Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042875 (vitamin E deficiency)
 916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Molecular mechanisms of vitamin E transport. 1575 33

Human alpha-tocopherol transfer protein (alpha-TTP) plays a central role in vitamin E homeostasis: mutations in the protein are a cause of a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED). Despite normal dietary intake of vitamin E, affected individuals suffer from a relative deficiency of this essential lipophilic antioxidant. Disease-associated mutations in alpha-TTP impair its ability to prevent the degradation and excretion of alpha-T. Recently, we and others solved the crystal structures of alpha-TTP bound to a molecule of (2R, 4'R, 8'R)-alpha-T, which has led to a better understanding of the molecular basis of its biochemical activity. Surprisingly, the ligand was found buried in the hydrophobic core of the protein, completely sequestered from the aqueous milieu. In this chapter, the implications of the structure of alpha-TTP bound to its ligand regarding the mechanism of alpha-T retention are discussed. A comparison to a crystal structure of the apo form of alpha-TTP indicates a possible specific conformational change that allows the entry and exit of the ligand. The effect of known disease-associated point mutations is examined in light of the crystal structure as well as recent biochemical studies. Despite the knowledge gained from these studies, the exact molecular mechanism by which alpha-TTP retains alpha-T remains enigmatic and will likely prove a fruitful area for future research.
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PMID:Structure and function of alpha-tocopherol transfer protein: implications for vitamin E metabolism and AVED. 1762 70