Biology:Hemopexin

From HandWiki
A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Hemopexin (or haemopexin; Hpx; Hx), also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the HPX gene[1][2][3] and belongs to the hemopexin family of proteins.[4] Hemopexin is the plasma protein with the highest binding affinity for heme.[5]

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.[6]

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.[6]

Hemopexin is different from haptoglobin, the latter always binds to free hemoglobin.[7][6] (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.[8]

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.[9]

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.[10]

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.[11]

Function

Hemopexin binds heme with the highest affinity of any known protein.[5] 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.[12] Hemopexin preserves the body's iron.[13] 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.[14] Hemopexin can downregulate the angiotensin II Type 1 receptor (AT1-R) in vitro.[15]

Clinical significance

The predominant source of circulating hemopexin is the liver with a plasma concentration of 1–2 mg/ml.[16] 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.[17] Hemopexin has been implicated in cardiovascular disease, septic shock, cerebral ischemic injury, and experimental autoimmune encephalomyelitis.[18] The circulating level of hemopexin is associated with prognosis in patients with septic shock.[18]

HPX is produced in the brain.[19] Deletion of the HPX gene can aggravate brain injury followed by stroma-free hemoglobin-induced intracerebral haemorrhage.[20] High hemopexin level in the cerebrospinal fluid is associated with poor outcome after subarachnoid hemorrhage.[19]

Circulating hemopexin can modulate in patients and in mice anthracycline-induced cardiotoxicity (e.g. heart failure).[21]

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.[16] 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.[5] Hp and hemopexin prevent heme toxicity by binding themselves to heme prior to monocyte or macrophage's arrivals and ensuing clearances,[5] 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.[22] Hemopexin is the major vehicle for the transportation of heme in the plasma.[5]

References

  1. ↑ "Entrez Gene: HPX hemopexin". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3263. 
  2. ↑ "Structure of the human hemopexin gene and evidence for intron-mediated evolution". Journal of Molecular Evolution 27 (2): 102–8. 1988. doi:10.1007/BF02138368. PMID 2842511. Bibcode: 1988JMolE..27..102A. 
  3. ↑ "The primary structure of human hemopexin deduced from cDNA sequence: evidence for internal, repeating homology". Nucleic Acids Research 13 (11): 3841–59. June 1985. doi:10.1093/nar/13.11.3841. PMID 2989777. 
  4. ↑ "A helping hand for collagenases: the haemopexin-like domain". Structure 3 (6): 527–30. June 1995. doi:10.1016/s0969-2126(01)00185-x. PMID 8590012. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Hemopexin: structure, function, and regulation". DNA and Cell Biology 21 (4): 297–306. April 2002. doi:10.1089/104454902753759717. PMID 12042069. 
  6. ↑ 6.0 6.1 6.2 "Intravascular hemolysis". http://eclinpath.com/hematology/anemia/mechanisms-of-anemia/intravascular-hemolysis-new/. 
  7. ↑ "Bilirubin and hemolytic anemia". http://eclinpath.com/chemistry/liver/cholestasis/bilirubin/bilirubin-and-hemolysis/. 
  8. ↑ Online Mendelian Inheritance in Man (OMIM) Orthosatic intolerance -604715
  9. ↑ "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. January 1985. doi:10.1073/pnas.82.1.73. PMID 3855550. Bibcode: 1985PNAS...82...73T. 
  10. ↑ Online Mendelian Inheritance in Man (OMIM) Hemopexin -142290
  11. ↑ "Differential transcriptional pattern of the hemopexin gene". The Italian Journal of Biochemistry 35 (5): 355–60. 1986. PMID 3026994. 
  12. ↑ "Identification of the receptor scavenging hemopexin-heme complexes". Blood 106 (7): 2572–9. October 2005. doi:10.1182/blood-2005-03-1185. PMID 15947085. http://www.bloodjournal.org/content/106/7/2572. 
  13. ↑ "Hemopexin: structure, function, and regulation". DNA and Cell Biology 21 (4): 297–306. April 2002. doi:10.1089/104454902753759717. PMID 12042069. 
  14. ↑ "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. July 2009. doi:10.1074/jbc.m109.017202. PMID 19433579. 
  15. ↑ "Hemopexin activity is associated with angiotensin II responsiveness in humans". Journal of Hypertension 31 (3): 537–41; discussion 542. March 2013. doi:10.1097/HJH.0b013e32835c1727. PMID 23254305. 
  16. ↑ 16.0 16.1 "Plasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases". Blood 32 (5): 811–5. November 1968. doi:10.1182/blood.V32.5.811.811. PMID 5687939. 
  17. ↑ Hoffbrand, A.V.; Moss, P.A.H.; Pettit, J.E. (2006). Essential Haematology (5th ed.). Oxford: Blackwell Publishing. p. 60. ISBN 978-1-4051-3649-5. https://archive.org/details/essentialhaemato00hoff. 
  18. ↑ 18.0 18.1 "Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases". Current Opinion in Lipidology 26 (5): 384–7. October 2015. doi:10.1097/MOL.0000000000000208. PMID 26339767. 
  19. ↑ 19.0 19.1 "Heme-Hemopexin Scavenging Is Active in the Brain and Associates With Outcome After Subarachnoid Hemorrhage". Stroke 47 (3): 872–6. March 2016. doi:10.1161/strokeaha.115.011956. PMID 26768209. https://eprints.soton.ac.uk/384573/1/__soton.ac.uk_ude_personalfiles_users_ig1_mydocuments_Clinical%2520Neurosciences_Subarachnoid%2520haemorrhage_Hx%2520paper_Stroke_Response%2520to%2520review_In%2520press_Garland%2520et%2520al_postprint.pdf. 
  20. ↑ "Deletion of the hemopexin or heme oxygenase-2 gene aggravates brain injury following stroma-free hemoglobin-induced intracerebral hemorrhage". Journal of Neuroinflammation 13: 26. February 2016. doi:10.1186/s12974-016-0490-1. PMID 26831741. 
  21. ↑ "Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice". Science Advances 8 (51): eadc9245. December 2022. doi:10.1126/sciadv.adc9245. PMID 36563141. Bibcode: 2022SciA....8C9245L. 
  22. ↑ "Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development". Frontiers in Physiology 5: 415. 2014. doi:10.3389/fphys.2014.00415. PMID 25389409. 

Further reading

External links

See also



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Hemopexin&oldid=3577510"