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BIOPHARMACEUTICALS BIOCHEMISTRY AND BIOTECHNOLOGY - PART 6

Glycosyl hóa không đầy đủ (N-liên kết) nhắc nhở giảm trong hoạt động cơ thể sống do giải phóng mặt bằng gan nhanh hơn của các phân tử EPO. Các chế phẩm enzim loại bỏ các thiết bị đầu cuối dư lượng đường sialic acid từ oligosaccharides ra dư lượng galactose nếu không ẩn. | HAEMOPOIETIC GROWTH FACTORS 265 essential role in the in vitro or in vivo biological activity of EPO. Interestingly removal of the N-linked sugars while having little effect on EPO s in vitro activity destroys its in vivo activity. The sugar components of EPO are likely to contribute to the molecule s solubility cellular processing and secretion in vivo metabolism. Incomplete N-linked glycosylation prompts decreased in vivo activity due to more rapid hepatic clearance of the EPO molecule. Enzymatic removal of terminal sialic acid sugar residues from oligosaccharides exposes otherwise hidden galactose residues. These residues are then free to bind specific hepatic lectins which promote EPO removal from the plasma. The reported plasma half-life ti 2 value for native EPO is 4-6 h. The t1 2 for desialated EPO is 2 min. Comparison of native human EPO with its recombinant form produced in CHO cells reveal very similar glycosylation patterns. Circular dichroism studies show that up to 50 of EPO s secondary structure is a-helical. The predicted tertiary structure is that of four anti-parallel helices formed by variable-sized loops similar to many other haemopoietic growth factors. Development of bioassays and radioimmunoassays along with the later development of specific mRNA probes allowed determination of the sites of production of EPO in the body. It has now been established that EPO in the human adult is synthesized almost exclusively by specialized kidney cells peritubular interstitial cells of the kidney cortex and upper medulla . Minor quantities are also synthesized in the liver which represents the primary EPO-producing organ of the fetus. EPO is present in serum and at very low concentrations in urine particularly of anaemic individuals. This cytokine hormone was first purified in 1971 from the plasma of anaemic sheep while small quantities of human EPO was later purified in 1977 from over 2500 litres of urine collected from anaemic patients. Large-scale .