Hemopexin

Last updated
HPX
Identifiers
Aliases HPX , HX, hemopexin
External IDs OMIM: 142290 MGI: 105112 HomoloGene: 511 GeneCards: HPX
Orthologs
SpeciesHumanMouse
Entrez

3263

15458

Ensembl

ENSG00000110169

ENSMUSG00000030895

UniProt

P02790

Q91X72

RefSeq (mRNA)

NM_000613

NM_017371

RefSeq (protein)

NP_000604

NP_059067

Location (UCSC) Chr 11: 6.43 – 6.44 Mb Chr 7: 105.24 – 105.25 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Hemopexin (or haemopexin; Hpx; Hx), also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the HPX gene [5] [6] [7] and belongs to the hemopexin family of proteins. [8] Hemopexin is the plasma protein with the highest binding affinity for heme. [9]

Contents

Hemoglobin itself circulating alone in the blood plasma (called free hemoglobin, as opposed to the hemoglobin situated in and circulating with the red blood cell.) will soon be oxidized into met-hemoglobin which then further disassociates into free heme along with globin chain. The free heme will then be oxidized into free met-heme and sooner or later the hemopexin will come to bind free met-heme together, forming a complex of met-heme and hemopexin, continuing their journey in the circulation until reaching a receptor, such as LRP1, on hepatocytes or macrophages within the spleen, liver and bone marrow. [10]

Hemopexin's arrival and subsequent binding to the free heme not only prevent heme's pro-oxidant and pro-inflammatory effects but also promotes free heme's detoxification. [10]

Hemopexin is different from haptoglobin, the latter always binds to free hemoglobin. [11] [10] (See Haptoglobin § Differentiation with hemopexin)

Cloning, expression, and discovery

Takahashi et al. (1985) determined that human plasma hemopexin consists of a single polypeptide chain of 439 amino acids residues with six intrachain disulfide bridges and has a molecular mass of approximately 63 kD. The amino-terminal threonine residue is modified by a mucin-type O-linked galactosamine oligosaccharide, and the protein has five N-linked glycan modifications. The 18 tryptophan residues are arranged in four clusters, and 12 of the tryptophans are conserved in homologous positions. Computer-assisted analysis of the internal homology in amino acid sequence suggested duplication of an ancestral gene thus indicating that hemopexin consists of two similar halves. [12]

Altruda et al. (1988) demonstrated that the HPX gene spans approximately 12 kb and is interrupted by 9 exons. The demonstration shows direct correspondence between exons and the 10 repeating units in the protein. The introns were not placed randomly; they fell in the center of the region of amino acid sequence homology in strikingly similar locations in 6 of the 10 units and in a symmetric position in each half of the coding sequence. From these observations, Altruda et al. (1988) concluded that the gene evolved through intron-mediated duplications of a primordial sequence to a 5-exon cluster. [13]

Mapping of hemopexin gene

Cai and Law (1986) prepared a cDNA clone for hemopexin, by Southern blot analysis of human/hamster hybrids containing different combinations of human chromosomes, assigned the HPX gene to human chromosome 11. Law et al. (1988) assigned the HPX gene to 11p15.5-p15.4, the same location as that of the beta-globin gene complex by in situ hybridization. [14]

Differential transcriptional pattern of hemopexin gene

In 1986, the expression of the human HPX gene in different human tissues and cell lines was carried out by using a specific cDNA probe. From the results obtained it was concluded that this gene was expressed in the liver and it was below the level of detection in other tissues or cell lines examined. By S1 mapping, the transcription initiation site in hepatic cells was located 28 base pairs upstream from the AUG initiation codon of the hemopexin gene. [15]

Function

Hemopexin binds heme with the highest affinity of any known protein. [9] Its main function is scavenging the heme released or lost by the turnover of heme proteins such as hemoglobin and thus protects the body from the oxidative damage that free heme can cause. In addition, hemopexin releases its bound ligand for internalisation upon interacting with CD91. [16] Hemopexin preserves the body's iron. [17] Hemopexin -dependent uptake of extracellular heme can lead to the deactivation of Bach1 repression which leads to the transcriptional activation of antioxidant heme oxygenase-1 gene. Hemoglobin, haptoglobin (Hp) and Hx associate with high density lipoprotein (HDL) and influence the inflammatory properties of HDL. [18] Hemopexin can downregulate the angiotensin II Type 1 receptor (AT1-R) in vitro. [19]

Clinical significance

The predominant source of circulating hemopexin is the liver with a plasma concentration of 1–2 mg/ml. [20] Serum hemopexin level reflects how much heme is present in the blood. Therefore, a low hemopexin level indicates that there has been significant degradation of heme containing compounds. A low hemopexin level is one of the diagnostic features of an intravascular hemolytic anemia. [21] Hemopexin has been implicated in cardiovascular disease, septic shock, cerebral ischemic injury, and experimental autoimmune encephalomyelitis. [22] The circulating level of hemopexin is associated with prognosis in patients with septic shock. [22]

HPX is produced in the brain. [23] Deletion of the HPX gene can aggravate brain injury followed by stroma-free hemoglobin-induced intracerebral haemorrhage. [24] High hemopexin level in the cerebrospinal fluid is associated with poor outcome after subarachnoid hemorrhage. [23]

Circulating hemopexin can modulate in patients and in mice anthracycline-induced cardiotoxicity (e.g. heart failure). [25]

Relation to haptoglobin

In past there have been reports showing that in patients with sickle cell disease, spherocytosis, autoimmune hemolytic anemia, erythropoietic protoporphyria and pyruvate kinase deficiency, a decline in hemopexin concentration occurs in situations when haptoglobin (Hp) concentrations are low or depleted as a result of severe or prolonged hemolysis. [20] Both haptoglobin and hemopexin are acute-phase proteins, the synthesis of which are induced during infection and after inflammatory states to minimize tissue injury and facilitate tissue repair. [9] Hp and hemopexin prevent heme toxicity by binding themselves to heme prior to monocyte or macrophage's arrivals and ensuing clearances, [9] which may explain their effects on outcome in several diseases, and underlies the rationale for exogenous haptoglobin and hemopexin as therapeutic proteins in hemolytic or hemorrhagic conditions. [26] Hemopexin is the major vehicle for the transportation of heme in the plasma. [9]

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">Hemolysis</span> Rupturing of red blood cells and release of their contents

Hemolysis or haemolysis, also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid. Hemolysis may occur in vivo or in vitro.

<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">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">Haptoglobin</span> Mammalian protein found in Homo sapiens

Haptoglobin is the protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds with high affinity to free hemoglobin released from erythrocytes, and thereby inhibits its deleterious oxidative activity. Compared to Hp, hemopexin binds to free heme. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system.

<span class="mw-page-title-main">Hereditary spherocytosis</span> Medical condition

Hereditary spherocytosis (HS) is a congenital hemolytic disorder wherein a genetic mutation coding for a structural membrane protein phenotype causes the red blood cells to be sphere-shaped (spherocytosis), rather than the normal biconcave disk shape. This abnormal shape interferes with the cells' ability to flex during blood circulation, and also makes them more prone to rupture under osmotic stress, mechanical stress, or both. Cells with the dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes and results in hemolytic anemia.

<span class="mw-page-title-main">Hemolytic anemia</span> Medical condition

Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels or elsewhere in the human body (extravascular). This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically. Hemolytic anemia accounts for 5% of all existing anemias. It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects. The general classification of hemolytic anemia is either intrinsic or extrinsic. Treatment depends on the type and cause of the hemolytic anemia.

<span class="mw-page-title-main">Heme oxygenase</span> Class of enzymes

Heme oxygenase, or haem oxygenase, is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous ion, and carbon monoxide.

<span class="mw-page-title-main">Ankyrin</span> Protein family

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

<span class="mw-page-title-main">NFE2L2</span> Human protein and coding gene

Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome.

<span class="mw-page-title-main">Histidine-rich glycoprotein</span> Glycoprotein

Histidine-rich glycoprotein (HRG) is a glycoprotein that in humans is encoded by the HRG gene. The HRG protein is produced in the liver, and it could also be synthesized by monocytes, macrophages, and megakaryocytes. It possesses a multi-domain structure, which makes it capable of binding to numerous ligands and modulating various biological processes including immunity, vascularization and coagulation.

<span class="mw-page-title-main">Hemoglobinemia</span> Abnormally increased hemoglobin in blood plasma

Hemoglobinemia is a medical condition in which there is an excess of hemoglobin in the blood plasma. This is an effect of intravascular hemolysis, in which hemoglobin separates from red blood cells, a form of anemia.

The liver plays the major role in producing proteins that are secreted into the blood, including major plasma proteins, factors in hemostasis and fibrinolysis, carrier proteins, hormones, prohormones and apolipoprotein:

Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most common alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.

The hemopexin family is a family of evolutionarily related proteins. Hemopexin-like repeats occur in vitronectin and some matrix metalloproteinases family (matrixins). The HX repeats of some matrixins bind tissue inhibitor of metallopeptidases (TIMPs).

Vitreoscilla haemoglobin (VHb) is a type of haemoglobin found in the Gram-negative aerobic bacterium, Vitreoscilla. It is the first haemoglobin discovered from bacteria, but unlike classic hemoglobin it is composed only of a single globin molecule.

Intravascular hemolysis describes hemolysis that happens mainly inside the vasculature. As a result, the contents of the red blood cell are released into the general circulation, leading to hemoglobinemia and increasing the risk of ensuing hyperbilirubinemia.

Hemolytic jaundice, also known as prehepatic jaundice, is a type of jaundice arising from hemolysis or excessive destruction of red blood cells, when the byproduct bilirubin is not excreted by the hepatic cells quickly enough. Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice.

<span class="mw-page-title-main">Haptoglobin-related protein</span> Blood protein in primates

Haptoglobin-related protein (Hpr) is a serum protein that binds to haemoglobin of red blood cells and is present only in primates. It acts as a molecule of innate immunity in association with apolipoprotein L1 -containing high-density lipoprotein (HDL) particles. In humans, together with related serum protein, haptoglobin, it acts as a cell-killing agent as part of the trypanolytic factor against the protozoan parasite Trypanosoma brucei thereby providing natural resistance to African sleeping sickness. It is produced from the gene HPR that is located on the long arm of chromosome 16 within the HP gene cluster.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000110169 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030895 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: HPX hemopexin".
  6. ↑ Altruda F, Poli V, Restagno G, Silengo L (1988). "Structure of the human hemopexin gene and evidence for intron-mediated evolution". Journal of Molecular Evolution. 27 (2): 102–8. Bibcode:1988JMolE..27..102A. doi:10.1007/BF02138368. PMID   2842511. S2CID   11271490.
  7. ↑ Altruda F, Poli V, Restagno G, Argos P, Cortese R, Silengo L (June 1985). "The primary structure of human hemopexin deduced from cDNA sequence: evidence for internal, repeating homology". Nucleic Acids Research. 13 (11): 3841–59. doi:10.1093/nar/13.11.3841. PMC   341281 . PMID   2989777.
  8. ↑ Bode W (June 1995). "A helping hand for collagenases: the haemopexin-like domain". Structure. 3 (6): 527–30. doi: 10.1016/s0969-2126(01)00185-x . PMID   8590012.
  9. 1 2 3 4 5 Tolosano E, Altruda F (April 2002). "Hemopexin: structure, function, and regulation". DNA and Cell Biology. 21 (4): 297–306. doi:10.1089/104454902753759717. PMID   12042069.
  10. 1 2 3 "Intravascular hemolysis". eClinpath. Retrieved 2019-05-08.
  11. ↑ "Bilirubin and hemolytic anemia". eClinpath. Retrieved 2019-05-08.
  12. ↑ Online Mendelian Inheritance in Man (OMIM): Orthosatic intolerance - 604715
  13. ↑ Takahashi N, Takahashi Y, Putnam FW (January 1985). "Complete amino acid sequence of human hemopexin, the heme-binding protein of serum". Proceedings of the National Academy of Sciences of the United States of America. 82 (1): 73–7. Bibcode:1985PNAS...82...73T. doi: 10.1073/pnas.82.1.73 . PMC   396973 . PMID   3855550.
  14. ↑ Online Mendelian Inheritance in Man (OMIM): Hemopexin - 142290
  15. ↑ Poli V, Altruda F, Silengo L (1986). "Differential transcriptional pattern of the hemopexin gene". The Italian Journal of Biochemistry. 35 (5): 355–60. PMID   3026994.
  16. ↑ Hvidberg V, Maniecki MB, Jacobsen C, Højrup P, Møller HJ, Moestrup SK (October 2005). "Identification of the receptor scavenging hemopexin-heme complexes". Blood. 106 (7): 2572–9. doi: 10.1182/blood-2005-03-1185 . PMID   15947085.
  17. ↑ Tolosano E, Altruda F (April 2002). "Hemopexin: structure, function, and regulation". DNA and Cell Biology. 21 (4): 297–306. doi:10.1089/104454902753759717. PMID   12042069.
  18. ↑ Watanabe J, Grijalva V, Hama S, Barbour K, Berger FG, Navab M, Fogelman AM, Reddy ST (July 2009). "Hemoglobin and its scavenger protein haptoglobin associate with apoA-1-containing particles and influence the inflammatory properties and function of high density lipoprotein". The Journal of Biological Chemistry. 284 (27): 18292–301. doi: 10.1074/jbc.m109.017202 . PMC   2709397 . PMID   19433579.
  19. ↑ Krikken JA, Lely AT, Bakker SJ, Borghuis T, Faas MM, van Goor H, Navis G, Bakker WW (March 2013). "Hemopexin activity is associated with angiotensin II responsiveness in humans". Journal of Hypertension. 31 (3): 537–41, discussion 542. doi:10.1097/HJH.0b013e32835c1727. PMID   23254305. S2CID   23501030.
  20. 1 2 Muller-Eberhard U, Javid J, Liem HH, Hanstein A, Hanna M (November 1968). "Plasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases". Blood. 32 (5): 811–5. doi: 10.1182/blood.V32.5.811.811 . PMID   5687939.
  21. ↑ Hoffbrand A, Moss P, Pettit J (2006). Essential Haematology (5th ed.). Oxford: Blackwell Publishing. p.  60. ISBN   978-1-4051-3649-5.
  22. 1 2 Mehta NU, Reddy ST (October 2015). "Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases". Current Opinion in Lipidology. 26 (5): 384–7. doi:10.1097/MOL.0000000000000208. PMC   4826275 . PMID   26339767.
  23. 1 2 Garland P, Durnford AJ, Okemefuna AI, Dunbar J, Nicoll JA, Galea J, Boche D, Bulters DO, Galea I (March 2016). "Heme-Hemopexin Scavenging Is Active in the Brain and Associates With Outcome After Subarachnoid Hemorrhage" (PDF). Stroke. 47 (3): 872–6. doi: 10.1161/strokeaha.115.011956 . PMID   26768209. S2CID   11532383.
  24. ↑ Ma B, Day JP, Phillips H, Slootsky B, Tolosano E, Doré S (February 2016). "Deletion of the hemopexin or heme oxygenase-2 gene aggravates brain injury following stroma-free hemoglobin-induced intracerebral hemorrhage". Journal of Neuroinflammation. 13: 26. doi: 10.1186/s12974-016-0490-1 . PMC   4736638 . PMID   26831741.
  25. ↑ Liu J, Lane S, Lall R, Russo M, Farrell L, Debreli Coskun M, et al. (December 2022). "Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice". Science Advances. 8 (51): eadc9245. Bibcode:2022SciA....8C9245L. doi:10.1126/sciadv.adc9245. PMC   9788780 . PMID   36563141.
  26. ↑ Schaer DJ, Vinchi F, Ingoglia G, Tolosano E, Buehler PW (2014). "Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development". Frontiers in Physiology. 5: 415. doi: 10.3389/fphys.2014.00415 . PMC   4211382 . PMID   25389409.

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