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<b>General Background</b> The tocopherols (|FRAME: ALPHA-TOCOPHEROL|, |FRAME: BETA-TOCOPHEROL|, |FRAME: GAMA-TOCOPHEROL| and |FRAME: DELTA-TOCOPHEROL|) and their corresponding tocotrienols are synthesized by plants and have vitamin E antixoidant activity (see MetaCyc pathway |FRAME: PWY-1422|). They differ in the number and location of methyl groups on the chromanol ring. The naturally occurring form of |FRAME: ALPHA-TOCOPHEROL| is (2<i>R</i>,4'<i>R</i>,8'<i>R</i>)-α-tocopherol (synonym (<i>R,R,R</i>)-α-tocopherol). Synthetic α-tocopherols are a racemic mixture of eight different <i>R</i> and <i>S</i> stereoisomers. Only the 2<i>R</i> forms are recognized as meeting human requirements. Reviewed in |CITS: [17628169]|. The <i>in vivo</i> function of vitamin E is to scavenge peroxyl radicals via its phenolic (chromanol) hydroxyl group, thus protecting lipids against free radical-catalyzed peroxidation. The tocopheryl radical formed can then be reduced by reductants such as |FRAME: ASCORBATE| (see pathway |FRAME: PWY-6370|). Other major products of |FRAME: ALPHA-TOCOPHEROL| oxidation include α-tocopherylquinone and epoxy-α-tocopherols. The metabolites α-tocopheronic acid and its lactone, known as the Simon metabolites, are generally believed to be artefacts. In addition to these oxidation products, the other major class of tocopherol metabolites is the carboxyethyl-hydroxychromans (this pathway). These metabolites are produced in significant amounts in response to excess vitamin E ingestion. Reviewed in |CITS: [17628169] [17306359]| and |CITS: [17561088]|. Vitamin E is fat-soluble and its utilization requires intestinal fat absorption mechanisms. It is secreted from the intestine into the lymphatic system in chylomicrons which subsequently enter the plasma. Lipolysis of these chylomicrons can result in delivery of vitamin E to tissues, transfer to high-density lipoproteins (and subsequently to other lipoproteins via the phospholipid exchange protein), or retention in chylomicron remnants. These remnants are taken up by the liver. Natural (<i>R,R,R</i>)-α-tocopherol and synthetic 2<i>R</i>-α-tocopherols are then preferentially secreted from the liver into plasma as a result of the specificity of the α-tocopherol transfer protein. This protein, along with the metabolism of excess vitamin E in the liver and excretion into urine and bile, mediate the supply of |FRAME: ALPHA-TOCOPHEROL| in plasma and tissues. Reviewed in |CITS: [17628169]| and |CITS: [17439363]|. <b>About This Pathway</b> In the pathway shown here, the triple arrows represent a series of proposed reactions of |FRAME: ALPHA-TOCOPHEROL| and |FRAME: GAMA-TOCOPHEROL| metabolism. The compounds shown here, |FRAME: ALPHA-TOCOPHEROL|, |FRAME: CPD-11960|, |FRAME: CPD-11961| and |FRAME: CPD-11962|, have been identified <i>in vivo</i>, although most of the proposed intermediates have only been identified <i>in vitro</i> using cultured cell lines, with results varying as to cell line studied |CITS: [11997390] [15671218] [19819327]|, in |CITS: [15753130]| and reviewed in |CITS: [17628169] [17306359]|. The proposed reactions include: dehydrogenation of |FRAME: CPD-11960| to a carboxylate (13'-carboxy-α-tocopherol) by an unidentified microsomal enzyme(s) probably via an aldehyde intermediate (in |CITS: [19819327]| and in |CITS: [15753130]|); conversion of the carboxylate to an acyl-CoA ester; four cycles of β-oxidation resulting in side chain shortening, producing |FRAME: CPD-11961| |CITS: [19819327]|; and an additional cycle of |FRAME: CPD-11961| β-oxidation, producing |FRAME: CPD-11962| (see pathway |FRAME: FAO-PWY|). More recently, <i>in vivo</i> studies of intracellular compartmentalization in this pathway suggest that the initial β-oxidation steps in |FRAME: ALPHA-TOCOPHEROL| degradation are localized in peroxisomes, while the final steps are localized in mitochondria |CITS: [19819327]|. In the pathway shown here, evidence suggests that the ω hydroxylation of |FRAME: ALPHA-TOCOPHEROL| is likely catalyzed by the products of genes CYP3A4 |CITS: [11061988]| or |FRAME: G-11650| |CITS: [17284776]|. This alcohol must then be dehydrogenated to a carboxylate, probably via an aldehyde intermediate, by enzymes found in the cytoplasm and endoplasmic reticulum. Based on analogy with the intracellular trafficking and degradation of a 2-methyl-branched fatty acids such as |FRAME: PRISTANATE|, the carboxylate would then be activated to an acyl-CoA ester and undergo β-oxidation. The two initial cycles of β-oxidation would occur in peroxisomes, which contain enzymes highly active toward medium and long chain branched chain acyl-CoA substrates. The final three cycles of β-oxidation would occur in mitochondria. However, exclusively mitochondrial β-oxidation was not ruled out |CITS: [19819327]|. Reviewed in |CITS: [17628169]| and |CITS: [17439363]|. Most of the |FRAME: CPD-11962| metabolites produced undergo conjugation before excretion in urine or bile, by unknown excretion mechanisms. Conjugation occurs via sulfation by as yet unidentified sulfotransferases, or by glucuronidation by as yet unidentified UDP-glucuronosyltransferases (not shown). In addition, |FRAME: ALPHA-TOCOPHEROL| and |FRAME: GAMA-TOCOPHEROL| can be directly excreted into bile. The metabolite |FRAME: CPD-11962| itself has been shown to promote natriuresis (urinary sodium excretion) and has anti-proliferative and anti-inflammatory activities. Reviewed in |CITS: [17628169]| and |CITS: [17306359]|.
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α-tocopherol degradation
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| biopax3:name |
vitamin E degradation
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| biopax3:standardName |
α-tocopherol degradation
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