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This article is about the hemopexin protein. For the family of proteins containing hemopexin-like repeats, see hemopexin family.
Hemopexin (or haemopexin; Hpx; Hx), also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the HPXgene[1][2][3] and belongs to hemopexin family of proteins.[4]Heme released during degradation of hemoglobin is bound by albumin and rapidly transferred to Hx, the plasma protein with the highest binding affinity for heme. Hx prevents heme's pro-oxidant and pro-inflammatory effects and it also promotes its detoxification. The Hx-heme complex is cleared by the receptor CD91.
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 blocked by an O-linked galactosamineoligosaccharide, 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 Hx consists of two similar halves.[5]
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.[6]
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.[7]
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.[8]
Function
Hx binds heme with the highest affinity of any known protein. 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[9]. Hx preserves the body's iron.[10] 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.[11] Hx can downregulate the angiotensin II Type 1 receptor (AT1-R) in vitro.[12]
Clinical significance
The predominant source of circulating Hx is the liver with a plasma concentration of 1–2 mg/ml.[13] 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.[14] Hx has been implicated in cardiovascular disease, septic shock, cerebral ischemic injury, and experimental autoimmune encephalomyelitis.[15][16] The circulating level of Hx is associated with prognosis in patients with septic shock.[15]
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 Hp concentrations are low or depleted as a result of severe or prolonged hemolysis.[13] Both Hp and Hx are acute-phase proteins, induced during infection and inflammatory states to minimize tissue injury and facilitate tissue repair. Hp and Hx prevent heme toxicity prior to monocyte or macrophage clearance, which may explain their effect on outcome in several diseases, and underlies the rationale for exogenous Hp and Hx as therapeutic proteins in hemolytic or hemorrhagic conditions.[19]
↑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. PMID2842511.
↑Poli V, Altruda F, Silengo L (1986). "Differential transcriptional pattern of the hemopexin gene". The Italian Journal of Biochemistry. 35 (5): 355–60. PMID3026994.
↑Tolosano E, Altruda F (April 2002). "Hemopexin: structure, function, and regulation". DNA and Cell Biology. 21 (4): 297–306. doi:10.1089/104454902753759717. PMID12042069.
↑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. PMID23254305.
↑ 13.013.1Muller-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. PMID5687939.
↑Hoffbrand A, Moss P, Pettit J (2006). Essential Haematology (5th ed.). Oxford: Blackwell Publishing. p. 60. ISBN978-1-4051-3649-5.
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. PMID17185359.
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. PMID620056.
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. PMID2735186.
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. PMID2833500.
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. PMID2842511.
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. PMID3036819.
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. PMID3220477.
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. PMID3372522.
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. PMID6510521.
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. PMID8463269.
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. PMID8474687.
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. PMID8612795.
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. PMID8855948.
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. PMID10443938.
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. PMID10737728.
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. PMID10981817.