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Vitamin K2

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General structure of vitamin K2 (MK-n)

Vitamin K2 or menaquinone (MK) (/ˌmɛnəˈkwɪnoʊn/) is one of three types of vitamin K, the other two being vitamin K1 (phylloquinone) and K3 (menadione). K2 is both a tissue and bacterial product (derived from vitamin K1 in both cases) and is usually found in animal products or fermented foods.[1]

The number n of isoprenyl units in their side chain differs and ranges from 4 to 13, hence Vitamin K2 consists of various forms.[2] It is indicated as a suffix (-n), e. g. MK-7 or MK-9. The most common in the human diet is the short-chain, water-soluble menatetrenone (MK-4), 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.

However, at least one published study concluded that "MK-4 present in food does not contribute to the vitamin K status as measured by serum vitamin K levels. MK-7, however significantly increases serum MK-7 levels and therefore may be of particular importance for extrahepatic tissues."[3]

Long-chain menaquinones (longer than MK-4) include MK-7, MK-8 and MK-9 and are more predominant in fermented foods such as natto and cheonggukjang.[4] Longer-chain menaquinones (MK-10 to MK-13) are produced by anaerobic bacteria in the colon, but they are not well absorbed at this level and have little physiological impact.[1]

When there are no isoprenyl side chain units, the remaining molecule is vitamin K3. This is usually made 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,[failed verification] it is no longer used for this purpose.[1] K3 is now known to be a circulating intermediate in the animal production of MK-4.[5]

Description

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See also: Vitamin K

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 (abbreviated MK-4) has four isoprene residues in its side chain. Menaquinone-4 (also known as menatetrenone from its four isoprene residues) is the most common type of vitamin K2 in animal products since MK-4 is normally synthesized from vitamin K1 in certain animal tissues (arterial walls, pancreas, and testes) 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 (K1) in the colon by Escherichia coli bacteria.[6] However, these menaquinones synthesized by bacteria in the gut appear to contribute minimally to overall vitamin K status.[7][8] MK-4 and MK-7 are both found in the United States in dietary supplements for bone health.

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".[9][full citation needed] The number of repeating units is indicated in the name of the particular menaquinone (e.g., MK-4 means that four isoprene units are repeated in the carbon tail). The chain length influences lipid solubility and thus transport to different target tissues.

Vitamin K structures. MK-4 and MK-7 are both subtypes of K2.

Mechanism of action

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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" (i.e., in conversion of peptide-bound glutamic acid (Glu) to γ-carboxy glutamic acid (Gla) in these proteins).[10]

Carboxylation reaction – the Vitamin K cycle

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 (KO) for reuse in carboxylation.

Several human Gla-containing proteins synthesized in several different types of tissues have been discovered:

  • Coagulation factors (II, VII, IX, X), as well as anticoagulation proteins (C, S, Z). These Gla-proteins are synthesized in the liver and play an important role in blood homeostasis.
  • Osteocalcin. This non-collagenous protein is secreted by osteoblasts and plays an essential role in the formation of mineral in bone.
  • Matrix gla protein (MGP). This calcification inhibitory protein is found in numerous body tissues, but its role is most pronounced in cartilage and in arterial vessel walls.
  • Growth arrest-specific protein 6 (GAS6). GAS6 is secreted by leucocytes and endothelial cells in response to injury and helps in cell survival, proliferation, migration, and adhesion.
  • Proline-rich Gla-proteins (PRGP), transmembrane Gla-proteins (TMG), Gla-rich protein (GRP) and periostin. Their precise functions are still unknown.

Health effects

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Vitamin may have a protective effect on bone mineral density and reduced risk of hip, vertebral and non-vertebral fractures.[11] These effects appear to be accentuated when combined with vitamin D and in the setting of osteoporosis.[1]

Research suggests that Vitamin K2 (Menaquinone 7, MK-7]) may reduce the rate and severity of night time leg cramps.[12]

Utilisation

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With regard to utilisation, reports suggest[clarification needed] that Vitamin K2 is preferred by the extrahepatic tissues (bone, cartilage, vasculature), which may be produced as MK-4 by the animal from K1,[citation needed] or it may be of bacterial origin (from MK-7, MK-9, and other MKs).[citation needed]

Absorption profile

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Vitamin K is absorbed along with dietary fat from the small intestine and transported by chylomicrons in the circulation.[13] Most of vitamin K1 is carried by triacylglycerol-rich lipoproteins (TRL) and rapidly cleared by the liver; only a small amount is released into the circulation and carried by LDL-C and HDL-C. MK-4 is carried by the same lipoproteins (TRL, LDL-C, and HDL-C) 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-C (VLDL-C). Since LDL-C 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.[14]

Dietary intake in humans

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The European Food Safety Authority (EU) 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 (AI) for vitamin K, but no value specifically for K2.[citation needed]

Parts of the scientific literature, dating back to 1998, suggest that the AI values are based only on the hepatic requirements (i.e. related to the liver).[15][16] This hypothesis is supported by the fact that the majority of the Western population exhibits a substantial fraction of undercarboxylated extra-hepatic proteins.[citation needed] 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.[17][18]

There is no known toxicity associated with high doses of menaquinones (vitamin K2). Unlike the other fat-soluble vitamins, vitamin K is not stored in any significant quantity in the liver. All data available as of 2017 demonstrate that vitamin K has no adverse effects in healthy subjects.[citation needed] 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.[19]

Dietary sources

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Apart from animal livers, the richest dietary source of menaquinones are fermented foods (from bacteria, not molds or yeasts); sources include cheeses consumed in Western diets (e.g., containing MK-9, MK-10, and MK-11) and fermented soybean products (e.g., in traditional nattō consumed in Japan, containing MK-7 and MK-8).[citation needed] (Here and following it is noteworthy that most food assays measure only fully unsaturated menaquinones.[citation needed])

MK-4 is synthesized by animal tissues and is found in meat, eggs, and dairy products.[20] 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.[14] In one report, no substantial differences in MK-4 levels were observed between wild game, free-range animals, and factory farm animals.[21]

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.[22][non-primary source needed] As of 2001, the richest known source of natural K2 was nattō fermented using the nattō strain of Bacillus subtilis,[23] which is reportedly a good source of long-chain MK-7.[citation needed] 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.[relevant?][24][better source needed] Still it is unknown whether B. subtilis will produce K2 using other legumes (e.g., chickpeas, or lentils) or even B. subtilis fermented oatmeal. According to Rebecca Rocchi et al., 2024, creating natto by using Bacillus subtilis to ferment boiled red lentils, chickpeas, or green peas produced greater amounts of MK-7 than creating natto by using Bacillus subtilis to ferment boiled soybeans, lupins, or brown beans.[25]

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;[citation needed] the intense smell and strong taste of nattō appear to make this soya food a less attractive source of K2 for Western tastes.

Supplement companies sell nattō extract reportedly standardized with regards to K2 content, in capsule form.[citation needed]

Analysis of foods

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Food Vitamin K2 (μg per 100 g
or μg/100 ml)[21]: Table 2  		Proportion of compounds
Nattō, fermented 1,034.0 0% MK-4, 1% MK-5, 1% MK-6, 90% MK-7, 8% MK-8
Goose liver pâté 369.0 100% MK-4
Hard cheeses (15 samples) 76.3 6% MK-4, 2% MK-5, 1% MK-6, 2% MK-7, 22% MK-8, 67% MK-9
Cheddar 23.5 (235 ng/g)[26] (ng/g) 51.2 MK-4, 3.8 MK-6, 18.8 MK-7, 36.4 MK-8, 125 MK-9
Eel 63.1[26] 100% MK-4
Eel 2.2[21]: Table 2  1.7 MK-4, 0.1 MK-6, 0.4 MK-7
Soft cheeses (15 samples) 56.5 6.5% MK-4, 0.5% MK-5, 1% MK-6, 2% MK-7, 20% MK-8, 70% MK-9
Camembert 68.1 (681 ng/g)[26] (ng/g) 79.5 MK-4, 13.4 MK-5, 10.1 MK-6, 32.4 MK-7, 151 MK-8, 395 MK-9
Milk (4% fat, USA)† 38.1[27] 2% MK-4, 46% MK-9, 7% MK-10, 45% MK-11
Egg yolk (Netherlands) 32.1 98% MK-4, 2% MK-6
Goose leg 31.0 100% MK-4
Curd cheeses (12 samples) 24.8 2.6% MK-4, 0.4% MK-5, 1% MK-6, 1% MK-7, 20% MK-8, 75% MK-9
Egg yolk (USA) 15.5[28] 100% MK-4
Butter 15.0 100% MK-4
Chicken liver (pan-fried) 12.6[28] 100% MK-4
Chicken leg 8.5 100% MK-4
Ground beef (medium fat) 8.1[28] 100% MK-4
Calf's liver (pan-fried) 6.0[28] 100% MK-4
Hot dog 5.7[28] 100% MK-4
Bacon 5.6[28] 100% MK-4
Whipping cream 5.4 100% MK-4
Sauerkraut 4.8 8% MK-4, 17% MK-5, 31% MK-6, 4% MK-7, 17% MK-8, 23% MK-9
Pork steak 3.7 57% MK-4, 13% MK-7, 30% MK-8
Duck breast 3.6 100% MK-4
Buttermilk 2.5 8% MK-4, 4% MK-5, 4% MK-6, 4% MK-7, 24% MK-8, 56% MK-9
Beef 1.1 100% MK-4
Buckwheat bread 1.1 100% MK-7
Whole milk yogurt 0.9 67% MK-4, 11% MK-5, 22% MK-8
Whole milk (Netherlands)† 0.9 89% MK-4, 11% MK-5
Egg white 0.9 100% MK-4
Salmon 0.5 100% MK-4
Cow's liver (pan-fried) 0.4[28] 100% MK-4
Mackerel 0.4 100% MK-4
Skimmed milk yogurt 0.1 100% MK-8

Notes:

  • † – The reported amounts in comparable milk from the USA and the Netherlands differ by more than 40 times, so these numbers should be considered suspect.

Anticoagulants

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Recent studies found a clear association between long-term oral (or intravenous) anticoagulant treatment (OAC) 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.[29]

Furthermore, OAC is often linked to undesired soft-tissue calcification in both children and adults.[30][31] This process has been shown to be dependent upon the action of K vitamins. Vitamin K deficiency results in undercarboxylation of MGP. Also in humans on OAC treatment, two-fold more arterial calcification was found as compared to patients not receiving vitamin K antagonists.[32][33] 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.[34][35] Anticoagulant therapy is usually instituted to avoid life-threatening diseases, and high vitamin K intake interferes with anticoagulant effects.[citation needed] Patients on warfarin (Coumadin) or being treated with other vitamin K antagonists are therefore advised not to consume diets rich in K vitamins.[citation needed]

In other organisms

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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.[36]

Variations in biosynthetic pathways mean that bacteria also produce analogues of Vitamin K2. For example, MK9(II-H), which replaces the second geranylgeranyl unit with a saturated phytyl, is produced by Mycobacterium phlei. There also exists a possibility of cis–trans isomerism due to the double bonds present. In M. phlei, the 3'-methyl-cis MK9(II-H) form seems to be more biologically active than trans MK9(II-H).[37] However, with human enzymes, the naturally abundant trans form is more efficient.[38]

One hydrogenated MK that sees relevant amounts of human consumption is MK-9(4H), found in cheese fermented by Propionibacterium freudenreichii. This variation has the second and third units replaced with phytyl.[39]

See also

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References

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  2. ^ Mladěnka, Přemysl; Macáková, Kateřina; Kujovská Krčmová, Lenka; Javorská, Lenka; Mrštná, Kristýna; Carazo, Alejandro; Protti, Michele; Remião, Fernando; Nováková, Lucie (2022-03-10). "Vitamin K – sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity". Nutrition Reviews. 80 (4): 677–698. doi:10.1093/nutrit/nuab061. ISSN 1753-4887. PMC 8907489. PMID 34472618.
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  28. ^ a b c d e f g Rhéaume-Bleue, Kate (August 27, 2013). Vitamin K2 and the Calcium Paradox: How a Little-Known Vitamin Could Save Your Life. Harper. pp. 66–67. ISBN 978-0-06-232004-9.
  29. ^ Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ (1999). "Changes in bone density after exposure to oral anticoagulants: a meta-analysis". Osteoporosis International. 9 (5): 441–8. doi:10.1007/s001980050169. PMID 10550464. S2CID 12494428.
  30. ^ Barnes C, Newall F, Ignjatovic V, Wong P, Cameron F, Jones G, Monagle P (April 2005). "Reduced bone density in children on long-term warfarin". Pediatric Research. 57 (4): 578–81. doi:10.1203/01.pdr.0000155943.07244.04. PMID 15695604.
  31. ^ Hawkins D, Evans J (May 2005). "Minimising the risk of heparin-induced osteoporosis during pregnancy". Expert Opinion on Drug Safety. 4 (3): 583–90. doi:10.1517/14740338.4.3.583. PMID 15934862. S2CID 32013673.
  32. ^ Schurgers LJ, Aebert H, Vermeer C, Bültmann B, Janzen J (November 2004). "Oral anticoagulant treatment: friend or foe in cardiovascular disease?". Blood. 104 (10): 3231–2. doi:10.1182/blood-2004-04-1277. PMID 15265793.
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  37. ^ Dunphy, Patrick J.; Gutnick, David L.; Phillips, Philip G.; Brodie, Arnold F. (January 1968). "A New Natural Naphthoquinone in Mycobacterium phlei". Journal of Biological Chemistry. 243 (2): 398–407. doi:10.1016/S0021-9258(18)99307-5.
  38. ^ Cirilli, I; Orlando, P; Silvestri, S; Marcheggiani, F; Dludla, PV; Kaesler, N; Tiano, L (September 2022). "Carboxylative efficacy of trans and cis MK7 and comparison with other vitamin K isomers". BioFactors. 48 (5): 1129–1136. doi:10.1002/biof.1844. PMC 9790681. PMID 35583412.
  39. ^ Hojo, K; Watanabe, R; Mori, T; Taketomo, N (September 2007). "Quantitative measurement of tetrahydromenaquinone-9 in cheese fermented by propionibacteria". Journal of Dairy Science. 90 (9): 4078–83. doi:10.3168/jds.2006-892. PMID 17699024.
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