Iron-binding proteins

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Iron-binding proteins are carrier proteins and metalloproteins that are important in iron metabolism [1] and the immune response. [2] [3] Iron is required for life.

Contents

Iron-dependent enzymes catalyze a variety of biochemical reactions and can be divided into three broad classes depending on the structure of their active site: non-heme mono-iron, non-heme diiron , or heme centers. [4] A well-known family of iron-dependent enzymes include oxygenases that facilitate hydroxyl group addition of one or both atoms from o2. Notable enzymes include tryptophan dioxygenase, ferredoxin, and 2-oxoglutarate dioxygenase. [5]

Heme proteins

The heme group uses four equatorial ligands in the porphyrin ring, with the two axial ligands being the histidine side chain and molecular oxygen. MbAction.png
The heme group uses four equatorial ligands in the porphyrin ring, with the two axial ligands being the histidine side chain and molecular oxygen.

Heme proteins are proteins that contain a heme prosthetic group. The heme group consists of a porphyrin ring coordinated with an iron ion. Four nitrogen atoms in the porphyrin ring act as a ligand for the iron in the center. In many cases, the equatorial porphyrin is complemented by one or two axial ligands. An example of this is in hemoglobin, where the porphyrin works together with a histidine side chain and a bound O2 molecule, forming an octahedral complex.

Hemoglobin

A visual depiction of the conformational change undergone by hemoglobin upon oxygen binding. Hemoglobin t-r state ani.gif
A visual depiction of the conformational change undergone by hemoglobin upon oxygen binding.

Hemoglobin is an oxygen-transport protein found in virtually all vertebrates. Hemoglobin A is the main type found in human adults. It is a tetramer consisting of two alpha and two beta subunits. Each of the four monomeric units contain a heme prosthetic group in which a ferric cation is bound between four nitrogen atoms of a porphyrin ring. Along with a histidine, the apo form has five ligands surrounding the iron atom. Oxygen binds to the empty sixth position to form an octahedral complex in the holo form. [6] Oxygen binding is fully cooperative for each of the subunits because as the first oxygen binds to one of the four heme groups, the protein undergoes a drastic conformational change that sharply increases the oxygen affinity of the other three subunits. [7]

Hemoglobin has various affinities, depending on pH, structure, and CO2 partial pressure. Fetal hemoglobin is a variant containing two gamma subunits instead of two beta subunits. Fetal hemoglobin is the predominant form up until the infant is several months old, and it has a greater oxygen affinity to compensate for the low oxygen tension of supplied maternal blood during pregnancy. [8] Hemoglobin has a lower oxygen affinity at low pH. This allows for rapid dissociation as oxygenated hemoglobin is transported to cells throughout the body. Because of the CO2 production and aqueous formation of carbonic acid in respiring cells, oxygenated hemoglobin dissociates in order to deliver the necessary oxygen to the cells. [9] Hemoglobin has a binding affinity for carbon monoxide that is 250 times greater than for oxygen. This is the basis of carbon monoxide poisoning, as hemoglobin can no longer transport oxygen to cells.

Cytochromes

Cytochromes are heme-containing enzymes that act as single-electron transporters, most notably as electron shuttles in oxidative phosphorylation and photosynthesis. Types of well-studied cytochromes include cytochromes a-c, cytochrome oxidase, and cytochrome P450. [10] These proteins act as electron shuttles by switching the oxidation state of the heme iron atom between ferrous (Fe2+) and ferric (Fe3+). Various cytochromes in combination with other redox-active molecules form a gradient of standard reduction potentials that increases the efficiency of energy coupling during electron-transfer events.

Iron-sulfur proteins

Iron-sulfur proteins are those with an iron structure that includes sulfur. There are a variety of forms iron and sulfur can take in proteins, but the most common are [2Fe 2S] and [4Fe 4S]. Clusters are often associated with cysteine residues in the protein chain. [11]

Non-heme proteins

Transferrin

Structure visualization of human serum transferrin. Protein TF PDB 1a8e.png
Structure visualization of human serum transferrin.

Transferrin is found in human plasma, and it is used to traffic and import non-heme iron. [12] It travels freely in the extracellular space. [13] When its iron is needed by the cell, it is brought into the cytosol by a transferrin receptor. Transferrin can bind two Fe(III) ions, along with an anion (usually carbonate). To release the iron, the carbonate anion is protonated. This changes the carbonate's interaction with the protein, changing the conformation and allowing Fe(III) to be transferred.

Transferrin has a molecular weight of about 80 kDa. It is a glycoprotein, meaning that it has sugars attached to its amino acid chain.

Lactoferrin

Lactoferrin is a member of the transferrin family and is the predominant protein found in mammal exocrine secretions, such as tears, milk, and saliva. It is composed of approximately 700 residues and exists mainly as a tetramer, with the monomer:tetramer ratio being 1:4 at 10 μM protein concentrations. [14] The tertiary structure is composed of two lobes, termed N and C lobes, each containing one iron-binding pocket. Each pocket contributes four amino acids (two tyrosines, one histidine, and one aspartate) and, along with two carbonate or bicarbonate anions, forms a six-membered coordinate around the iron cation. It is this specific combination that makes lactoferrin's iron affinity 300 times greater than transferrin. [15]

Depiction of lactoferrin (left) competitively binding iron over an E. coli siderophore (right). Lactoferrin and an E. Coli siderophore.svg
Depiction of lactoferrin (left) competitively binding iron over an E. coli siderophore (right).

Lactoferrin has significant antimicrobial properties. It is found in the highest concentration of 150 ng/mL in human colostrum (the type of milk produced at the end stages of pregnancy), providing much needed immune support to newly born infants. [16] It was widely believed that lactoferrin was only a bacteriostatic agent due to its high iron affinity and its ability to sequester free iron atoms from pathogenic microbes. It is now known, however, that the major antimicrobial driving force lies in the bactericidal properties of its iron-bound pocket and a specific peptide lactoferricin located at the N-lobe. Lactoferrin is able to bind to the LPS (lipopolysaccharide) layer of bacteria, and in its holo form the iron atom oxidizes the lipopolysaccharides to lyse the outer membrane and simultaneously produce toxic hydrogen peroxide. [17] Additionally, upon cleavage of lactoferrin by trypsin, the peptide lactoferricin is produced which binds to H+-ATPase, disrupting proton translocation and ultimately killing the cell. [18]

Ferritin

Protein structure of fully assembled ferritin. A single subunit is colored in purple. Ferritin.png
Protein structure of fully assembled ferritin. A single subunit is colored in purple.

Ferritin is an iron reservoir for an individual cell. It is found in all cells types and localized in the cytosol. Ferritin is a large protein composed of 24 subunits surrounding a core full of iron atoms. It is capable of holding 0-4500 iron atoms, [19] which can be used as a reservoir for cellular needs. Iron is stored when there is excess, and retrieved when iron is needed again. [12] The subunits are a mixture of H (heavy or heart) and L (light or liver). The subunits form a cluster 70-80 Angstroms wide, which is then filled with iron ferrihydrite. [20]

Ferritin is a highly conserved protein through all domains of life. It is so conserved that subunits from horses and humans can assemble together into a functional protein. [12] Each subunit is composed of five alpha helices.

Ferritin is used to diagnose low iron levels in humans. [19] It can be used to indicate the level of bioavailable iron, which is helpful for diagnosing anemia. The usual range for men is 18-270 ng/mL and the range for women is 18-160 ng/mL. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Hemoglobin</span> Metalloprotein that binds with oxygen

Hemoglobin is a protein containing iron that facilitates the transport of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the exception of the fish family Channichthyidae. Hemoglobin in the blood carries oxygen from the respiratory organs to the other tissues of the body, where it releases the oxygen to enable aerobic respiration which powers the animal's metabolism. A healthy human has 12 to 20 grams of hemoglobin in every 100 mL of blood. Hemoglobin is a metalloprotein, a chromoprotein, and globulin.

<span class="mw-page-title-main">Myoglobin</span> Iron and oxygen-binding protein

Myoglobin is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compared to hemoglobin, myoglobin has a higher affinity for oxygen and does not have cooperative binding with oxygen like hemoglobin does. Myoglobin consists of non-polar amino acids at the core of the globulin, where the heme group is non-covalently bounded with the surrounding polypeptide of myoglobin. In humans, myoglobin is found in the bloodstream only after muscle injury.

<span class="mw-page-title-main">Hemoprotein</span> Protein containing a heme prosthetic group

A hemeprotein, or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen carrying, oxygen reduction, electron transfer, and other processes. Heme is bound to the protein either covalently or noncovalently or both.

<span class="mw-page-title-main">Cytochrome c oxidase</span> Complex enzyme found in bacteria, archaea, and mitochondria of eukaryotes

The enzyme cytochrome c oxidase or Complex IV, is a large transmembrane protein complex found in bacteria, archaea, and the mitochondria of eukaryotes.

<span class="mw-page-title-main">Heme</span> Chemical coordination complex of an iron ion chelated to a porphyrin

Heme, or haem, is a ring-shaped iron-containing molecular component of hemoglobin, which is necessary to bind oxygen in the bloodstream. It is composed of four pyrrole rings with 2 vinyl and 2 propionic acid side chains. Heme is biosynthesized in both the bone marrow and the liver.

<span class="mw-page-title-main">Hemerythrin</span> InterPro Family

Hemerythrin (also spelled haemerythrin; Ancient Greek: αἷμα, romanized: haîma, lit. 'blood', Ancient Greek: ἐρυθρός, romanized: erythrós, lit. 'red') is an oligomeric protein responsible for oxygen (O2) transport in the marine invertebrate phyla of sipunculids, priapulids, brachiopods, and in a single annelid worm genus, Magelona. Myohemerythrin is a monomeric O2-binding protein found in the muscles of marine invertebrates. Hemerythrin and myohemerythrin are essentially colorless when deoxygenated, but turn a violet-pink in the oxygenated state.

<span class="mw-page-title-main">Metalloprotein</span> Protein that contains a metal ion cofactor

Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins contain zinc-binding protein domains although there may be up to 3000 human zinc metalloproteins.

<span class="mw-page-title-main">Transferrin</span> Mammalian protein found in Homo sapiens

Transferrins are glycoproteins found in vertebrates which bind and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.

Cooperativity is a phenomenon displayed by systems involving identical or near-identical elements, which act dependently of each other, relative to a hypothetical standard non-interacting system in which the individual elements are acting independently. One manifestation of this is enzymes or receptors that have multiple binding sites where the affinity of the binding sites for a ligand is apparently increased, positive cooperativity, or decreased, negative cooperativity, upon the binding of a ligand to a binding site. For example, when an oxygen atom binds to one of hemoglobin's four binding sites, the affinity to oxygen of the three remaining available binding sites increases; i.e. oxygen is more likely to bind to a hemoglobin bound to one oxygen than to an unbound hemoglobin. This is referred to as cooperative binding.

<span class="mw-page-title-main">Lactoferrin</span> Mammalian protein found in Homo sapiens

Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMNs and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum has the highest concentration, followed by human milk, then cow milk (150 mg/L).

Bioinorganic chemistry is a field that examines the role of metals in biology. Bioinorganic chemistry includes the study of both natural phenomena such as the behavior of metalloproteins as well as artificially introduced metals, including those that are non-essential, in medicine and toxicology. Many biological processes such as respiration depend upon molecules that fall within the realm of inorganic chemistry. The discipline also includes the study of inorganic models or mimics that imitate the behaviour of metalloproteins.

<span class="mw-page-title-main">Hemoglobin A</span> Normal human hemoglobin in adults

Hemoglobin A (HbA), also known as adult hemoglobin, hemoglobin A1 or α2β2, is the most common human hemoglobin tetramer, accounting for over 97% of the total red blood cell hemoglobin. Hemoglobin is an oxygen-binding protein, found in erythrocytes, which transports oxygen from the lungs to the tissues. Hemoglobin A is the most common adult form of hemoglobin and exists as a tetramer containing two alpha subunits and two beta subunits (α2β2). Hemoglobin A2 (HbA2) is a less common adult form of hemoglobin and is composed of two alpha and two delta-globin subunits. This hemoglobin makes up 1-3% of hemoglobin in adults.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">2,3-Bisphosphoglyceric acid</span> Chemical compound

2,3-Bisphosphoglyceric acid (2,3-BPG), also known as 2,3-diphosphoglyceric acid (2,3-DPG), is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG).

<span class="mw-page-title-main">Heme B</span> Chemical compound

Heme B or haem B is the most abundant heme. Hemoglobin and myoglobin are examples of oxygen transport proteins that contain heme B. The peroxidase family of enzymes also contain heme B. The COX-1 and COX-2 enzymes (cyclooxygenase) of recent fame, also contain heme B at one of two active sites.

<span class="mw-page-title-main">Heme A</span> Chemical compound

Heme A is a heme, a coordination complex consisting of a macrocyclic ligand called a porphyrin, chelating an iron atom. Heme A is a biomolecule and is produced naturally by many organisms. Heme A, often appears a dichroic green/red when in solution, is a structural relative of heme B, a component of hemoglobin, the red pigment in blood.

<span class="mw-page-title-main">Iron-responsive element-binding protein</span> Protein family

The iron-responsive element-binding proteins, also known as IRE-BP, IRBP, IRP and IFR , bind to iron-responsive elements (IREs) in the regulation of human iron metabolism.

<span class="mw-page-title-main">Iron in biology</span> Use of Iron by organisms

Iron is an important biological element. It is used in both the ubiquitous iron-sulfur proteins and in vertebrates it is used in hemoglobin which is essential for blood and oxygen transport.

<span class="mw-page-title-main">Nitric oxide dioxygenase</span>

Nitric oxide dioxygenase (EC 1.14.12.17) is an enzyme that catalyzes the conversion of nitric oxide (NO) to nitrate (NO−
3) . The net reaction for the reaction catalyzed by nitric oxide dioxygenase is shown below:

Iron preparation is the formulation for iron supplements indicated in prophylaxis and treatment of iron-deficiency anemia. Examples of iron preparation include ferrous sulfate, ferrous gluconate, and ferrous fumarate. It can be administered orally, and by intravenous injection, or intramuscular injection.

References

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  5. ↑ Cheng AX, Han XJ, Wu YF, Lou HX (January 2014). "The function and catalysis of 2-oxoglutarate-dependent oxygenases involved in plant flavonoid biosynthesis". International Journal of Molecular Sciences. 15 (1): 1080–95. doi: 10.3390/ijms15011080 . PMC   3907857 . PMID   24434621.
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  9. ↑ Hasselbalch KA (December 1964). "Calculation Of The Hydrogen Ion Concentration Of Blood From Free And Bound Carbon Dioxide Oxygen Binding As A Function Of Ph". Survey of Anesthesiology. 8 (6): 607–32. doi:10.1097/00132586-196412000-00059.
  10. ↑ L., Lehninger, Albert (2000). Lehninger principles of biochemistry . Nelson, David L. (David Lee), 1942-, Cox, Michael M. (3rd. ed.). New York: Worth Publishers. ISBN   1572591536. OCLC   42619569.{{cite book}}: CS1 maint: multiple names: authors list (link)
  11. ↑ Johnson, Deborah C.; Dean, Dennis R.; Smith, Archer D.; Johnson, Michael K. (Feb 18, 2005). "Structure, Function, and Formation of Biological Iron-Sulfur Clusters". Annual Review of Biochemistry. 74 (1): 247–281. doi:10.1146/annurev.biochem.74.082803.133518. ISSN   0066-4154. PMID   15952888.
  12. 1 2 3 Aisen P, Enns C, Wessling-Resnick M (October 2001). "Chemistry and biology of eukaryotic iron metabolism". The International Journal of Biochemistry & Cell Biology. 33 (10): 940–59. doi:10.1016/s1357-2725(01)00063-2. PMID   11470229.
  13. ↑ "TF - Serotransferrin precursor - Homo sapiens (Human) - TF gene & protein". www.uniprot.org. Retrieved 2018-11-11.
  14. ↑ Baker EN, Baker HM (November 2005). "Molecular structure, binding properties and dynamics of lactoferrin". Cellular and Molecular Life Sciences. 62 (22): 2531–9. doi:10.1007/s00018-005-5368-9. PMID   16261257. S2CID   218464085.
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  17. ↑ Farnaud S, Evans RW (November 2003). "Lactoferrin--a multifunctional protein with antimicrobial properties". Molecular Immunology. 40 (7): 395–405. doi:10.1016/S0161-5890(03)00152-4. PMID   14568385.
  18. ↑ Kuwata H, Yip TT, Yip CL, Tomita M, Hutchens TW (April 1998). "Bactericidal domain of lactoferrin: detection, quantitation, and characterization of lactoferricin in serum by SELDI affinity mass spectrometry". Biochemical and Biophysical Research Communications. 245 (3): 764–73. doi:10.1006/bbrc.1998.8466. PMID   9588189.
  19. 1 2 Andrews NC (July 2008). "Forging a field: the golden age of iron biology". Blood. 112 (2): 219–30. doi:10.1182/blood-2007-12-077388. PMC   2442739 . PMID   18606887.
  20. ↑ Crichton RR, Charloteaux-Wauters M (May 1987). "Iron transport and storage". European Journal of Biochemistry. 164 (3): 485–506. doi: 10.1111/j.1432-1033.1987.tb11155.x . PMID   3032619.
  21. ↑ "What Is a Ferritin Blood Test? What Do the Results Mean?". WebMD. Retrieved 2018-11-11.
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