Vitamin D-Binding Protein (DBP)


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JosŽ M. Ena
E-mail address: joseena@ubu.es


Last updated: January, 1997






Introduction
The vitamin D-binding protein (DBP), also called Group Specific Component (Gc) is a glycoprotein present in the plasma of most vertebrates and it has a molecular weight of about 52.000 in humans. Since its discovery in 1947, it has been known to be a highly polymorphic protein and up to now, more than 120 genetic variants have been recorded. It is the main carrier for vitamin D and its hydroxylated metabolites in the plasma of vertebrates, showing the highest affinity for 25-hydroxy-cholecalciferol. In addition, DBP binds actin with high affinity, causing its depolymerization or preventing the polymerization of actin released into the blood.

This protein has a strong structural homology with albumin and alpha-fetoprotein, both of which are genetically related to DBP, and consequently DBP shares some of their functional properties, such as the capacity to bind fatty acids, particularly palmitic and oleic acids. Moreover, it has been reported that araquidonic acid can affect the binding of vitamin D by DBP in vitro. As well as being present in the circulation, DBP has been detected on the surface of several cell types such as cytotrophoblast isolated from human placentae, yolk sac endodermal cells, and some T-lymphocytes. In B-cells, DBP seems to participate in the linkage of surface immunoglobulins.

DBP is known to be synthesised in significant amounts only by the liver and secreted into the blood, though mRNA has also been found in many tissues (kindney, testis, abdominal fat, fetal yolk sac), but in levels 100-1000-fold less than in liver.

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Structure

The the three internal domains based on the predicted disulfide bonding pattern (Brown, 1976) both in rat albumin and DBP are very similar. The main difference is the truncation in DBP of the third domain.

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Properties
  1. DBP binds vitamin D metabolites in serum. It acts as a carrier for these metabolites preventing cells from a the massive uptake and its toxic effects.
  2. DBP binds monomeric actin (G-actin) with a high affinity. Prevents the polymerization of G-actin to form F-actin in the blood steam.
  3. DBP can bind fatty acids in vitro and has fatty acids bound in vivo. The binding of arachidonic acid competes with the binding of 25-hydroxy-cholecalciferol. Possible physiological function unknown.
  4. DBP is associated to membranes of some cell types. Besides, it has been described a receptor-mediated uptake of DBP in B-lymphoid cells.

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DBP in milk
DBP has also been detected in the mature milk of several species, but in levels much lower than in serum; the level in human milk is only about 2% that of serum. However, DBP concentrations in cow's colostrum and early milk are much higher than in definitive milk. Interestingly, the vitamin D activity in fresh human and bovine milk is found in the whey and not in the fat, but following secretion of milk, the vitamin D activity migrates to the lipid phase. It has been shown that DBP present in colostrum or milk of ruminant species derives from serum and no synthesis of DBP has been detected in the mammary gland of these species.

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Bibliographic references
(In alphabetical order. Reviews in bold characters)

Bouillon, R., Muls, E. and DeMoor, P. (1980). Influence of thyroid function on the serum concentration of 1,25-dihydroxyvitamin D3. J. Clin. Endocrinol. Metab., 51, 793-797.

Bouillon, R. and Van Baelen, H. (1981). Transport of vitamin D: significance of free and total concentration of the vitamin D metabolites. Calcif. Tissue Int., 33, 451-453.

Bouillon, R., Van Assche, F. A., Van Baelen, H., Henys, W. and DeMoor, P. (1981). Influence of the vitamin D-binding protein on the serum concentration of 1,25 dihydroxyvitamin D3. Significance of the free 1,25 dihydroxyvitamin D3 concentration. J. Clin. Invest., 67, 589-596.

Braun, A., Brandhofer, A. and Cleve, H. (1990). Interaction of the vitamin D-binding protein (group-specific component) and its ligand 25-hydroxy-vitamin D3: Binding differences of the various genetic types disclosed by isoelectric focusing. Electrophoresis, 11, 478-483.

Brommage, R. and DeLuca, H. F. (1985). Evidence that 1,25-dihydroxyvitamin D3 is the phisiologically active metabolite of vitamin D3. Endocrine Rev., 6, 491-511.

Brown, J.R. (1976). Structural origins of mammalian albumin. Fed. Proc. 35, 2141.

Calvo, M. and Ena, J. M. (1989). Relations between vitamin D and fatty acid binding proerties of vitamin D-binding protein. Biochem. Biophys. Res. Commun., 163, 14-17.

Cancela, L., Le Boulch, N. and Miravet, L. (1986). Relationship between the vitamin D content of maternal milk and the vitamin D status of nursing women and breast-fed infants. J. Endocrinol., 110, 43-50.

Chapuis-Cellier. C., Gianazza, E. and Arnaud, P. (1982). Interaction of group specific component (Vitamin D-binding protein) with immobilized Cibacron Blue F3-GA. Biocim. Biophys. Acta, 709, 353-357.

Cleve, H. and Constans, J. (1988). The mutans of the DBP. More than 120 variants of the Gc/DBP system. Vox Sang. 54, 215-225.

Constans, J., Viau, M. and Bouissou, C. (1980). Affinity differences for the 25-OHD3 associated with the genetic heterogeneity of the vitamin D-binding protein. FEBS Lett., 111, 107-111.

Cooke, N. E., Walgate, J. and Haddad, J. G. (1979). Human serum vitamin D-binding protein for vitamin D and its metabolites. I. Physiochemical and immunological identification in human tissues. J. Biol. Chem., 254, 5965-5971.

Cooke, N. E. and David, E. V. (1985). Serum vitamin D-binding protein is a third member of the albumin and alpha-fetoprotein gene family. J. Clin. Invest., 76, 2420-2424.

Cooke, N. E. and Haddad, J. G. (1989). Vitamin D-binding protein (Gc-globulin). Endocrine Rev., 10, 294-307.

Emerson, D. L., Galbraith, R. M. and Arnaud, P. (1984). Electrophoretic demonstration of interactions between Gc (vitamin D-binding protein), actin and 25-hydroxycholecalciferol. Electrophoresis, 5, 22-26.

Ena, J. M., Esteban, C., PŽrez, M. D., Uriel, J. and Calvo, M. (1989). Fatty acids bound to vitamin D-binding protein (DBP) from human and bovine sera. Biochem. Internat., 19, 1-7.

Ena, J.M., Perez, M.D., Aranda, P., Sanchez. L. and Calvo, M,. (1992) Presence and changes in the concentration of vitamin D-binding protein throughout early lactation in human and bovine colostrum and milk. J. Nutr. Biochem. 3, 498-502.

Esteban, C., Geuskens, M., Ena, J.M., Mishal, Z., Macho, A., Torres, J.M. and Uriel, J. (1992). Receptor-mediated uptake and processing of Vitamin D-binding protein in human B-lymphoid cells. J. Biol. Chem. 267, 10177-10183.

Fraser, D. R. (1980). Regulation of the metabolism of vitamin D. Physiol. Rev., 60, 551-613.

Goldbloom, R. (1989). Do healthy, breast-fed infants require vitamin D supplements?. Pediatric Notes, 13, 42.

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Greer, F. R. and Marshall, S. (1989). Bone mineral content, serum vitamin D metabolite concentrations, and ultraviolet B light exposure in infants fed human milk with and without vitamin D2 supplements. J. Pediatr., 114, 204-212.

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