Harpers

VITAMINS & MINERALS / 487Free radicalchain reactionPUFAOO PUFA OOHROR2TocOHTocOPHOSPHOLIPASEA 2MEMBRANESCYTOSOLPUFA H(in phospholipid)Vitamin C ox ,GS SGVitamin C red ,GSHPUFA OOH,H 2 O 2GSHSUPEROXIDEDISMUTASECATALASESeGLUTATHIONEPEROXIDASE–O 2SuperoxideH 2 O,PUFA OHFigure 45–6. Interaction and synergism between antioxidant systems operating in the lipidphase (membranes) of the cell and the aqueous phase (cytosol). (R•, free radical; PUFA-OO•, peroxylfree radical of polyunsaturated fatty acid in membrane phospholipid; PUFA-OOH, hydroperoxypolyunsaturated fatty acid in membrane phospholipid released as hydroperoxy free fatty acid intocytosol by the action of phospholipase A 2 ; PUFA-OH, hydroxy polyunsaturated fatty acid; TocOH,vitamin E (α-tocopherol); TocO•, free radical of α-tocopherol; Se, selenium; GSH, reduced glutathione;GS-SG, oxidized glutathione, which is returned to the reduced state after reaction withNADPH catalyzed by glutathione reductase; PUFA-H, polyunsaturated fatty acid.)GSSGVitamin K Is the Coenzymefor Carboxylation of Glutamatein the Postsynthetic Modificationof Calcium-Binding ProteinsVitamin K is the cofactor for the carboxylation of glutamateresidues in the post-synthetic modification of proteinsto form the unusual amino acid γ-carboxyglutamate(Gla), which chelates the calcium ion. Initially,vitamin K hydroquinone is oxidized to the epoxide(Figure 45–8), which activates a glutamate residue inthe protein substrate to a carbanion, that reacts nonenzymicallywith carbon dioxide to form γ-carboxyglutamate.Vitamin K epoxide is reduced to the quinone bya warfarin-sensitive reductase, and the quinone is reducedto the active hydroquinone by either the samewarfarin-sensitive reductase or a warfarin-insensitivequinone reductase. In the presence of warfarin, vitaminK epoxide cannot be reduced but accumulates, and isexcreted. If enough vitamin K (a quinone) is providedin the diet, it can be reduced to the active hydroquinoneby the warfarin-insensitive enzyme, and carboxylationcan continue, with stoichiometric utilizationof vitamin K and excretion of the epoxide. A high doseof vitamin K is the antidote to an overdose of warfarin.Prothrombin and several other proteins of the bloodclotting system (Factors VII, IX and X, and proteins Cand S) each contain between four and six γ-carboxyglutamateresidues which chelate calcium ions and so permitthe binding of the blood clotting proteins to membranes.In vitamin K deficiency or in the presence of warfarin, anabnormal precursor of prothrombin (preprothrombin)containing little or no γ-carboxyglutamate, and incapableof chelating calcium, is released into the circulation.