Molecular mechanisms of vitamin E transport.
Vitamin E is the most important lipid-soluble antioxidant in humans. Specific tocopherol-binding proteins favor the retention of the most potent vitamin E homologue, RRR-alpha-tocopherol (RRR-alpha-T) in man. The crystal structures of both the ligand-charged and the apo-forms of human alpha-tocopherol transfer protein (alpha-TTP) and of human supernatant protein factor (SPF) have been solved. The renewed interest in the biological function of tocopherol binders is based on the discovery of ataxia with vitamin E deficiency, a neurological disorder that is caused by genetic defects of the alpha-TTP gene and/or vitamin E deficiency. The analysis of the crystal structure of alpha-TTP provides the molecular basis of vitamin E retention in man. SPF has been reported to enhance cholesterol biosynthesis by facilitating the conversion of squalene to lanosterol. Nevertheless, the physiological role of SPF as well as its ligand specificity is not known. Investigations on the substrate specificity of SPF have uncovered binding of RRR-alpha-tocopherylquinone (RRR-alpha-TQ). RRR-alpha-TQ represents the major physiological oxidation product of RRR-alpha-T. The three-dimensional overlay of the ligand-charged structures of SPF and alpha-TTP indicates that ligand specificity in both proteins is mostly modulated by side-chain variations rather than by the backbone. Recent reports point towards the in vivo reduction of RRR-alpha-TQ to RRR-alpha-TQH(2) and its protective role in low-density lipoprotein oxidation. On the basis of these reports, it is proposed that SPF may enhance cholesterol biosynthesis indirectly by mediating the transfer of RRR-alpha-TQ to low-density lipoprotein, thus reducing oxidation of low-density lipoprotein and its subsequent cellular uptake by scavenger receptors.
Stocker
Achim
A
Institute of Microbiology, Swiss Federal Institute of Technology Zürich, Schmelzbergstr. 7, 8092 Zürich, Switzerland. achim.stocker@micro.biol.ethz.ch
D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D002352:Carrier Proteins / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption; D008074:Lipoproteins / Q000502:physiology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D024505:Tocopherols / Q000737:chemistry; D024508:Tocotrienols / Q000737:chemistry; D015534:Trans-Activators / Q000502:physiology; D014810:Vitamin E / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
D002352:Carrier Proteins; D008074:Lipoproteins; C432422:SEC14L2 protein, human; D024508:Tocotrienols; D015534:Trans-Activators; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D024505:Tocopherols