Haptoglobin
Description
Molecular Structure and Genetic Variants
Haptoglobin consists of α- and β-chains linked by disulfide bonds, forming tetramers (αβ)₂ in its simplest form . Genetic polymorphisms in the HP gene produce three major phenotypes:
| Genotype | Structure | Hb Binding Affinity | Serum Concentration Range (g/L) |
|---|---|---|---|
| Hp1-1 | Tetramer (α₁β)₂ | High | 0.37–2.19 |
| Hp2-1 | Hetero-oligomers | Intermediate | 0.38–2.12 |
| Hp2-2 | Large covalent polymers | Low | 0.12–1.51 |
The Hp2 allele arose from a partial duplication of Hp1, introducing additional cysteine residues that enable oligomerization . These structural differences influence functional efficacy, with Hp2-2 showing reduced hemoglobin (Hb) binding capacity compared to Hp1-1 .
Hemoglobin Clearance
Hp binds free Hb with high affinity (Kd ~10⁻¹⁵ M), forming an irreversible complex that prevents Hb-induced oxidative damage . Key mechanisms include:
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Structural stabilization: Hp shields Hb’s reactive heme groups, inhibiting lipid peroxidation and protein denaturation .
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Receptor-mediated clearance: The Hp-Hb complex binds CD163 on macrophages, triggering endocytosis and heme metabolism .
Immunomodulation
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Anti-inflammatory effects: Hp suppresses lipopolysaccharide (LPS)-induced cytokine release by sequestering LPS from Toll-like receptor 4 .
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Macrophage polarization: Hp-Hb complexes promote anti-inflammatory M2 macrophage activation via CD163 signaling .
Diagnostic Applications
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Intravascular hemolysis: Serum Hp levels <0.1 g/L indicate acute hemolysis .
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Chronic diseases: Low Hp correlates with diabetic nephropathy progression and cardiovascular risk, particularly in Hp2-2 individuals .
Disease Associations
Recent Research Advances
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Sepsis: Terminal fucosylation at Asn207/211 of Hpβ enhances pro-inflammatory cytokine release, correlating with disease severity (NCT05911711 trial) .
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Structural insights: Crystal structures reveal Hp binds Hb at the αβ dimer interface, overlapping with Hb’s tetramerization site .
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Therapeutic targeting: Hp2-2 phenotype-specific interventions are being explored for diabetic complications due to reduced antioxidant capacity .
Glycosylation and Pathological States
Hp glycosylation patterns vary in disease:
Product Specs
Recombinant Human Haptoglobin, produced in E.Coli, is a single, non-glycosylated polypeptide chain. It includes a His tag fused to the protein, resulting in a total molecular weight of 33 kDa (including a 4 kDa His-tag).
Each mg of lyophilized Haptoglobin is supplied in a buffer containing 1xPBS, 0.4% SDS, and 4mM DTT.
The purity of this product is greater than 90.0% as determined by SDS-PAGE analysis.
L ILGGHLDAKG SFPWQAKMVS HHNLTTGATL INEQWLLTTA KNLFLNHSEN ATAKDIAPTL TLYVGKKQLV EIEKVVLHPN YSQVDIGLIK LKQKVSVNER VMPICLPSKD YAEVGRVGYV SGWGRNANFK FTDHLKYVML PVADQDQCIR HYEGSTVPEK KTPKSPVGVQ PILNEHTFCA GMSKYQEDTC YGDAGSAFAV HDLEEDTWYA TGILSFDKSC AVAEYGVYVK VTSIQDWVQK TIAEN
Product Science Overview
Haptoglobin (Hp) is an abundant plasma glycoprotein primarily synthesized in the liver. It plays a crucial role in binding free hemoglobin (Hb) released during hemolysis, thereby preventing the toxic effects of free Hb in the kidney, vasculature, and surrounding tissues . The complex formed between haptoglobin and hemoglobin (Hb:Hp complex) provides protective activities that mitigate the harmful impact of free Hb .
Haptoglobin is a member of the peptidase S1 family of serine proteases . It captures and combines with free plasma hemoglobin to facilitate hepatic recycling of heme iron and prevent kidney damage . Additionally, haptoglobin acts as an antioxidant, has antibacterial activity, and modulates various aspects of the acute phase response .
There are two main allelic variants of haptoglobin: HP1 and HP2 . The HP2 variant is considered the ancestral form and is characterized by an α2-chain containing an extra cysteine residue, which pairs with additional α-chains to generate multimers with molecular weights ranging from 200 to 900 kDa . The two human HP1 alleles (HP1F and HP1S) differ by a two-amino-acid substitution polymorphism within the α-chain and are derived from HP2 by recurring exon deletions .
Recombinant haptoglobin (human) is produced using mammalian cell lines, such as FS293F cells . The production process involves co-expression of active complement C1r subcomponent-like protein (C1r-LP) to ensure efficient expression of mature and fully functional haptoglobin . This recombinant approach allows for the production of phenotype-specific haptoglobin polymers, which can be used as therapeutic proteins to attenuate the toxic effects of cell-free hemoglobin in conditions such as sickle cell disease and other hemolytic disorders .
Haptoglobin has been evaluated as a therapeutic protein in preclinical studies to mitigate the toxic effects of cell-free hemoglobin . Proof-of-concept studies have demonstrated its efficacy in hemolysis associated with transfusion and sickle cell anemia . The recombinant production of phenotype-specific haptoglobin polymers offers opportunities for developing optimized hemoglobin-binding therapeutics .
