A-Tocopherol-binding protein

Catignani, G. L., 1975, An a-tocopherol binding protein in rat liver cytoplasm, Biochem. Biophys. Res. Commun. 67 66. 

Retention within tissues depends on intracellular binding proteins which, like the liver a-tocopherol transfer protein, have the highest affinity for RRR-a-tocopherol. The retention of a-tocopherol in tissues varies. In the lungs the vitamin has a half-life of 7.6 days, in liver 9.8 days, in skin 23.4 days, in brain 29.4 days, and in the spinal cord 76.3 days (Ingold et al., 1987). 

In intestinal mucosal cells, all vitamers of vitamin E cue incorporated into chylomicrons, and tissues take up some vitamin E from chylomicrons. Most, however, goes to the liver in chylomicron remnants, a -Tocopherol, which binds to the liver a-tocopherol transfer protein, is then exported in very low-density lipoprotein (VLDL) and is available for tissue uptake (Traber and Aral, 1999 Stocker and Azzi, 2000). Later, it appears in low-density Upoprotein (LDL) and high-density lipoprotein, as a result of metabolism of VLDL in the circulation. The other vitamers, which do not bind well to the a-tocopherol transfer protein, are not incorporated into VLDL, but are metabolized in the Uver and excreted. This explains thelower biological potency of the othervitcimers,despitesimilar, or higher, in vitro antioxidant activity. 

Stocker A and Azzi A (2000) Tocopherol-binding proteins their function and physiological significance. Antioxidants and Redox Signaling2,397-404. 

The bioactivity of E-vitamers is defined as their ability to prevent or reverse specific vitamin E deficiency symptoms, such as fetal resorption in rats and muscular dystrophy and encephalomalacia in chicken (Machlin, 1991). The bioactivities of different E-vitamers parallel their bioavailability, indicating that bioactivity is more a function of the amounts available in the body than the chemical activities of these vitamers. Because diets are reasonably abundant in E-vitamers, vitamin E deficiency is rare in humans and is almost limited to malnourished people, people with fat malabsorption or those with a defect in the hepatic tocopherol binding protein (Dutta-Roy et al., 1994). 

Dutta-Roy, A.K., Gordon, M.J., Campbell, F.M., Duthie, G.G., and James, W.P. 1994. Vitamin E Requirements, Transport and Metabolism Role of CX-Tocopherol Binding Proteins. J. Nutr. Biochem. 5 562-570. 

How the above described vitamins influence in vitro 3H-tryptophan nuclear receptor binding is not clear. Based upon the experiments with added dithiothreitol, it appears that some vitamins act on the sulfhydryl groups of the receptor, which become modified, which interferes with 3H-tryptophan binding. Reviews of reports by others indicate that certain vitamins can bind to hepatic nuclei. Examples include (1) 3H-a-tocopherol, which has been reported to become incorporated into isolated rat liver nuclei in a nonspecific manner by binding to chromatin nonhistone chromosomal protein,196 and (2) rat liver nuclei, which contain receptors for a folate-binding protein.197 As yet, it is not known whether others act similarly or not. Thus, whether competitive binding to nuclei between vitamins and tryptophan occurs is not known. 

In the last decade, several proteins have been described that can bind tocopherols, however, their role in intracellular distribution of the tocopherols remains to be shown in detail." A 14.2 kDa tocopherol-binding protein (TBP) was shown to enhance up to ten-fold the transport of a-tocopherol to the mitochondria.Among the tocopherol-binding proteins, only a-TTP and several human tocopherol associated proteins (hTAPl, hTAP2, hTAP3) have been cloned and shown in vitro to bind tocopherol with reasonable affinity (Table 12.1). -" ... 

Dutta-Roy, A.K., Alpha-tocopherol-binding proteins purification and characterization, Methods Enzymol. 282, 278-297, 1997. 

Dutta-Roy, A.K., Molecular mechanism of cellular uptake and intracellular translocation of alpha-tocopherol role of tocopherol-binding proteins. Food. Chem. Toxicol. 

Inhibition by a-tocopherol of protein kinase C has been reviewed in Azzi et al. (1992, 1995, 1996) and Newton (1995). Such an inhibition is not caused by a direct binding of a-tocopherol to the enzyme but by preventing its activation via phosphorylation (Tasinato et al. 1995). a-Tocopherol exerts its action independently of its free-radical scavenging capacity and most probably by interacting with a yet not characterised receptor molecule in smooth muscle cells (Boscoboinik et al. 1991, 1994, 1995). a-Tocopherol prevents uniquely protein kinase C-o phosphorylation and its functional activation. 

There are two mechanisms for tissue uptake of vitamin E. Lipoprotein lipase releases the vitamin by hydrolysing the triacylglycerols in chylomicrons and VLDL, while separately there is uptake of LDL-bound vitamin E by means of LDL receptors. Retention within tissues depends on binding proteins, and it is likely that the differences in biological activity of the vitamers are due to differential protein binding. y-Tocopherol and a-tocotrienol bind relatively poorly, whereas 5 i i -a-tocopherol and RRR-a-tocopherol acetate do not bind to liver tocopherol-binding protein to any significant extent. 

Kuhlenkamp, 1, Ronk, M, Yusin, M, Stolz, A and Kaplowitz, N (1993) Identification and purification of a human liver cytosolic tocopherol binding protein. Prot. Express. Purific.,... 

For example, in a recent computational study on the mechanisms of membrane recognition and binding by a-Tocopherol Transfer Protein (ot-TTP), simulations with the MARTINI force field were well able to capture the primary mechanism of a-TTP recruiting at the plasma membrane by phosphoinositides through contact formation with an evolutionarily well conserved basic patch at the protein surface. On the contrary, CG simulations were not capable of determining the interaction pattern between the membrane and the sequence-variable N-terminal domain, which is known to be crucial for biological discrimination and targeting of different cellular compartments by different members of this protein family. It was instead possible to describe such interactions by atomistic models of the same system. ... 

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