Hemopexinhemopexin, hemopexin function
|1 Cloning, expression, and discovery
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 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 Hx consists of two similar halves
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
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 11p155-p154, the same location as that of the beta-globin gene complex by in situ hybridization
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
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 Hx preserves the body's iron 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 Hx can downregulate the angiotensin II Type 1 receptor AT1-R in vitro
The predominant source of circulating Hx is the liver with a plasma concentration of 1–2 mg/ml 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 Hx has been implicated in cardiovascular disease, septic shock, cerebral ischemic injury, and experimental autoimmune encephalomyelitis The circulating level of Hx is associated with prognosis in patients with septic shock
HPX is produced in the brain Deletion of the HPX gene can aggravate brain injury followed by stroma-free hemoglobin-induced intracerebral haemorrhage High Hx level in the cerebrospinal fluid is associated with poor outcome after subarachnoid hemorrhage
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 Hp concentrations are low or depleted as a result of severe or prolonged hemolysis 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
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