11096-26-7 Usage
Description
Erythropoietin (EPO) is a glycoprotein hormone that stimulates the production of red blood cells. It is highly conserved across various species, including humans, mice, dogs, and others, with more than 80% amino acid sequence identity. EPO contains three N-linked glycosylation sites, which are essential for its biological activities in vivo. Recombinant EPO, such as the brand Eprex, is currently used to treat anemia associated with renal transplant or end-stage renal disease. There are ongoing research and development efforts to widen its indications for use in other forms of anemia.
Uses
Used in Pharmaceutical Industry:
EPO is used as a therapeutic agent for treating anemia associated with renal transplant or end-stage renal disease. It helps in increasing the production of red blood cells, thereby improving the oxygen-carrying capacity of the blood.
Used in Biological Research:
EPO is used as a subject of study in biological research to understand its role in attenuating cardiac dysfunction in rats by inhibiting endoplasmic reticulum stress-induced diabetic cardiomyopathy.
Used in Drug Development:
Small mimetic peptides, agonistic antibodies, and EPO fusion proteins are being developed as agonists and antagonists to target EPO or its receptor (EPOR) for various therapeutic applications. Soluble EPOR is also being investigated as a potential inhibitor of EPO/EPOR-dependent cell proliferation in glioma cells.
Discovery
This is the primary regulator of erythropoiesis. It is produced predominantly in the fetal liver and the adult kidney to
promote the survival, proliferation, and differentiation of
erythroid progenitor cells. Other nonhematopoietic roles
include neuro-, cardio-, and reno-protection as well as
wound healing.?The relationship between anemia and hypoxia/atmospheric pressure was perceived around the 16th century,
predicted experimentally by Carnot and Deflandre. The
tentative name erythropoietin (EPO) was proposed independently by Komiya and by Bonsdorff and Jalavisto. Reissmann and Erslev confirmed the humoral activity
in the blood. Jacobson and colleagues found that the kidney primarily produced EPO. The human EPO protein
was finally purified directly from approximately 2550 L
of human urine of patients with aplastic anemia. The
subsequent molecular cloning of cDNA and the genomic
DNA of human EPO was accomplished concurrently by
two research groups in 1985.
Structure
Mature EPOs are heavily glycosylated to
reach 30%–40% (w/w) of the whole molecule. The terminal sialic acids provide stability in the circulation, and
are essential for in vivo activity. The tertiary structure
displays four-α-helical bundles shared among typical
cytokines.?The mature human EPO consists of 165 aa residues
after posttranslational cleavage of an Arg166 at the
C-terminus.?Mr. of human EPO polypeptide backbone is 18.2 kDa,
34 kDa on SDS-PAGE (glycosylated native form), or more
than 40 kDa (fully glycosylated recombinant EPO
expressed by CHO cells). The isoelectric point (pH 3–5)
varies depending on glycosylation. The level of biological
activity is reasonable against short-term heat treatment,
6M urea, 6M GuHCl, or ordinary surfactants, when renaturation is performed properly.
Gene, mRNA, and precursor
The human EPO gene is located in the q11 to q22
region of chromosome 7 [NC_000007. (100,720,
800.100723700)]. Human EPO mRNA
encodes a 193-aa polypeptide. Heterogeneity in the size
of EPO mRNA has been reported; for example, EPO
mRNA of larger size is found in the brain.?The production sites vary depending on either species
or ontogenic stages. In mammals, the predominant sites of
EPO production shift from the fetal liver to the adult kidney along with the transition of hematopoietic tissues. In
mice, hepatocytes in the fetus and adult renal cells in the
peritubular interstitium produce EPO. In nonmammalian vertebrates, EPO is generated predominantly in the
lung and the liver of the African clawed toad. In teleost?fish, the heart is one of the major production sites of EPO.
EPO for murine primitive erythropoiesis is produced in
neuroepithelial and neural crest cells.
Synthesis and release
Human EPO regulates erythropoiesis in a hypoxiainducible manner. Levels of HIF-1α in EPO-producing cellsincrease exponentially as O2 concentration
declines because ubiquitination and proteasomal degradation of HIF-1αdecrease. Then EPO expression is directly
upregulated by the transcriptional activation via interaction of a 30 enhancer complex with the 50 promoter. The number of EPO-producing cells
in the human kidney correlates positively with circulating
levels of EPO, but the range of EPO expression per cell has
not been determined. Ninety percent of the circulating
EPO originates from the kidneys and the rest from various
organs, including the liver, brain, spleen, lung, and testis.
Receptors
The EPO receptor (EPOR) is a glycoprotein that belongs
to the type I superfamily of single-transmembrane cytokine receptors. A soluble form of EPOR lacking a
transmembrane region generated by the alternative splicing of EPOR mRNA is found in human blood. The tertiary
structure of human EPO and the homodimerized EPOR
complex has been determined.?Intracellular EPO-EPOR signaling is triggered by the
binding of EPO, and EPORs homodimerize to activate
a cascade of JAK2 and STAT3/5, PI3K, and/or RAS/
MAPK.
Biological functions
As a primary target of EPO for erythropoiesis, EPOR is
expressed in the organs of hematopoiesis, including the
fetal liver as well as the adult bone marrow and spleen.
EPO-EPOR signaling regulates the proliferation/differentiation and survival of the erythroid progenitors,
providing an important stage-specific function of erythroid differentiation. The numbers of EPOR expressed
in various cells are relatively low and range between
100 and 3000 per cell with the binding affinity (ED50) to
EPO ranging from 0.1–3 nM. A wide distribution of EPOR
expression is confirmed on renal cells, endothelial cells,
cardiomyocytes, the brain, and peripheral nervous system where EPO may exert pleiotropic or antiapoptotic
effects.
Clinical implications
EPO maintains the number of circulating red blood
cells, that is, hemoglobin levels, by stimulating the proliferation and differentiation of erythrocyte progenitors in
the bone marrow. Therefore, EPO is mainly administered
as hormonal replacement therapy to patients with renal
failure who have experienced the compromised production of EPO. Additionally, the nonhemopoietic role of
erythropoietin has been evaluated in clinical trials,
including the reduction of hyperglycemia and the retardation of proliferative retinopathy in diabetic patients.
Use for diagnosis and treatment
Recombinant human EPO has been among themost successful therapeutic biologics. Originally, epoetin-α and -β
produced by CHO cells were developed and launched
for the treatment of chronic renal anemia to achieve optimal
hemoglobin levels and improve the QOL. Its application
has extended to cancer-related anemia involving?chemotherapy/radiation, inflammatory bowel disease
(Crohn’s disease and ulcer colitis), and others. The circulating levels of human EPO have been determined by RIA or
ELISA for the diagnosis of different types of anemia. The
second generation of erythropoiesis-stimulating agents
(ESAs), such as a long-acting analog darbepoetin with
two additional glycans andits various generics,is following
the first generation. Doping with EPO has become a serious
issue in athletics competitions.
Originator
Amgen (USA)
Biochem/physiol Actions
Erythropoietin (EPO), produced primarily by the kidney, is the primary regulatory factor of erythropoiesis. It promotes the proliferation, differentiation, and survival of the erythroid progenitors. Erythropoietin stimulates erythropoiesis by inducing growth and differentiation of burst forming units and colony forming units into mature red blood cells. EPO produced by kidney cells is increased in response to hypoxia or anemia. The biological effects of erythropoietin are mediated by the erythropoietin receptor, which binds EPO with high affinity and is a potent EPO antagonist.
Check Digit Verification of cas no
The CAS Registry Mumber 11096-26-7 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,1,0,9 and 6 respectively; the second part has 2 digits, 2 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 11096-26:
(7*1)+(6*1)+(5*0)+(4*9)+(3*6)+(2*2)+(1*6)=77
77 % 10 = 7
So 11096-26-7 is a valid CAS Registry Number.
