TBPP_transferrin

glycoprotein, 79 kD, 679 AS, produced in liver, plasma concentration 2-4 g/L, 2 binding sites for ferric iron (Fe3+), iron saturation about 35%

Alpha-helices and Beta-sheets, 2 lobes: N- and C-lobe, each of them 2 subdomains: C1&C2, N1&N2, each lobe has one binding site for Fe3+, stabilized by 19 disulfide bonds, subdomains of lobs are discontinous, N- and C-lobe different AS: Tyr (2x), Asp, His, Arg to anchor carbonate.

empty transferrin: apotransferrin, 1 Fe3+: monoferric transferrin, 2 Fe3+: diferric transferrin, very high affinity for binding at pH 7,4 (in cytoplasm, outside the cell), binding is reversible at lower pH (inside of the cell)

expressed as a homo-dimer, 3 domains, "butterfly", binds iron-loaded transferrin with high affinity, each member of dimer can bind a molecule transferrin

to trasport iron between sites of adsorption, recycling, storage and utilization. Adsorption: small intestine (via food), recycling: spleen (degradation of erythrocytes), storage: liver, utilization: synthesis of heme in bone marrow

non-heme iron (Fe3+) must be reduced to get inside of the cell through Ferrireductase (at apical side) --> DMT1 mediates protondependent Fe2+ import --> HCP1 transports dietary heme iron --> heme oxygenase releases iron from protoporphyrin: entrance of the same pool as non-heme iron --> some iron stored within ferritin --> ferroportin exports some iron, where it is oxidized to Fe3+ for incorporation into transferrin (at basal side)

Fe3+: ferric, chemically inert, Fe2+: ferrous, highly reactive, fenton, only Fe2+ can be taken up by enterocyte receptors = need for ferric reductases, Fe3+ to enable binding by Transferrin

Hepcidin regulates iron release from the liver (in case of iron overload in the body, hepcidin stopps the transport), from liver to intestine, plasma and to splen. From plasma to liver, intestine, bone marrow and a small part gets lost. Erythrocytes come to the splen and the iron from the splen to plasma.

in fraction IV1- and IV4-precipitate (Cohn fractionation), CSL uses IV4 as starting material, 2 methods: directly from IV4 precipitate or co-purification process with Hp, Hx (patent application). 1. method: extraction, filtration --> chr. --> concentration/diafiltration --> pasteurization --> viral filtration --> UF/DF --> sterile filtration. in method 2 (in addition): Ammonium sulfate (salting out), one more time UF/DF: removal of salts. control of purity: by SDS-page

no transferrin product on the market, from Finland with Finnish Red Cross, studied in hematologic stem cell transplant patients (iron overload), 2002: single dose in 7 patients demonstrated safety and the expected biochemical effects, 2006: same type of patient, treatment of congenitial atransferrinaemia: extremely rare

group of disorders caused by defective production of hemoglobin Beta-chains (no beta-globin production = major or some residual Beta-globin = intermedia), severe anaemia in 2-6 month after birth (switch Hb-F to adult Hb), hepato-and splenomegaly (growth of organs) due to increased erythrocyte destruction, thickening of bones due to bone marrow hyperplasia, phenotype can be different (position of mutation). A lot of extra Alpha-chains: precipitation, no balance anymore, very short half-life of the cells

RBC transfusions (2-4 weeks in the major genotype) but aggravation of iron overload, needs to be corrected by regular iron chelation therapy. Spleen removal (in severe cases), future: gene therapy. Intermedia mouse model: by treatment with transferrin: normalization of RBC survival, less RBC needed, reduced Alpha-globin precipitation, reversion of splenomegaly and decrease of serum erythropoietin.

probably not, convincing hypothesis for the intermedia genotype, concept doesnt hold up in the major genotype, medical need: low in intermedia but high in major

transferrin receptor expressed at blood-brain barrier, fusion transferrin with a drug to be delivered directly into the brain?: Alzheimer, Parkinson, other neurodegenerative disorders.