Vitamin K is the fat-soluble vitamin that is the essential cofactor for the gamma-glutamyl carboxylase (GGCX) enzyme — the enzyme that catalyses the gamma-carboxylation of the glutamate (Glu) residues in the target proteins to the gamma-carboxyglutamate (Gla) residues. The gamma-carboxylation of the glutamate residues is a post-translational modification that is essential for the function of the vitamin K-dependent proteins — the gamma-carboxyglutamate residues are the calcium-binding sites of these proteins, and they enable the proteins to bind the calcium and to attach to the phospholipid membranes in the presence of the calcium. The vitamin K-dependent proteins include the clotting factors (factor II/prothrombin, factor VII, factor IX, factor X, and the proteins C and S — which are synthesised in the liver and which are essential for the blood coagulation), the osteocalcin (which is synthesised by the osteoblasts and which is essential for the bone mineralisation and for the incorporation of the calcium into the bone matrix), and the matrix Gla protein (MGP, which is synthesised by the vascular smooth muscle cells and which is the most potent inhibitor of the vascular calcification that has been identified). Without adequate vitamin K and functional GGCX, the gamma-carboxylation of these proteins is impaired, the clotting factors are not fully functional (producing the bleeding diathesis), the osteocalcin cannot bind the calcium (producing the impaired bone mineralisation), and the MGP cannot inhibit the vascular calcification (producing the accelerated atherosclerosis and the cardiovascular disease) — the hallmark of the vitamin K deficiency. The typical dietary vitamin K intake is 100-300mcg daily (from the leafy green vegetables, the vegetable oils, and the fermented foods), and the estimated adequate intake is 120mcg daily for men and 90mcg daily for women — but the vitamin K deficiency is more common than generally recognised, particularly in people with the malabsorption, with the liver disease, with the long-term antibiotic therapy (which kills the vitamin K-producing gut bacteria), and in newborns (who have a sterile gut and who are unable to synthesise the vitamin K-dependent clotting factors until the gut flora is established).
Gamma-Glutamyl Carboxylase and the Clotting Factors
The gamma-glutamyl carboxylase (GGCX) is the enzyme that catalyses the gamma-carboxylation of the glutamate residues in the clotting factors and in the other vitamin K-dependent proteins. It requires the reduced form of vitamin K (vitamin K hydroquinone) as a cofactor, and it uses the energy of the vitamin K oxidation (to the vitamin K epoxide) to drive the carboxylation reaction. The vitamin K epoxide is then recycled back to the vitamin K hydroquinone by the vitamin K epoxide reductase (VKOR) — and this vitamin K cycle is the target of the warfarin anticoagulant drugs, which inhibit the VKOR and thereby prevent the recycling of the vitamin K and the gamma-carboxylation of the clotting factors. Without adequate functional vitamin K cycle, the clotting factors (particularly factor II/prothrombin, factor VII, factor IX, and factor X) are secreted in the under-carboxylated (PIVKA — Proteins Induced By the Absence of Vitamin K) form, which is not fully functional as a cofactor for the coagulation cascade — producing the bleeding diathesis, the prolonged prothrombin time (PT), and the international normalised ratio (INR) that are the hallmark of the vitamin K deficiency and of the warfarin therapy.
The clinical importance of the vitamin K for the coagulation is underscored by the observation that the vitamin K supplementation reverses the bleeding diathesis in people with the vitamin K deficiency and in people taking the warfarin anticoagulant therapy. The vitamin K1 (phylloquinone) is used to reverse the warfarin anticoagulation (typically at a dose of 2.5-10mg orally, depending on the INR and the clinical urgency), and the vitamin K1 injection is used to treat the haemorrhagic disease of the newborn (at a dose of 0.5-1mg IM, which is given routinely to all newborns in the first 24 hours after birth as a prophylactic measure against the VKDB — vitamin K deficiency bleeding).
Vitamin K and the Bone Health
The vitamin K is also essential for the bone health — it is required for the gamma-carboxylation of the osteocalcin, which is the most abundant non-collagenous protein in the bone and which is essential for the bone mineralisation and for the incorporation of the calcium into the hydroxyapatite crystals of the bone matrix. The osteocalcin is synthesised by the osteoblasts, and it is secreted into the bone matrix in the under-carboxylated form (because the osteoblasts produce the osteocalcin and release it into the bone matrix before it is fully carboxylated). In the bone matrix, the osteocalcin binds the calcium and the hydroxyapatite, and it thereby contributes to the structural integrity of the bone and to the regulation of the bone mineralisation. Without adequate vitamin K and functional osteocalcin, the bone mineralisation is impaired, the bone density is reduced, and the fracture risk is increased — particularly in the postmenopausal women, who are already at increased risk of osteoporosis due to the oestrogen deficiency. Multiple RCTs have demonstrated that the vitamin K supplementation (at 100-500mcg daily of vitamin K2/menaquinone) reduces the fracture risk and improves the bone mineral density in postmenopausal women with the osteoporosis — making the vitamin K one of the most important nutritional interventions for the prevention of the osteoporosis and of the fragility fractures.
Practical Application
For general vitamin K supplementation for the bone health and for the cardiovascular health, the evidence-based approach is to supplement with 100-500mcg of vitamin K2 (menaquinone-4 or menaquinone-7, the more bioavailable and more potent forms of vitamin K) daily, in addition to the dietary vitamin K1 (phylloquinone) from the leafy green vegetables. The vitamin K1 is adequate for the coagulation function, but the vitamin K2 (particularly the MK-7 form) is preferred for the bone health and for the cardiovascular health because it has a longer half-life and because it is more effective at carboxylating the osteocalcin and the MGP. The vitamin K2 is generally well-tolerated with no significant adverse effects, but it should be used with caution in people who are taking the warfarin anticoagulant (because the vitamin K2 can interfere with the warfarin therapy by antagonising its anticoagulant effect). For comprehensive bone and cardiovascular support, vitamin K pairs well with the vitamin D (which promotes the intestinal calcium absorption and which is required for the synthesis of the osteocalcin and of the MGP — the vitamins K and D work synergistically for the bone health and for the cardiovascular health), with the calcium (which is the primary mineral component of the bone), with the magnesium (which is a cofactor for many of the enzymes of the bone matrix synthesis), and with the strontium (which has complementary effects on the bone formation and on the bone resorption).
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