View source for Hemopexin

{{About|the hemopexin protein|the family of proteins containing hemopexin-like repeats|hemopexin family}}
{{Infobox_gene}}
'''Hemopexin''' (or '''haemopexin'''; HPX), also known as '''beta-1B-glycoprotein''' is a [[protein]] that in humans is encoded by the ''HPX'' [[gene]]<ref name="entrez">{{cite web | title = Entrez Gene: HPX hemopexin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3263| accessdate = }}</ref><ref name="pmid2842511">{{cite journal | vauthors = Altruda F, Poli V, Restagno G, Silengo L | title = Structure of the human hemopexin gene and evidence for intron-mediated evolution | journal = Journal of Molecular Evolution | volume = 27 | issue = 2 | pages = 102–8 | year = 1988 | pmid = 2842511 | doi = 10.1007/BF02138368 }}</ref><ref name="pmid2989777">{{cite journal | vauthors = Altruda F, Poli V, Restagno G, Argos P, Cortese R, Silengo L | title = The primary structure of human hemopexin deduced from cDNA sequence: evidence for internal, repeating homology | journal = Nucleic Acids Research | volume = 13 | issue = 11 | pages = 3841–59 | date = June 1985 | pmid = 2989777 | pmc = 341281 | doi = 10.1093/nar/13.11.3841 }}</ref> and belongs to [[hemopexin family]] of proteins.<ref name="pmid8590012">{{cite journal | vauthors = Bode W | title = A helping hand for collagenases: the haemopexin-like domain | journal = Structure | volume = 3 | issue = 6 | pages = 527–30 | date = June 1995 | pmid = 8590012 | doi = 10.1016/s0969-2126(01)00185-x }}</ref> Hemoglobin and its scavenger protein hemopexin (Hx) associate with HDL{{expand acronym}} 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.<ref>{{cite web|title=Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases|pmid = 26339767}}</ref>

== 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 [[disulfide bridge]]s 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 [[homology (biology)|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.<ref>{{OMIM|604715|Orthosatic intolerance}}</ref>

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.<ref>{{cite journal | vauthors = Takahashi N, Takahashi Y, Putnam FW | title = Complete amino acid sequence of human hemopexin, the heme-binding protein of serum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 1 | pages = 73–7 | date = January 1985 | pmid = 3855550 | pmc=396973 | doi=10.1073/pnas.82.1.73}}</ref>

== Mapping of hemopexin gene ==
Cai and Law (1986) prepared a [[CDNA|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]].<ref>{{OMIM|142290 |Hemopexin}}</ref>

== 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]].<ref name="pmid12042069">{{cite journal | vauthors = Tolosano E, Altruda F | title = Hemopexin: structure, function, and regulation | journal = DNA and Cell Biology | volume = 21 | issue = 4 | pages = 297–306 | date = April 2002 | pmid = 12042069 | doi = 10.1089/104454902753759717 }}</ref> Hemopexin, an acute phase protein, can downregulate the [[angiotensin]] (ang) II type 1 receptor (AT1-R) in vitro.<ref>{{cite journal | vauthors = Krikken JA, Lely AT, Bakker SJ, Borghuis T, Faas MM, van Goor H, Navis G, Bakker WW | title = Hemopexin activity is associated with angiotensin II responsiveness in humans | journal = Journal of Hypertension | volume = 31 | issue = 3 | pages = 537–41 | date = March 2013 | pmid = 23254305 | doi = 10.1097/HJH.0b013e32835c1727 }}</ref>

Hx-dependent uptake of extracellular heme can lead to the deactivation of [[BACH1|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 ischemia|cerebral ischemic injury]], and experimental autoimmune [[encephalomyelitis]].<ref>{{cite journal | vauthors = Mehta NU, Reddy ST | title = Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases | journal = Current Opinion in Lipidology | volume = 26 | issue = 5 | pages = 384–7 | date = October 2015 | pmid = 26339767 | doi = 10.1097/MOL.0000000000000208 | pmc=4826275}}</ref>

== 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]].<ref>{{cite book|last1=Hoffbrand|first1=A.V.|last2=Moss|first2=P.A.H.|last3=Pettit|first3=J.E. | name-list-format = vanc |title=Essential Haematology|date=2006|publisher=Blackwell Publishing|location=Oxford|isbn=978-1-4051-3649-5|page=60|edition=5th}}</ref>

== 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.<ref name=Muller>Muller-Eberhard et al., 1968 {{full}}</ref>
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&nbsp;mg/ml.<ref name=Muller/> 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 current 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.<ref name="pmid25389409">{{cite journal | vauthors = Schaer DJ, Vinchi F, Ingoglia G, Tolosano E, Buehler PW | title = Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development | journal = Frontiers in Physiology | volume = 5 | issue = | pages = 415 | year = 2014 | pmid = 25389409 | pmc = 4211382 | doi = 10.3389/fphys.2014.00415 }}</ref>

== Mutations ==
Deletion of the hemopexin or heme oxygenase-2 gene can aggravate brain injury followed by stroma-free hemoglobin-induced [[intracerebral haemorrhage]].<ref name="pmid26831741">{{cite journal | vauthors = Ma B, Day JP, Phillips H, Slootsky B, Tolosano E, Doré S | title = Deletion of the hemopexin or heme oxygenase-2 gene aggravates brain injury following stroma-free hemoglobin-induced intracerebral hemorrhage | journal = Journal of Neuroinflammation | volume = 13 | issue = | pages = 26 | year = 2016 | pmid = 26831741 | pmc = 4736638 | doi = 10.1186/s12974-016-0490-1 }}</ref>

== 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 [[HeLa|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.<ref>{{cite journal | vauthors = Poli V, Altruda F, Silengo L | title = Differential transcriptional pattern of the hemopexin gene | journal = The Italian Journal of Biochemistry | volume = 35 | issue = 5 | pages = 355–60 | pmid = 3026994 | year=1986}}</ref>

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Piccard H, Van den Steen PE, Opdenakker G | title = Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins | journal = Journal of Leukocyte Biology | volume = 81 | issue = 4 | pages = 870–92 | date = April 2007 | pmid = 17185359 | doi = 10.1189/jlb.1006629 }}
* {{cite journal | vauthors = Morgan WT, Muller-Eberhard U, Lamola AA | title = Interaction of rabbit hemopexin with bilirubin | journal = Biochimica et Biophysica Acta | volume = 532 | issue = 1 | pages = 57–64 | date = January 1978 | pmid = 620056 | doi = 10.1016/0005-2795(78)90447-6 }}
* {{cite journal | vauthors = Liu HM, Atack JR, Rapoport SI | title = Immunohistochemical localization of intracellular plasma proteins in the human central nervous system | journal = Acta Neuropathologica | volume = 78 | issue = 1 | pages = 16–21 | year = 1989 | pmid = 2735186 | doi = 10.1007/BF00687397 }}
* {{cite journal | vauthors = Smith A, Tatum FM, Muster P, Burch MK, Morgan WT | title = Importance of ligand-induced conformational changes in hemopexin for receptor-mediated heme transport | journal = The Journal of Biological Chemistry | volume = 263 | issue = 11 | pages = 5224–9 | date = April 1988 | pmid = 2833500 | doi =  }}
* {{cite journal | vauthors = Altruda F, Poli V, Restagno G, Silengo L | title = Structure of the human hemopexin gene and evidence for intron-mediated evolution | journal = Journal of Molecular Evolution | volume = 27 | issue = 2 | pages = 102–8 | year = 1988 | pmid = 2842511 | doi = 10.1007/BF02138368 }}
* {{cite journal | vauthors = Altruda F, Poli V, Restagno G, Argos P, Cortese R, Silengo L | title = The primary structure of human hemopexin deduced from cDNA sequence: evidence for internal, repeating homology | journal = Nucleic Acids Research | volume = 13 | issue = 11 | pages = 3841–59 | date = June 1985 | pmid = 2989777 | pmc = 341281 | doi = 10.1093/nar/13.11.3841 }}
* {{cite journal | vauthors = Taketani S, Kohno H, Naitoh Y, Tokunaga R | title = Isolation of the hemopexin receptor from human placenta | journal = The Journal of Biological Chemistry | volume = 262 | issue = 18 | pages = 8668–71 | date = June 1987 | pmid = 3036819 | doi =  }}
* {{cite journal | vauthors = Law ML, Cai GY, Hartz JA, Jones C, Kao FT | title = The hemopexin gene maps to the same location as the beta-globin gene cluster on human chromosome 11 | journal = Genomics | volume = 3 | issue = 1 | pages = 48–52 | date = July 1988 | pmid = 3220477 | doi = 10.1016/0888-7543(88)90158-9 }}
* {{cite journal | vauthors = Morgan WT, Alam J, Deaciuc V, Muster P, Tatum FM, Smith A | title = 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 | journal = The Journal of Biological Chemistry | volume = 263 | issue = 17 | pages = 8226–31 | date = June 1988 | pmid = 3372522 | doi =  }}
* {{cite journal | vauthors = Takahashi N, Takahashi Y, Putnam FW | title = Complete amino acid sequence of human hemopexin, the heme-binding protein of serum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 1 | pages = 73–7 | date = January 1985 | pmid = 3855550 | pmc = 396973 | doi = 10.1073/pnas.82.1.73 }}
* {{cite journal | vauthors = Takahashi N, Takahashi Y, Putnam FW | title = Structure of human hemopexin: O-glycosyl and N-glycosyl sites and unusual clustering of tryptophan residues | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 7 | pages = 2021–5 | date = April 1984 | pmid = 6371807 | pmc = 345428 | doi = 10.1073/pnas.81.7.2021 }}
* {{cite journal | vauthors = Frantíková V, Borvák J, Kluh I, Morávek L | title = Amino acid sequence of the N-terminal region of human hemopexin | journal = FEBS Letters | volume = 178 | issue = 2 | pages = 213–6 | date = December 1984 | pmid = 6510521 | doi = 10.1016/0014-5793(84)80603-1 }}
* {{cite journal | vauthors = Smith A, Alam J, Escriba PV, Morgan WT | title = Regulation of heme oxygenase and metallothionein gene expression by the heme analogs, cobalt-, and tin-protoporphyrin | journal = The Journal of Biological Chemistry | volume = 268 | issue = 10 | pages = 7365–71 | date = April 1993 | pmid = 8463269 | doi =  }}
* {{cite journal | vauthors = Morris CM, Candy JM, Edwardson JA, Bloxham CA, Smith A | title = Evidence for the localization of haemopexin immunoreactivity in neurones in the human brain | journal = Neuroscience Letters | volume = 149 | issue = 2 | pages = 141–4 | date = January 1993 | pmid = 8474687 | doi = 10.1016/0304-3940(93)90756-B }}
* {{cite journal | vauthors = Hrkal Z, Kuzelová K, Muller-Eberhard U, Stern R | title = Hyaluronan-binding properties of human serum hemopexin | journal = FEBS Letters | volume = 383 | issue = 1-2 | pages = 72–4 | date = March 1996 | pmid = 8612795 | doi = 10.1016/0014-5793(96)00225-6 }}
* {{cite journal | vauthors = Hunt RC, Hunt DM, Gaur N, Smith A | title = Hemopexin in the human retina: protection of the retina against heme-mediated toxicity | journal = Journal of Cellular Physiology | volume = 168 | issue = 1 | pages = 71–80 | date = July 1996 | pmid = 8647924 | doi = 10.1002/(SICI)1097-4652(199607)168:1<71::AID-JCP9>3.0.CO;2-5 }}
* {{cite journal | vauthors = Miller YI, Smith A, Morgan WT, Shaklai N | title = Role of hemopexin in protection of low-density lipoprotein against hemoglobin-induced oxidation | journal = Biochemistry | volume = 35 | issue = 40 | pages = 13112–7 | date = October 1996 | pmid = 8855948 | doi = 10.1021/bi960737u }}
* {{cite journal | vauthors = Grinberg LN, O'Brien PJ, Hrkal Z | title = The effects of heme-binding proteins on the peroxidative and catalatic activities of hemin | journal = Free Radical Biology & Medicine | volume = 27 | issue = 1-2 | pages = 214–9 | date = July 1999 | pmid = 10443938 | doi = 10.1016/S0891-5849(99)00082-9 }}
* {{cite journal | vauthors = Nakajima S, Moriyama T, Hayashi H, Sakata I, Nakae Y, Takemura T | title = Hemopexin as a carrier protein of tumor-localizing Ga-metalloporphyrin-ATN-2 | journal = Cancer Letters | volume = 149 | issue = 1-2 | pages = 221–6 | date = February 2000 | pmid = 10737728 | doi = 10.1016/S0304-3835(99)00367-5 }}
* {{cite journal | vauthors = Shipulina N, Smith A, Morgan WT | title = Heme binding by hemopexin: evidence for multiple modes of binding and functional implications | journal = Journal of Protein Chemistry | volume = 19 | issue = 3 | pages = 239–48 | date = April 2000 | pmid = 10981817 | doi = 10.1023/A:1007016105813 }}
{{refend}}

== External links ==
* {{MeshName|Hemopexin}}

== See also ==
*[[Haptoglobin]]
*[[Hemoglobin]]
*[[Heme]]

{{Glycoproteins}}
{{Beta globulins}}
{{Acute phase proteins}}

[[Category:Blood proteins]]
[[Category:Single-pass transmembrane proteins]]