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Hemopexin

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This article is about the hemopexin protein. For the family of proteins containing hemopexin-like repeats, see hemopexin family.
HPX
Identifiers
AliasesHPX, HX, hemopexin
External IDsOMIM: 142290; MGI: 105112; HomoloGene: 511; GeneCards: HPX; OMA:HPX - orthologs
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 MbChr 7: 105.24 – 105.25 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

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 CD91, 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 Hx 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 Hx 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 Hx, 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

Hx 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, Hx releases its bound ligand for internalisation upon interacting with CD91.[16] Hx preserves the body's iron.[17] Hx-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] Hx can downregulate the angiotensin II Type 1 receptor (AT1-R) in vitro.[19]

Clinical significance

The predominant source of circulating Hx is the liver with a plasma concentration of 1–2 mg/ml.[20] Serum Hx level reflects how much heme is present in the blood. Therefore, a low Hx level indicates that there has been significant degradation of heme containing compounds. A low Hx level is one of the diagnostic features of an intravascular hemolytic anemia.[21] Hx has been implicated in cardiovascular disease, septic shock, cerebral ischemic injury, and experimental autoimmune encephalomyelitis.[22] The circulating level of Hx 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 Hx level in the cerebrospinal fluid is associated with poor outcome after subarachnoid hemorrhage.[23]

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 Hx concentration occurs in situations when haptoglobin (Hp) concentrations are low or depleted as a result of severe or prolonged hemolysis.[20] Both Hp and Hx 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 Hx 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 Hp and Hx as therapeutic proteins in hemolytic or hemorrhagic conditions.[25] Hemopexin is the major vehicle for the transportation of heme in the plasma.[9]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000110169 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b c d e 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. ^ a b c "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. ^ a b 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. ^ a b 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. ^ a b 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ 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.

Further reading

See also

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