Vitamin K is a generic name for a group of fat-soluble compounds called vitamin K1 (or phylloquinone) and vitamin K2 (menaquinones, Figure #), which both can act as cofactor for γ-glutamyl carboxylase. All K-vitamers have a 2-methyl-1,4-naphthoquinone ring structure in common but differ in the length and degree of saturation of an aliphatic side chain at the 3-position. Vitamin K2 is a group name for structurally related compounds, containing a side chain built of repeating unsaturated 5-carbon (prenyl) units; these isomers are designated menaquinone-n (MK-n) according to the number (n) of prenyl units. For example: menaquinone-4 (MK-4) consists of a naphthoquinone ring structure with a side chain of 4 prenyl units at the 3-position (Figure #). The hydrophobicity of menaquinones increases proportionally with increasing side chain length. A third form of vitamin K, menadione (K3), is a synthetic product. It is the 2-methyl-1,4-naphthoquinone ring structure without a side chain.

Phylloquinone is mainly found in green leafy vegetables like spinach, kale, sprouts and broccoli [11, 13]. These green leafy vegetables contain approximately 1000-8000 µg phylloquinone per kg. Other minor sources of phylloquinone are fruit, dairy produce and grains. Menaquinones are synthesised by a selected number of bacteria and mostly occur in fermented foods like cheeses and other dairy produces [198]. A large pool of menaquinones is synthesised by the intestinal microflora: MK-10 and 11 by bacteroides, MK-8 by enterobacteria, MK-7 by veillonella species, and MK-6 by Eubacterium lentum. Very high concentrations of MK-7 (ranging from 9 to 12 mg/kg) are found in fermented soy beans (natto) [198]. MK-4 is not produced by the intestinal microflora, but relatively high concentrations of it are found in egg yolk, dairy and meats [198]. Besides these dairy sources, MK-4 is also synthesised by the conversion of menadione into MK-4 by a number of tissues and by the conversion of vitamin K1 into MK-4 [188].

The degree to which vitamin K is absorbed in the intestine depends on the side chain, the composition of the food matrix and on the efficiency of liberation from the food matrix. Compared to MK-4 through MK-7, the menaquinones with longer side chains (i.e. MK-8 to MK-13) are not efficiently absorbed [2, 199]. Fat-solubilised vitamin K in for example a meal of spinach with butter has a higher absorption rate than vitamin K from spinach alone [69, 235]. 

Vitamin K is taken up in the digestive tract by the absorptive enterocytes of the small-intestine and packed with cholesterol, lipids, and lipoproteins into chylomicrons. After exocytosis these chylomicrons enter the blood circulation via the lymphatic system and are rapidly degraded into chylomicron remnants. In this way, most of the absorbed vitamin K1 is delivered to the liver by chylomicron remnants which are cleared from the circulation via apolipoprotein E (ApoE) receptor mediated uptake [126, 205]. The clearance rate is dependent on the ApoE genotype. Three regularly encountered ApoE genotypes are E2, E3, and E4, which promote chylomicron remnant clearance in the order E2 < E3 < E4 [255]. As a result, subjects with an ApoE2/2 or ApoE2/3 genotype tend to have higher plasma vitamin K1 concentrations compared to those with the genotypes ApoE3/3, ApoE3/4, or ApoE4/4 [107]. Very little is known about the vitamin K transport to and uptake by extra-hepatic tissues like the arterial vessel wall and bone. It has been shown that vitamin K1 is predominantly carried by the triacylglycerol-rich lipoprotein fraction (TGRLP) [114] and that cultured osteoblasts can internalise vitamin K1 from LDL, chylomicron remnants, VLDL, and HDL by an ApoE-dependent mechanism [146]. In contrast, besides the TGRLP fraction MK-4 is also carried by the LDL and HDL fraction [200]. Another source for extra-hepatic MK-4 is provided by the conversion of vitamin K1 into MK-4 [227]. 

Not the form in which it occurs in food (vitamin K-quinone), but the reduced form vitamin K hydroquinone (KH2) is the active cofactor used by the enzyme γ-glutamyl carboxylase. KH2 is converted into vitamin K epoxide (KO), and KO is subsequently reduced into vitamin K and vitamin KH2 in two reactions by the action of one or more dithiol dependent vitamin K epoxide reductases (VKOR, Figure 3.2) [223]. This recycling mechanism is called the vitamin K-cycle and explains why the daily requirement for vitamin K is low and why vitamin K deficiency is rarely seen in healthy subjects [150, 226]. Besides in the dithiol-dependent pathway, vitamin K (and not KO) may also be reduced by DT-diaphorase, an NAD(P)H-dependent dehydrogenase. Although the DT-diaphorase is highly expressed in the liver, the dithiol-dependent pathway is the most active one for KH2 generation [249].

Cofactor activities of K1 and MK-4 in in vitro carboxylase studies are comparable as indicated by almost equal concentrations for half-maximal reaction velocity in specific assays for carboxylase and VKOR [26]. For the in vivo biological activity vitamin K-deficient rats were used to test the potency of various forms of vitamin K to counteract hypoprothrombinaemia. Two studies suggested respectively a 2-5 [73] and a 8 fold higher activity of K1 [131]. In other words, vitamin K1 has a higher biological γ -glutamyl carboxylase cofactor activity in the liver than has MK-4. Since both vitamins have comparable in vitro cofactor activity, differences in biological activity may be explained by different tissue distribution. Supportive for this theory is the observed 10-fold higher hepatic accumulation of K1 than of MK-4 whereas MK-4 was preferentially taken up by a number of extra-hepatic tissues [189].