Vitamin K2


Vitamin K2 or menaquinone is one of three types of vitamin K, the other two being vitamin K1 and K3. K2 is both a tissue and bacterial product and is usually found in animal products or fermented foods.
There are nine chemical variants of vitamin K2, determined by number of isoprenyl units in their side chains. The most common in the human diet is the short-chain, water-soluble menatetrenone, which is usually produced by tissue and/or bacterial conversion of vitamin K1, and is commonly found in animal products. It is known that production of MK-4 from dietary plant vitamin K1 can be accomplished by animal tissues alone, as it proceeds in germ-free rodents.
Long-chain menaquinones include MK-7, MK-8 and MK-9 and are more predominant in fermented foods such as natto. Longer-chain menaquinones are produced by anaerobic bacteria in the colon, but they are not well absorbed at this level and have little physiological impact.
When there are no isoprenyl side chain units, the remaining molecule is vitamin K3. This can only be manufactured synthetically, and is used in animal feed. It was formerly given to premature infants, but due to inadvertent toxicity in the form of hemolytic anemia and jaundice, it is no longer used for this purpose.

Description

Vitamin K2, the main storage form in animals, has several subtypes, which differ in isoprenoid chain length. These vitamin K2 homologues are called menaquinones, and are characterized by the number of isoprenoid residues in their side chains. Menaquinones are abbreviated MK-n, where M stands for menaquinone, the K stands for vitamin K, and the n represents the number of isoprenoid side chain residues. For example, menaquinone-4 has four isoprene residues in its side chain. Menaquinone-4 is the most common type of vitamin K2 in animal products since MK-4 is normally synthesized from vitamin K1 in certain animal tissues by replacement of the phytyl tail with an unsaturated geranylgeranyl tail containing four isoprene units, thus yielding menaquinone-4 which is Water Soluble in nature. This homolog of vitamin K2 may have enzyme functions distinct from those of vitamin K1.
MK-7 and other long-chain menaquinones are different from MK-4 in that they are not produced by human tissue. MK-7 may be converted from phylloquinone in the colon by Escherichia coli bacteria. However, these menaquinones synthesized by bacteria in the gut appear to contribute minimally to overall vitamin K status. MK-4 and MK-7 are both found in the United States in dietary supplements for bone health.
The U.S. Food and Drug Administration has not approved any form of vitamin K for the prevention or treatment of osteoporosis. MK-4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.
All K vitamins are similar in structure: they share a "quinone" ring, but differ in the length and degree of saturation of the carbon tail and the number of repeating isoprene units in the "side chain". The number of repeating units is indicated in the name of the particular menaquinone. The chain length influences lipid solubility and thus transport to different target tissues.

Mechanism of action

The mechanism of action of vitamin K2 is similar to vitamin K1. K vitamins were first recognized as a factor required for coagulation, but the functions performed by this vitamin group were revealed to be much more complex. K vitamins play an essential role as cofactor for the enzyme γ-glutamyl carboxylase, which is involved in vitamin K-dependent carboxylation of the gla domain in "Gla proteins" to γ-carboxy glutamic acid.
Carboxylation of these vitamin K-dependent Gla-proteins, besides being essential for the function of the protein, is also an important vitamin recovery mechanism since it serves as a recycling pathway to recover vitamin K from its epoxide metabolite for reuse in carboxylation.
Several human Gla-containing proteins synthesized in several different types of tissues have been discovered:
MK-4 or MK-7 has a protective effect on bone mineral density and reduced risk of hip, vertebral and non-vertebral fractures. These effects appear to be accentuated when combined with vitamin D and in the setting of osteoporosis. The possible health benefits suggested for further investigation relate to bone strength and arterial health.

Absorption profile

Vitamin K is absorbed along with dietary fat from the small intestine and transported by chylomicrons in the circulation. Most of vitamin K1 is carried by triacylglycerol-rich lipoproteins and rapidly cleared by the liver; only a small amount is released into the circulation and carried by LDL and HDL. MK-4 is carried by the same lipoproteins and cleared fast as well. The long-chain menaquinones are absorbed in the same way as vitamin K1 and MK-4, but are efficiently redistributed by the liver in predominantly LDL. Since LDL has a long half life in the circulation, these menaquinones can circulate for extended times resulting in higher bioavailability for extra-hepatic tissues as compared to vitamin K1 and MK-4. Accumulation of vitamin K in extra-hepatic tissues has direct relevance to vitamin K functions not related to hemostasis.

Dietary intake in humans

The European Food Safety Authority and the US Institute of Medicine, on reviewing existing evidence, have decided there is insufficient evidence to publish a dietary reference value for vitamin K or for K2. They have, however, published an adequate intake for vitamin K, but no value specifically for K2. Evidence suggests K2 is converted from dietary K1 in mice, so they might not require a dietary intake of K2.
Parts of the scientific literature, dating back to 1998, suggest that the AI values are based only on the hepatic requirements. This hypothesis is supported by the fact that Thus, complete activation of coagulation factors is satisfied, but there does not seem to be enough vitamin K2 for the carboxylation of osteocalcin in bone and MGP in the vascular system.
There is no known toxicity associated with high doses of menaquinones. Unlike the other fat-soluble vitamins, vitamin K is not stored in any significant quantity in the liver; therefore the toxic level is not a described problem. All data available as of 2017 demonstrate that vitamin K has no adverse effects in healthy subjects. The recommendations for the daily intake of vitamin K, as issued recently by the US Institute of Medicine, also acknowledge the wide safety margin of vitamin K: "a search of the literature revealed no evidence of toxicity associated with the intake of either K1 or K2". Animal models involving rats, if generalisable to humans, show that MK-7 is well tolerated.

Dietary sources

Apart from animal livers, the richest dietary source of menaquinones are fermented foods ; sources include cheeses consumed in Western diets and fermented soybean products.
MK-4 is synthesized by animal tissues and is found in meat, eggs, and dairy products. Cheeses have been found to contain MK-8 at 10–20 μg per 100 g and MK-9 at 35–55 μg per 100 g. In one report, no substantial differences in MK-4 levels were observed between wild game, free-range animals, and factory farm animals.
In addition to its animal origins, menaquinones are synthesized by bacteria during fermentation and so, as stated, are found in most fermented cheese and soybean products. As of 2001, the richest known source of natural K2 was nattō fermented using the nattō strain of Bacillus subtilis, which is reportedly a good source of long-chain MK-7. In nattō, MK-4 is absent as a form of vitamin K, and in cheeses it is present among the vitamins K only in low proportions. As of this date, it is unknown whether B. subtilis will produce K2 using other legumes.
Food frequency questionnaire-derived estimates of relative intakes of Vitamins K in one northern European country suggest that for that population, about 90% of total vitamin K intakes are provided by K1, about 7.5% by MK-5 through MK-9 and about 2.5% by MK-4; the intense smell and strong taste of nattō appear to make this soya food a less attractive source of K2 for Western tastes.
With regard to utilisation, reports suggest that Vitamin K2 is preferred by the extrahepatic tissues, which may be produced as MK-4 by the animal from K1, or it may be of bacterial origin. Discussion is ongoing as to what extent K2 produced by human intestinal bacteria contributes to daily vitamin K2 needs.
Supplement companies sell nattō extract reportedly standardized with regards to K2 content, in capsule form.
FoodVitamin K2 Proportion of compounds
Nattō, cooked1,034.00% MK-4, 1% MK-5, 1% MK-6, 90% MK-7, 8% MK-8
Goose liver pâté369.0100% MK-4
Australian emu oil360100% MK-4
Hard cheeses76.36% MK-4, 2% MK-5, 1% MK-6, 2% MK-7, 22% MK-8, 67% MK-9
Soft cheeses56.56.5% MK-4, 0.5% MK-5, 1% MK-6, 2% MK-7, 20% MK-8, 70% MK-9
Milk 38.12% MK-4, 46% MK-9, 7% MK-10, 45% MK-11
Egg yolk 32.198% MK-4, 2% MK-6
Goose leg31.0100% MK-4
Grass-fed ghee and butter oil19.6–43.1
average 29.9
Curd cheeses24.82.6% MK-4, 0.4% MK-5, 1% MK-6, 1% MK-7, 20% MK-8, 75% MK-9
Egg yolk 15.5100% MK-4
Butter15.0100% MK-4
Chicken liver 14.1100% MK-4
Chicken liver 12.6100% MK-4
Cheddar cheese 10.26% MK-4, 94% other MK
Meat franks9.8100% MK-4
Salami9.0100% MK-4
Chicken breast8.9100% MK-4
Chicken leg8.5100% MK-4
Ground beef 8.1100% MK-4
Luncheon meat7.7100% MK-4
Chicken liver 6.7100% MK-4
Minced meat6.7100% MK-4
Calf's liver 6.0100% MK-4
Hot dog5.7100% MK-4
Bacon5.6100% MK-4
Whipping cream5.4100% MK-4
Sauerkraut4.88% MK-4, 17% MK-5, 31% MK-6, 4% MK-7, 17% MK-8, 23% MK-9
Pork steak3.757% MK-4, 13% MK-7, 30% MK-8
Duck breast3.6100% MK-4
Buttermilk2.58% MK-4, 4% MK-5, 4% MK-6, 4% MK-7, 24% MK-8, 56% MK-9
Plaice2.29% MK-4, 14% MK-6, 4% MK-7, 73% MK-8
Eel2.277% MK-4, 5% MK-6, 18% MK-7
Fermented cod liver oil1.869% MK-4, 18% MK-6, 6% MK-8, 7% MK-9
Chocolate1.5100% MK-4
Beef1.1100% MK-4
Buckwheat bread1.1100% MK-7
Whole milk yogurt0.967% MK-4, 11% MK-5, 22% MK-8
Whole milk 0.989% MK-4, 11% MK-5
Egg white0.9100% MK-4
Venison back0.7100% MK-4
Salmon0.5100% MK-4
Cow's liver 0.4100% MK-4
Mackerel0.4100% MK-4
Pork liver0.3100% MK-4
Rabbit leg0.1100% MK-4
Skimmed milk yogurt0.1100% MK-8

Notes:
Prawns, herring, kale, spinach, broccoli, green peas, bananas, apples, oranges, margarine, corn oil, sunflower oil, olive oil, rye bread, wheat bread, sourdough bread, and tea contain vitamin K1 but not vitamin K2. Skimmed milk and coffee do not contain any vitamin K.

Anticoagulants and vitamin K2 supplementation

Recent studies found a clear association between long-term oral anticoagulant treatment and reduced bone quality due to reduction of active osteocalcin. OAC might lead to an increased incidence of fractures, reduced bone mineral density or content, osteopenia, and increased serum levels of undercarboxylated osteocalcin.
Furthermore, OAC is often linked to undesired soft-tissue calcification in both children and adults. This process has been shown to be dependent upon the action of K vitamins. Vitamin K deficiency results in undercarboxylation of MGP. Vascular calcification was shown to appear in warfarin-treated experimental animals within two weeks. Also in humans on OAC treatment, two-fold more arterial calcification was found as compared to patients not receiving vitamin K antagonists. Among consequences of anticoagulant treatment: increased aortic wall stiffness, coronary insufficiency, ischemia, and even heart failure. Arterial calcification might also contribute to systolic hypertension and ventricular hypertrophy. Coumarins, by interfering with vitamin K metabolism, are thought by some to lead to excessive calcification of cartilage and the tracheobronchial arteries.
Anticoagulant therapy is usually instituted to avoid life-threatening diseases, and high vitamin K intake interferes with anticoagulant effects. Patients on warfarin or being treated with other vitamin K antagonists are therefore advised not to consume diets rich in K vitamins. However, the latest research proposes to combine vitamins K with OAC to stabilize the International normalized ratio.
Individuals taking anticoagulant medications, such as warfarin, should consult their doctor before taking vitamin K2.

In other organisms

Many bacteria synthesize menaquinones from chorismic acid. They use it as a part of the electron transport chain, playing a similar role as other quinones such as ubiquinone. Oxygen, heme, and menaquinones are needed for many species of lactic acid bacteria to conduct respiration.