Interaction of a-Tocopherol and Proteins

Vitamin E is actually a family of differentially methylated tocols and tocotrienols, the most biologically active of which is a-tocopherol. a-Tocopherol is now accepted as the premier lipid soluble antioxidant. The absorption of vitamin E into tissues after ingestion largely parallels that of other lipids. A number of different lipoproteins serve as carriers of bulk lipids through the blood stream and the lymph. Eventually these aggregates reach the liver where phospholipids, triglycerides and fatty acids are 'repackaged' into new structures for transport back to specific tissues in the body. Tocopherol is secreted by the liver into the bloodstream in VLDL and LDL particles.
 
 

a-Tocopherol Transfer Protein (a-TTP)

a-Tocopherol contains three stereogenic centres and thus exists as a mixture of eight stereoisomers in the all-racemic form that is provided in most commercially available vitamin preparations. Recent work at the National Research Council of Canada using differentially deuterated optical isomers of a-tocopherol has shown that the natural isomer (D or R,R,R) disappears more quickly from the liver after dosing than the enantiomer (L or S,S,S). This implies that these two stereoisomers of a-tocopherol are discriminated from each other and suggests that there is an interaction with another chiral entity, likely a macromolecule. Indeed, researchers have now identified a 32 kDa protein in mammalian livers (including human, rat, bovine, and mouse) that acts as a binding or a-tocopherol transfer protein ( a-TTP). Recently, another "tocopherol associated protein" (TAP) has been discovered.

There are now several a-TTP sequences available. The links below are to the NCBI databases where both the protein and nucleotide sequences can be retrieved:

 

This protein was identified only as "hypothetical protein" in both submissions made to NCBI by the Sanger Sequencing Centre, UK (Collins and Huckle) and Genome Sequencing Center, Washington University, St. Louis (Sulston & Waterston). The real protein was later identified by Swiss scientists as being capabable of binding tocopherol and is reported in their article:

Achim Stocker, Sabine Zimmer, Stefan E. Spycher, and Angelo Azzi. Identification of a Novel Cytosolic Tocopherol-Binding Protein: Structure, Specificity, and Tissue Distribution
IUBMB Life(48)1, 1999

a-TTP shows homology to several other proteins and enzymes

Alignment of human TTP, CRAL, TAP, PTP-MEG2, and SEC14p

A number of SEC14 gene products (phosphatidylinositol - phosphatidylcholine transfer proteins) are also homologous

One crystal structure is available from the SEC14 series:

You will need the biomolecular viewer RasMol to view this file. You can get it and other helpful hints from Eric Martz's excellent page devoted to this viewing and teaching tool. As always, maythanks to Roger Sayles who gave us this program. Go to RasMol Homepage

a-Tocopherol Inhibition of Protein Kinase C

Swiss workers have published accounts of their work investigating the inhibition of smooth muscle cell proliferation by a-tocopherol and have discussed their results in terms of their initial observation that a-tocopherol inhibits protein kinase C (PKC). It has not been shown unequivocally whether a-tocopherol binds to PKC or not, although it is conceivable that it may shift the equilibrium betwween the soluble and memrbane bound forms of the enzyme. No correlation appears to exist between the antioxidant activity of various tocopherol analogues and their ability to inhibit PKC. PKC is an important component of the secondary messenger system and has been linked to several pathological conditions that encompass gene regulation, cell differentiation and cancer.

More info on Protein Kinases

Phospholiopase A2

It has been demonstrated that a-tocopherol inhibits phospholipase A2 activity in platelets as well as in rat cardiac tissue, and thus has a role in modulating the arachidonic acid cascade. This is understood to occur wihtout recourse to tocopherol's antioxidant activity. While a-tocopherol attenuates the activity of phospholipase A2 and thus the release of arachidonate from platelets, it appears to stimulate this enzyme's activity in cultured endothelial cells stimulating prostacyclin synthesis. There is currently no explanation for the differing modulation of phospholipase A2 activities seen in these experiments.

CoA-Independent Acyltransferase

Investigations of phospholipid metabolism in endothelial cells has provided further details of tocopherol's modifying effects on enzyme activity. Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine; alkylacetyl-GPC) is synthesized from 1-O-alkyl-2-arachidonyl-GPC by the phospholipase A2 mediated release of archidonate to give alkyl-GPC, followed by acetylation at the 2-position by an acetyltransferase. Experiments performed with cultured endothelial cells showed that a CoA-independent acyltransferase is capable of reacylating alkyl-GPC. This is important insofar as it limits the accumulation of lysophospholipids such as alkyl-GPC which are cytotoxic at high concentrations. This activity was enhanced by a-tocopherol in a dose dependent manner at concentrations below 23 mM.

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