Vitamin K cycle

Anticoagulants. Figure 2 Coumarin (Warfarin) and the vitamin K cycle. Abbreviations glu, glutamate gla, y-carboxyglutamate. (Modified from [2], with permission from Chest.)... 

Vitamin K carboxylase is a transmembraneous protein in the lipid bilayer of the endoplasmatic reticulum (ER). It is highly glycosilated and its C-terminal is on the luminal side of the membrane. Besides its function as carboxylase it takes part as an epoxidase in the vitamin K cycle (Fig. 1). For the binding of the y-carboxylase the vitamin K-dependent proteins have highly conserved special recognition sites. Most vitamin K-dependent proteins are carboxy-lated in the liver and in osteoblasts, but also other tissues might be involved, e.g., muscles. 

Vitamin K. Figure 1 The vitamin K cycle, w indicates where warfarin or other vitamin K antagonist inhibit the cycle. 

In the case of prothrombin and related clotting factors, interruption of the vitamin K cycle leads to the production of nonfunctional, undercarboxylated proteins, which are duly exported from hepatocytes into blood (Thijssen 1995). They are nonfunctional because there is a requirement for the additional carboxyl residues in the clotting process. Ionized carboxyl groups can establish links with negatively charged sites on neighboring phospholipid molecules of cell surfaces via calcium bridges. 

FIGURE 11.3 Action of warfarin and related rodenticides on the vitamin K cycle. 

T. M. Guenthner, D. Cai, R. Wallin, Co-Purification of Microsomal Epoxide Hydrolase with the Warfarin-Sensitive Vitamin Kx Oxide Reductase of the Vitamin K Cycle , Biochem. Pharmacol. 1998, 55, 169 - 175. 

Vitamin K cycle—metabolic interconversions of vitamin K associated with the synthesis of vitamin K-dependent clotting factors. Vitamin K1 or K2 is activated by reduction to the hydroquinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is coupled to prothrombin carboxylation by the enzyme carboxylase. The reactivation of vitamin K epoxide is the warfarin-sensitive step (warfarin). The R on the vitamin K molecule represents a 20-carbon phytyl side chain in vitamin Ki and a 30- to 65-carbon polyprenyl side chain in vitamin K2. 

FIGURE 9p25 Vitamin K cycle. The cufactor probably ncmalnf a. sociated with the mem-branes of the endoplasmic reticulum during the reactions depicted in the figure. 

Vitamirt E deficiency, 628,631-634 selenium deficiency and, S3S-839 Vitamin K, 492,493, 524-525 anbcoaguiation cascade, 535-536 aascaement of status, 538-539 blood cloning cascade and, 524,527-534 chemical stnicture, 525 teseanch, 526-528 vitamin K cycle, 526 warfarin and, 526-527, 536 Vltamir K cycle, 526 Vitamin K doficiertcy, 525,537... 

Within metabohcally active and vitamin K using tissue, especially liver, a microsomal vitamin K cycle exists (Figure 30-7). The vitamin (quinone) is normafty reduced by a thiol-sensitive flavoprotein system to the hydroquinone, which then can couple to the oxygen- and carbon dioxideusing y-carboxyiation of glutamyl residues in specific pro-... 

FIGURE 4.2 The vitamin K cycle as it functions in protein glutamyl carboxylation reaction. The conversion of protein-bound glutamic acid into Y-carboxyglutamic acid is catalysed by a carboxylase. During the carboxylation reaction vitamin K hydroquinone (KH2) is converted to vitamin K epoxide (KO). X—(SH)2 and X—S2 represent, respectively, the reduced and oxidised forms of thioredoxin. The NADH-dependent and dithiol-dependent vitamin K reductases are different enzymes. Both the dithiol-dependent K- and KO-reductases are inhibited by dicoumarol (1) and warfarin (11). 

FIGURE 54-6 The vitamin K cycle y-glutamyl carboxy lotion of vitamin K-dependentpr( eins. The enzyme -glutamyl carboxylase couples the oxidation of the reduced hydroquinone form (KH2) of vitamin Kj or K2, to -carboxylation of Glu residues on vitamin K-dependent proteins, generating the epoxide of vitamin K (KO) and 7-carboxyglutamate (Gla) residues in vitamin K-dependent precursor proteins in the endoplasmic reticulum. A 2,3-epoxide reductase regenerates vitamin KH2 and is the warfarin-sensitive step. The R on tiie vitamin K molecule represents a 20-carbon phytyl side chain in vitamin and a 5- to 65-carbon prenyl side chain in vitamin K2. 

Another idea is that the toxic metabolite of paracetamol inhibits the enzymes in the vitamin K cycle, and so has additive effects with anticoagulants, but so far this mechanism has only been investigated in vitro Yet another idea is that it is the indications for paracetamol use such as pain or fever that cause the interaction, rather than paracetamol per se, but this does not explain why an interaction has been found in otherwise healthy patients or subjects given paracetamol in controlled studies. 

Thijssen HH, Soute BA, Vervoort LM, Claessens JG. Paracetamol (acetaminq>hen) warfarin interaction NAPQl, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle. Thromb Haemost (2004) 92, 797-802. 

LMT Vervoort, JE Ronden, HHW Thijssen. The potent antioxidant activity of the vitamin K cycle in microsomal lipid peroxidation. Biochem Pharmacol 54(8) 871-876, 1997. 

The symptom of vitamin K deficiency is increased risk of haemorrhage, ease of bruising, nose bleeding and blood in the urine. In infants, vitamin K deficiency may result in intracranial bleeding. Vitamin K deficiency is rare in adults although vitamin K status is assessed in the newborn and in the USA a routine injection of vitamin K is recommended for newborn babies, particularly premature babies where the vitamin K cycle may not be fidly established. Human breast milk is relatively low in vitamin K. There has been some controversy over whether or not childhood leukaemia can be linked to injection of newborns with vitamin K, but a large retrospective study fotmd no link. Certain dmgs such as warfarin, sulphona-mides and cephalosporins can affect vitamin K function. 

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