Erythropoietin structure

Elhott S, Chang D, Delorme E, Dunn C, Egrie J, Giffin J, Lorenzini T, Talbot C, Hesterberg L. Isolation and characterization of conformation sensitive antieryth-ropoietin monoclonal antibodies effect of disulfide bonds and carbohydrate on recombinant human erythropoietin structure. Blood 1996 87 2714-22. 

Boissel, J.P., Lee, W.R., Presnell, S.R., Cohen, F.E. and Bunn, H.F. (1993) Erythropoietin structure-function relationships. Mutant proteins that test a model of tertiary structure. J. Biol. Chem. 268 15983-15993. 

Jelkmatm W. Erythropoietin structure, control of production, and function. Physiol Rev 1992 72(2) 449-489. 

Figure 17.12 Ribbon diagram of EMPl bound to the extracellular domain of the erythropoietin receptor (EBP). Binding of EMPl causes dimerization of erythropoietin receptor. The x-ray crystal structure of the EMPl-EBP complex shows a nearly symmetrical dimer complex in which both peptide monomers interact with both copies of EBP. Recognition between the EMPl peptides and EBP utilizes more than 60% of the EMPl surface and four of six loops in the erythropoietin-binding pocket of EBP.

In particular, three residues thought to be critical for binding erythropoietin (Phe 93, Met ISO, and Phe 205) are fully buried in the structure of the peptide-receptor complex. (From J.A. Wells, Science 273 449-450, 1996.)... 

Studies have shown that in patients with chemotherapy-related anemia, therapy with erythropoietin products (epoetin-alfa and darbepoetin) can increase hemoglobin, decrease transfusion requirements, and improve quality of life.12 Epoetin is recombinant human erythropoietin, and darbepoetin is structurally similar to endogenous erythropoietin. Both bind to the same receptor to stimulate red blood cell production. Darbepoetin differs from epoetin in that it is a glycosylated form and exhibits a longer half-life in the body. The half-lives of a single subcutaneous injection of epoetin or darbepoetin in patients are roughly 27 and 43 hours, respectively. 

Erythropoietin is a glycoprotein hormone that regulates the proliferation, differentiation, and maturation of erythroid cells. The EPO receptor is a member of the class 1 cytokine receptor superfamily. The crystal structure of an EPO-mimetic peptide and the extracellular portion of the... 

Yuen, C.T., Stoning, P.L., Tiplady, R.J. et al. (2003) Relationships between the A-glycan structures and biological activities of recombinant human erythropoietins produced using different culture conditions and purification procedures. British Journal of Haematology, 121 (3), 511-526. 

The pathogenesis of hypertension in patients with CKD is multifactorial and includes fluid retention, increased sympathetic activity, an endogenous digitalis-like substance, elevated levels of endothelin-1, erythropoietin use, hyperparathyroidism, and structural arterial changes. 

Structure and physiology of the kidney glomerular filtration tubular activity selective reabsorption and secretion, often using specific carrier mechanisms carbonic anhydrase and acid-base balance. The kidney also produces, and is sensitive to, hormones actions of the hormones ADH, aldosterone and PTH the kidney as a secretory organ erythropoietin, the renin-angiotensin system vitamin D3. 

Figure 4.8 Erythropoietin. Source Cheetham JC, Smith DM, Aoki KH, et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation, Nature Structural Biology 5 861-866 (1998).)...

Table 17.1 lists non-oncology compounds from diverse therapeutic, chemical, pharmacological areas and structures that induce clinical hematotoxicity. This demonstrates that bone marrow toxicity is not restricted to a small number of pharmacological or structural classes, thereby making it more difficult to understand specific mechanisms of toxicity. However, there are three classes of mechanisms of hematotoxicity, including antiproliferative, immune-mediated and other. Immune-mediated hematotoxicity and other indirect toxicities (e.g., a decrease of erythropoietin in kidney, leading to an impeded red cell production in the bone marrow) are not discussed in detail in this chapter as it requires involvement of the immune system or remote interactions and in vitro profiling assays have not been developed to detect these mechanisms. 

Figure 6.4. 3-D structure of erythropoietin. Photo from Cheetham et al. (1998), by courtesy of the...

Fig. 11.2. Domain structure of cytokine receptors. Schematic representation of the domain structure of selected cytokine receptors. WS motif conserved WSXWS sequence (W tryptophan S serine X non-conserved amino add) IL interleukin EpoR receptor for erythropoietin GHR growth hormone receptor LIF-R leukemia inhibitory factor receptor G-CSFR granulocyte colony stimulating factor receptor IFNR interferon receptor TNFR tumor necrosis factor receptor NGFR nerve growth factor receptor Fas, CD40 transmembrane receptors of lymphocytes.

Twenty years passed before researchers purified small amounts of erythropoietin and elucidated the primary amino-acid structure. Erythropoietin has 166 amino-acid residues and a molecular weight of 18.4kDa. The overall molecular weight is... 

Cai P, Smith D, Katz B, Pearce C, Venables D, Houck D (1998) Destruxin-A4 Chlorohy-drin, a Novel Destruxin from the Fungus OS-F68576 Isolation, Structure Determination, and Biological Activity as an Inducer of Erythropoietin. J Nat Prod 61 290... 

Antibodies directed against recombinant erythropoietin have been obtained from rabbits immunized with the hormone and Freunds complete adjuvant [64], Two sets of antibodies are present in the serum of rabbits that have been immunized, Fig. (3C). The results of oxidation of the erythropoietin with periodate, Fig. (25A), reaction of the antibodies with lectins of known carbohydrate specificity, Fig. (25B) and inhibition of the antibodies with the structural monosaccharide residues of the hormone, Fig. (26), have established the types of antibodies to be anti-carbohydrate antibodies and the immunodeterminants for these antibodies are oligosaccharides with the following structure N-acetyl neuraminyl a(2->3)... 

The rate of protein clearance has been estimated as 10% of the rate of fluid clearance from alveoli [173]. IgG clearance is probably mediated by FcRn transcytosis in distal type I alveolar epithelium and more proximal bronchial epithelium. Type I alveolar epithelium and bronchial epithelium contain the necessary subcellular structures for FcRn-mediated transcytosis vesicles, membrane invaginations, caveolae, and clathrin-coated pits [173,174], FcRn mRNA is expressed in lung although the cell types and locations have not yet been determined [112], Moreover, primary alveolar epithelial monolayer cell cultures express functional FcRn [173], plgA-R/SC transcytosis is thought to contribute little to distal (alveolar) airway IgG transport but might mediate more proximal (bronchial or bronchiolar) IgA transport [173], Uptake of an aerosolized IgG Fc-erythropoietin fusion molecule and subsequent erythropoietin-induced reticulocytosis has been demonstrated in human and nonhuman primates [175],... 

Most patients with Al intoxication develop an erythropoietin-resistant microcytic anemia in the absence of iron deficiency, and this may be a useful early indication of Al toxicity [41,93,254,255]. The chemical similarity between Fe3+ and Al3+ suggest that both elements will have similar metabolic effects, suggesting that iron and Al compete during erythropoiesis, resulting from a reversible block in heme synthesis due either to a defect in porphyrin synthesis or to impaired iron utilization. It was also suggested that the main mechanisms for Al toxicity in the erythropoietic system are the interference of Al in the uptake and utilization of iron and an interaction of Al with cellular membrane components, affecting not only their structures but also their functions [256]. 

Wilson, I. A., and Jolliffe, L. K. (1999). The structure, organization, activation, and plasticity of the erythropoietin receptor. Cure. Opin. Struct. Biol. 9, 696-704. 

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