Hemopexin
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Hemopexin (or haemopexin; HPX), also known as beta-1B-glycoprotein is a protein that in humans is encoded by the HPX gene[3][4][5] and belongs to hemopexin family of proteins.[6] Hemoglobin and its scavenger protein hemopexin (Hx) associate with HDL and influence the inflammatory properties of HDL. In addition it can also be said that HDL from Hx-null mice is proinflammatory. Moreover, Hemopexin deficiency is associated with various other inflammatory diseases such as septic shock and experimental autoimmune encephalomyelitis.[7]
Cloning, expression and discovery
Takahashi et al. (1985) determined that human plasma beta-glycoprotein hemopexin consists of a single polypeptide chain of 439 amino acids residues with six intrachain disulphide bridges and has a molecular mass of approximately 63 kD. The amino-terminal threonine residue is blocked by an O-linked galactosamine oligosaccharide, and the protein has five glucosamine oligosaccharides N-linked to the acceptor sequence Asn-X-Ser/Thr. 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 hemopexin 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. As 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 hemopexin gene to human chromosome 11. Law et al. (1988) assigned the hemopexin gene to 11p15.5-p15.4, the same location as that of the beta-globin gene complex by in situ hybridization.[10]
Function
Hemopexin binds heme with the highest affinity of any known protein. Its 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 a specific receptor situated on the surface of liver cells. This function of hemopexin is to preserve the body's iron.[11] Hemopexin, an acute phase protein, can downregulate the angiotensin (ang) II type 1 receptor (AT1-R) in vitro.[12]
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. There are certain levels of circulating Hx which implicates in the prognosis for patients with septic shock. Therefore it can also be said that, Hx therapy has been shown to be beneficial in cardiovascular disease, cerebral ischemic injury, and experimental autoimmune encephalomyelitis.[13]
Clinical significance
Its levels in serum reflect how much heme is present in the blood. Therefore, low hemopexin levels indicates that there has been significant degradation of heme containing compounds and hemopexin is made to scavenge any heme it can. Low hemopexin levels are one of the diagnostic features of an intravascular hemolytic anemia.[14]
Controversies
In past there have been reports showing from patients with sickle cell disease, spherocytosis, autoimmune hemolytic anemia, erythropoietic protoporphyria and pyruvate kinase deficiency which have been suggested that Haptoglobin (Hp) depletion in plasma occurs prior to the decline of hemopexin (Hx) concentrations (Muller-Eberhard et al., 1968). Heme released during oxidation of Hb to met-Hb or from heme saturated hepatocytes is bound by albumin and rapidly transferred to Hx, the plasma protein with the highest binding affinity for heme. Hx is glycoprotein produced by the liver with a plasma concentration of 1–2 mg/ml (Muller-Eberhard et al., 1968). Hx prevents heme's pro-oxidant and pro-inflammatory effects and it also promotes its detoxification, specifically when Hp concentrations are low or depleted in cases of severe or prolonged hemolysis. Hp and Hx, both are acute-phase proteins,induced during infection and inflammatory states to minimize tissue injury and facilitate tissue repair.The cutrrent review also suggests that the primary mechanisms by which Hp and Hx prevent heme toxicity prior to monocyte or macrophage clearance, it also critically evaluate the difference in genetic phenotype function and describe the rationale for exogenous Hp and Hx as therapeutic proteins.[15]
Mutations
Deletion of the hemopexin or heme oxygenase-2 gene can aggravates brain injury followed by stroma-free hemoglobin-induced intracerebral haemorrhage.[16]
Differential transcriptional pattern of hemopexin gene
The expression of the human hemopexin gene in different human tissues and cell lines was carried out by using the specific cDNA probe. From the results obtained it can be concluded that this gene is expressed in liver and, in lower amount, in hepatoma cell lines but not in kidney, spleen, placental cells, and in HeLa, fibroblast cell lines.By S1 mapping it can also said that the transcription initiation site in hepatic cells is 28 base pairs upstream from the AUG initiation codon of the hemopexin gene.[17]
References
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ "Entrez Gene: HPX hemopexin".
- ↑ 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. doi:10.1007/BF02138368. PMID 2842511.
- ↑ 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.
- ↑ 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.
- ↑ "Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases". PMID 26339767.
- ↑ Online Mendelian Inheritance in Man (OMIM) Orthosatic intolerance -604715
- ↑ 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. PMID 3855550.
- ↑ Online Mendelian Inheritance in Man (OMIM) Hemopexin -142290
- ↑ 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.
- ↑ 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. doi:10.1097/HJH.0b013e32835c1727. PMID 23254305.
- ↑ 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. PMID 26339767.
- ↑ Hoffbrand A, Moss P, Pettit J (2006). Essential Haematology (5th ed.). Oxford: Blackwell Publishing. p. 60. ISBN 978-1-4051-3649-5.
- ↑ 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.
- ↑ Ma B, Day JP, Phillips H, Slootsky B, Tolosano E, Doré S (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.
- ↑ Poli V, Altruda F, Silengo L. "Differential transcriptional pattern of the hemopexin gene". The Italian Journal of Biochemistry. 35 (5): 355–60. PMID 3026994.
Further reading
- Piccard H, Van den Steen PE, Opdenakker G (April 2007). "Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins". Journal of Leukocyte Biology. 81 (4): 870–92. doi:10.1189/jlb.1006629. PMID 17185359.
- Morgan WT, Muller-Eberhard U, Lamola AA (January 1978). "Interaction of rabbit hemopexin with bilirubin". Biochimica et Biophysica Acta. 532 (1): 57–64. doi:10.1016/0005-2795(78)90447-6. PMID 620056.
- Liu HM, Atack JR, Rapoport SI (1989). "Immunohistochemical localization of intracellular plasma proteins in the human central nervous system". Acta Neuropathologica. 78 (1): 16–21. doi:10.1007/BF00687397. PMID 2735186.
- Smith A, Tatum FM, Muster P, Burch MK, Morgan WT (April 1988). "Importance of ligand-induced conformational changes in hemopexin for receptor-mediated heme transport". The Journal of Biological Chemistry. 263 (11): 5224–9. PMID 2833500.
- 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. doi:10.1007/BF02138368. PMID 2842511.
- 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.
- Taketani S, Kohno H, Naitoh Y, Tokunaga R (June 1987). "Isolation of the hemopexin receptor from human placenta". The Journal of Biological Chemistry. 262 (18): 8668–71. PMID 3036819.
- Law ML, Cai GY, Hartz JA, Jones C, Kao FT (July 1988). "The hemopexin gene maps to the same location as the beta-globin gene cluster on human chromosome 11". Genomics. 3 (1): 48–52. doi:10.1016/0888-7543(88)90158-9. PMID 3220477.
- Morgan WT, Alam J, Deaciuc V, Muster P, Tatum FM, Smith A (June 1988). "Interaction of hemopexin with Sn-protoporphyrin IX, an inhibitor of heme oxygenase. Role for hemopexin in hepatic uptake of Sn-protoporphyrin IX and induction of mRNA for heme oxygenase". The Journal of Biological Chemistry. 263 (17): 8226–31. PMID 3372522.
- 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. doi:10.1073/pnas.82.1.73. PMC 396973. PMID 3855550.
- Takahashi N, Takahashi Y, Putnam FW (April 1984). "Structure of human hemopexin: O-glycosyl and N-glycosyl sites and unusual clustering of tryptophan residues". Proceedings of the National Academy of Sciences of the United States of America. 81 (7): 2021–5. doi:10.1073/pnas.81.7.2021. PMC 345428. PMID 6371807.
- Frantíková V, Borvák J, Kluh I, Morávek L (December 1984). "Amino acid sequence of the N-terminal region of human hemopexin". FEBS Letters. 178 (2): 213–6. doi:10.1016/0014-5793(84)80603-1. PMID 6510521.
- Smith A, Alam J, Escriba PV, Morgan WT (April 1993). "Regulation of heme oxygenase and metallothionein gene expression by the heme analogs, cobalt-, and tin-protoporphyrin". The Journal of Biological Chemistry. 268 (10): 7365–71. PMID 8463269.
- Morris CM, Candy JM, Edwardson JA, Bloxham CA, Smith A (January 1993). "Evidence for the localization of haemopexin immunoreactivity in neurones in the human brain". Neuroscience Letters. 149 (2): 141–4. doi:10.1016/0304-3940(93)90756-B. PMID 8474687.
- Hrkal Z, Kuzelová K, Muller-Eberhard U, Stern R (March 1996). "Hyaluronan-binding properties of human serum hemopexin". FEBS Letters. 383 (1-2): 72–4. doi:10.1016/0014-5793(96)00225-6. PMID 8612795.
- Hunt RC, Hunt DM, Gaur N, Smith A (July 1996). "Hemopexin in the human retina: protection of the retina against heme-mediated toxicity". Journal of Cellular Physiology. 168 (1): 71–80. doi:10.1002/(SICI)1097-4652(199607)168:1<71::AID-JCP9>3.0.CO;2-5. PMID 8647924.
- Miller YI, Smith A, Morgan WT, Shaklai N (October 1996). "Role of hemopexin in protection of low-density lipoprotein against hemoglobin-induced oxidation". Biochemistry. 35 (40): 13112–7. doi:10.1021/bi960737u. PMID 8855948.
- Grinberg LN, O'Brien PJ, Hrkal Z (July 1999). "The effects of heme-binding proteins on the peroxidative and catalatic activities of hemin". Free Radical Biology & Medicine. 27 (1-2): 214–9. doi:10.1016/S0891-5849(99)00082-9. PMID 10443938.
- Nakajima S, Moriyama T, Hayashi H, Sakata I, Nakae Y, Takemura T (February 2000). "Hemopexin as a carrier protein of tumor-localizing Ga-metalloporphyrin-ATN-2". Cancer Letters. 149 (1-2): 221–6. doi:10.1016/S0304-3835(99)00367-5. PMID 10737728.
- Shipulina N, Smith A, Morgan WT (April 2000). "Heme binding by hemopexin: evidence for multiple modes of binding and functional implications". Journal of Protein Chemistry. 19 (3): 239–48. doi:10.1023/A:1007016105813. PMID 10981817.
External links
- Hemopexin at the US National Library of Medicine Medical Subject Headings (MeSH)