day to supply the 20-30 mg irons needed for over 2 million erythrocytes produced every second by the bone marrow. Although iron bound to transferrin is <0.1% (4 mg) of total body iron, it constitutes the most critical iron pool with the highest turnover rate (25 mg per day) [62, 63]. It has a relatively longer half-life of 8-10 days in vivo. It has been suggested that plasma aluminum, when it binds to transferrin, may lead to anemia since aluminum will enter the iron distribution pathway [64].

Figure 9.

A simple diagram of the iron homeostasis in human.

In contrast, lactoferrin possesses various biological properties, including antioxidants, antimicrobial and anti-inflammatory activities [65]. Lactoferrin’s affinity for iron is very high (double that of transferrin). This high iron affinity partly determines its function. Superimposition of the structure of transferrin and lactoferrin indicates that the lactoferrin has a relatively closed conformation compared to transferrin (Figure 10). This closed conformation may explain the higher iron affinity of lactoferrin since once iron is sequestered, it cannot escape. The high affinity of lactoferrin for iron will also enable it to deprive microorganisms of essential metals for growth. However, iron is a crucial nutrient for pathogenic microorganisms which require iron to survive and replicate. Thus, lactoferrin is considered to form part of the immune system since it deprives the pathogenic microorganisms of iron and combats the infection they cause [66]. While the apo-lactoferrin inhibits the growth of a large number of pathogenic bacteria, holo-lactoferrin shows significantly lower inhibition towards these pathogens.

Figure 10.

Superimposition of structure of transferrin (green) and lactoferrin (cyan). Iron bound to transferrin and lactoferrin is shown as brown spheres.

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8. Iron sequestration from transferrin by N. Meningitidis

N. Meningitidis is a pathogenic bacterium responsible for bacterial meningitis. It acquires iron from transferrin during infection through a transferrin receptor system composed of two proteins TbpA and TbpB [67]. TbpA is a 100 kDa TonB-dependent outer membrane protein required for iron uptake [68]. It can serve as a channel for iron transport across the outer membrane. TbpB is a bilobal protein (60-80 kDa) required for colonization in the host [69]. This protein extends from the outer membrane into the host milieu to interact with transferrin to initiate iron acquisition [70]. Together, these proteins sequester iron from transferrin. TbpA binds both holo- and apo-forms of transferrin [71]. However, TbpB binds only the holo-transferrin.

The crystal structure of TbpB with and without human transferrin has been reported [72]. Both TbpA and TbpB bind to transferrin C-lobe [73]. Within this structure, several amino acids residues of transferrin (His349, Lys511) and TbpB (Arg199, Glu222) are buried in the binding interface (Figure 11, top). His349 residue of transferrin interacts with TbpB through a tetrahedrally coordinated water involved in H-bonding with His143, Asp159, and Lys206 from TbpB (Figure 11, bottom). Protonation of His349 will cause an electrostatic repulsion with Lys511 leading to a conformational change which results in an open conformation of transferrin. Thus, His349 in human transferrin can act as a pH-inducible switch for iron release in the presence of the transferrin receptor [19, 49]. Structure-based pKa prediction suggests that TbpB binding to human transferrin leads to a reduction of the estimated pKa of human transferrin His349 from 6.2 (unbound form) to 1.9 (bound to TbpB) [74]. Thus, the binding of TbpB to transferrin may prevent His349 from becoming protonated and stabilize the holo C-lobe of transferrin. Therefore, TbpB does not initiate the opening of the human transferrin holo C-lobe that results in the iron release. Thus, the first step of iron acquisition by TbpB will involve binding to iron-loaded transferrin inside the host and maintaining the iron-loaded form until its delivery to TbpA in the second step.

Figure 11.

Structure of transferrin (green) and transferrin binding protein TbpB (cyan) complex (top: The brown sphere is transferrin-bound iron). Interaction of His349 in transferrin with various residues in TbpB via water (sphere, bottom).

Although the human Transferrin receptor interacts with transferrin via both N and C lobes, TbpB interacts with only the C-lobe of transferrin. Also, the human transferrin receptor binds to both apo- and holo-forms of transferrin, while TbpB binds specifically to holo-transferrin [75]. This is because the holo-form of C-lobe with a closed conformation will allow more effective docking of C-lobe of transferrin onto TbpB. However, the apo form of transferrin with an open structure will drastically reduce the binding interface between TbpB and transferrin. Unlike human transferrin receptor, TbpB interacts with a loop (residues 496-515) of human transferrin. Variation of this loop is observed among mammalian transferrins. This variation in the TbpB recognition site on transferrin seems to act as the barrier for cross-species specificity between TbpB and transferrin. Finally, bacterial transferrin binding protein (TbpB) competes with the human transferrin receptor for transferrin/iron. TbpB binding site on human transferrin partially overlaps with the transferrin receptor binding site. This overlapping binding site of the human transferrin receptor and pathogenic transferrin binding protein (e.g., TbpB) allows the pathogens to circumvent the mutation of transferrin.

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9. Conclusion

This chapter highlights the role of transferrin in iron metabolism, including the iron-binding by transferrin, transferrin receptor-mediated endocytosis of transferrin/transferrin-receptor complex, and consequent iron release, etc. Some of the released iron will be stored in ferritin, while the other part will be used by various proteins and enzymes constituting a pathway of iron regulation. This iron-binding and regulation by transferrin are critical considering the toxicity of iron. How the differences (amino acids, structure, iron-binding affinity, etc.) between serum transferrin and lactoferrin dictates their biological functions have been highlighted. Finally, the competition between the human transferrin receptor and bacterial transferrin binding protein (e.g., TbpB) for getting iron from transferrin has also been discussed. Understanding the interaction of transferrin with other proteins (e.g., transferrin binding protein from various pathogenic bacteria) may lead to drug development. Overall, elucidation of the role of transferrin in iron metabolism will help understanding iron-related diseases and improve treatment.

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Written By

Nitai Charan Giri

Submitted: 23 August 2021 Reviewed: 16 September 2021 Published: 05 October 2022

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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