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{{Short description|Group of vitamins and bacterial metabolites}}
{{more medical citations needed|date=April 2015}}
{{DISPLAYTITLE:Vitamin K<sub>2</sub>}}
[[File:Menachinon.svg|thumb|class=skin-invert-image|General structure of vitamin K<sub>2</sub> (MK-n)]]
'''Vitamin K<sub>2</sub>''' or '''menaquinone''' ('''MK''') ({{IPAc-en|ˌ|m|ɛ|n|ə|ˈ|k|w|ɪ|n|oʊ|n}}) is one of three types of [[vitamin K]], the other two being vitamin K<sub>1</sub> ([[phylloquinone]]) and K<sub>3</sub> ([[menadione]]). K<sub>2</sub> is both a tissue and [[bacteria]]l product (derived from vitamin K<sub>1</sub> in both cases) and is usually found in animal products or [[fermented foods]].<ref name="Myneni-2017">{{cite journal |vauthors=Myneni VD, Mezey E |title=Regulation of bone remodeling by vitamin K2 |journal=Oral Diseases |volume=23 |issue=8 |pages=1021–1028 |date=November 2017 |pmid=27976475 |pmc=5471136 |doi=10.1111/odi.12624}}</ref>


The number ''n'' of [[isoprenyl]] units in their side chain differs and ranges from 4 to 13, hence vitamin K<sub>2</sub> consists of various forms.<ref>{{Cite journal |last1=Mladěnka |first1=Přemysl |last2=Macáková |first2=Kateřina |last3=Kujovská Krčmová |first3=Lenka |last4=Javorská |first4=Lenka |last5=Mrštná |first5=Kristýna |last6=Carazo |first6=Alejandro |last7=Protti |first7=Michele |last8=Remião |first8=Fernando |last9=Nováková |first9=Lucie |date=2022-03-10 |title=Vitamin K – sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity |journal=Nutrition Reviews |volume=80 |issue=4 |pages=677–698 |doi=10.1093/nutrit/nuab061 |issn=1753-4887 |pmc=8907489 |pmid=34472618}}</ref> 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 K<sub>1</sub>, and is commonly found in animal products. It is known that production of MK-4 from dietary plant vitamin K<sub>1</sub> can be accomplished by animal tissues alone, as it proceeds in germ-free rodents.
Menaquinones are often referred to as Vitamin K2, which is somewhat misleading given that all menaquinones are not alike in their origin or their function. Menaquinones are primarily of bacterial origin, and differ in structure from phylloquinone (K1 ) in their 3-substituted lipophilic side chain. The major menaquinones contain 4–10 repeating isoprenoid units indicated by MK-4 to MK-10; forms up to 13 isoprenoid groups have been identified<ref>http://www.foodandnutritionresearch.net/index.php/fnr/article/view/5505</ref>.


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."<ref>{{cite journal |vauthors=Sato T, Schurgers LJ, Uenishi K |title=Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women |journal=Nutrition Journal |volume=11 |issue=93 |pages=93 |date=November 2012 |pmid=23140417 |pmc=3502319 |doi=10.1186/1475-2891-11-93 |doi-access=free}}</ref>
Menaquinone-4 (MK-4) is unique among the menaquinones in that it is not of bacterial origin. Instead, MK-4 is formed by a realkylation step from Menadione present in animal feeds or is the product of tissue-specific conversion directly from dietary phylloquinone<ref>http://www.foodandnutritionresearch.net/index.php/fnr/article/view/5505</ref>.


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]].<ref>{{Cite journal |last1=Kang |first1=Min-Ji |last2=Baek |first2=Kwang-Rim |last3=Lee |first3=Ye-Rim |last4=Kim |first4=Geun-Hyung |last5=Seo |first5=Seung-Oh |date=2022-03-03 |title=Production of Vitamin K by Wild-Type and Engineered Microorganisms |journal=Microorganisms |language=en |volume=10 |issue=3 |pages=554 |doi=10.3390/microorganisms10030554 |pmid=35336129 |pmc=8954062 |issn=2076-2607 |doi-access=free}}</ref> Longer-chain menaquinones (MK-10 to MK-13) are produced by [[anaerobic metabolism|anaerobic]] bacteria in the [[colon (organ)|colon]], but they are not well absorbed at this level and have little physiological impact.<ref name="Myneni-2017" />
==Forms==
{{main|Vitamin K}}
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 “side chains”.<ref>Shearer MJ.2003 in Physiology. Elsevier Sciences LTD. 6039-45.</ref> The number of side chains is indicated in the name of the particular menaquinone (e.g., MK-4 means that four molecular units - called isoprene units - are attached to the carbon tail) and this influences the transport to different target tissues.


When there are no isoprenyl side chain units, the remaining molecule is [[vitamin K3|vitamin K<sub>3</sub>]]. This is usually made synthetically, and is used in [[animal feed]]. It was formerly given to [[preterm birth|premature infants]], but due to inadvertent toxicity in the form of [[hemolytic anemia]] and [[jaundice]],{{failed verification|date=March 2023}} it is no longer used for this purpose.<ref name="Myneni-2017" /> K<sub>3</sub> is now known to be a circulating intermediate in the animal production of MK-4.<ref name="Shearer">{{Cite journal |last1=Shearer |first1=Martin J. |last2=Newman |first2=Paul |date=March 2014 |title=Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis |journal=Journal of Lipid Research |volume=55 |issue=3 |pages=345–362 |doi=10.1194/jlr.R045559 |doi-access=free |issn=0022-2275 |pmc=3934721 |pmid=24489112}}</ref>
[[File:Vitamin K structures.jpg|thumb|center|400px|Vitamin K structures. MK-4 and MK-7 are both subtypes of K<sub>2</sub>.]]


== Description ==
==Mechanism of action==
{{See also|Vitamin K}}
The [[mechanism of action]] of vitamin K<sub>2</sub> is similar to vitamin K<sub>1</sub>. Traditionally, K vitamins were recognized as the 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).
Vitamin K<sub>2</sub>, the main storage form in animals, has several subtypes, which differ in [[isoprene#Isoprenoids|isoprenoid]] chain length. These vitamin K<sub>2</sub> 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 K<sub>2</sub> in animal products since MK-4 is normally synthesized from [[phytomenadione|vitamin K<sub>1</sub>]] 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 K<sub>2</sub> may have enzyme functions distinct from those of vitamin K<sub>1</sub>.


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 (K<sub>1</sub>) in the colon by ''[[Escherichia coli]]'' [[bacteria]].<ref>{{cite journal |vauthors=Vermeer C, Braam L |title=Role of K vitamins in the regulation of tissue calcification |journal=Journal of Bone and Mineral Metabolism |volume=19 |issue=4 |pages=201–6 |year=2001 |pmid=11448011 |doi=10.1007/s007740170021 |s2cid=28406206}}</ref> However, these menaquinones synthesized by bacteria in the gut appear to contribute minimally to overall vitamin K status.<ref>{{cite journal |vauthors=Suttie JW |title=The importance of menaquinones in human nutrition |journal=Annual Review of Nutrition |volume=15 |pages=399–417 |year=1995 |pmid=8527227 |doi=10.1146/annurev.nu.15.070195.002151}}</ref><ref>{{cite journal |vauthors=Weber P |title=Vitamin K and bone health |journal=Nutrition |volume=17 |issue=10 |pages=880–7 |date=October 2001 |pmid=11684396 |doi=10.1016/S0899-9007(01)00709-2}}</ref> MK-4 and MK-7 are both found in the United States in dietary supplements for bone health.
[[File:Carboxylation reaction vitamin K cycle.png|thumb|center|500px|Carboxylation reaction - 'Vitamin K cycle']]


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".<ref>{{cite encyclopedia |last=Shearer |first=M. J. |year=2003 |title=Physiology |publisher=Elsevier Sciences |pages=6039–6045}}</ref>{{full citation needed|date=July 2017}} 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.
[[Carboxylation]] of these vitamin K-dependent [[Gla domain|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.
[[File:Vitamin K structures.svg|center|thumb|400x400px|class=skin-invert-image|Vitamin K structures. MK-4 and MK-7 are both subtypes of K<sub>2</sub>.]]


== Mechanism of action ==
Several human Gla-containing proteins synthesized in several different types of tissues have been discovered:
{{unreferenced section|date=January 2018}}
The [[mechanism of action]] of vitamin K<sub>2</sub> is similar to vitamin K<sub>1</sub>. 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).<ref>{{cite journal |author=EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) |title=Dietary reference values for vitamin K |journal=EFSA J |volume=15 |issue=5 |pages=e04780 See 2.2.1. Biochemical functions |year=2017 |doi=10.2903/j.efsa.2017.4780 |pmid=32625486 |pmc=7010012}}</ref>


[[File:Carboxylation reaction vitamin K cycle.png|thumb|center|500px|class=skin-invert-image|Carboxylation reaction – the vitamin K cycle]]
* 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 homeo-stasis.

[[Carboxylation]] of these vitamin K-dependent [[Gla domain|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 tissue have been discovered:

* Coagulation factors ([[Factor II|II]], [[Factor VII|VII]], [[Factor IX|IX]], [[Factor X|X]]), as well as anticoagulation proteins ([[Protein C|C]], [[Protein S|S]], [[Protein Z|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.
* [[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.
* [[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.
* [[GAS6|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.
* [[GAS6|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; whose precise functions are still unexplored.
* Proline-rich Gla-proteins (PRGP), transmembrane Gla-proteins (TMG), Gla-rich protein (GRP) and [[periostin]]. Their precise functions are still unknown.

== Health effects ==
Vitamin may have a protective effect on bone mineral density and reduced risk of hip, vertebral and non-vertebral fractures.<ref>Mott A, Bradley T, Wright K, Cockayne ES, Shearer MJ, Adamson J, Lanham-New SA, Torgerson DJ, "Correction to Effect of vitamin K on bone mineral density and fractures in adults: An updated systematic review and meta-analysis of randomised controlled trials. Osteoporos", Int. 2019;30:1543–1559. doi: 10.1007/s00198-019-04949-0</ref> These effects appear to be accentuated when combined with [[vitamin D]] and in the setting of [[osteoporosis]].<ref name="Myneni-2017" />

Research suggests that vitamin K<sub>2</sub> (Menaquinone 7, MK-7]) may reduce the rate and
severity of night time leg cramps.<ref>Tan J, Zhu R, Li Y, et al., "Vitamin K2 in Managing Nocturnal Leg Cramps: A Randomized Clinical Trial", JAMA Intern Med, October 28, 2024. doi:10.1001/jamainternmed.2024.5726</ref>

=== Utilisation ===
With regard to utilisation, reports suggest{{clarify|date=February 2019}} that vitamin K<sub>2</sub> is preferred by the extrahepatic tissues (bone, cartilage, vasculature), which may be produced as MK-4 by the animal from K<sub>1</sub>,{{citation needed|date=February 2019}} or it may be of bacterial origin (from MK-7, MK-9, and other MKs).{{citation needed|date=February 2019}}

== Absorption profile ==
{{more citations needed section|date=July 2019}}
Vitamin K is absorbed along with dietary fat from the small intestine and transported by [[chylomicron]]s in the circulation.<ref>{{cite book |author=Institute of Medicine, Panel on Micronutrients |chapter=5. Vitamin K |title=Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK222299/#ddd00194 |id=NBK222299 |publisher=National Academies Press |year=2001 |isbn=0-309-07279-4}}</ref> Most of vitamin K<sub>1</sub> 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 K<sub>1</sub> 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 K<sub>1</sub> and MK-4. Accumulation of vitamin K in extra-hepatic tissues has direct relevance to vitamin K functions not related to hemostasis.<ref name="Shearer-2008">{{cite journal |vauthors=Shearer MJ, Newman P |title=Metabolism and cell biology of vitamin K |journal=Thrombosis and Haemostasis |volume=100 |issue=4 |pages=530–47 |date=October 2008 |pmid=18841274 |doi=10.1160/th08-03-0147 |s2cid=7743991}}</ref>

== Dietary intake in humans ==
The [[European Food Safety Authority]] ([[European Union|EU]]) and the US [[Institute of Medicine]], on reviewing existing evidence, have decided there is insufficient evidence to publish a [[Dietary Reference Values|dietary reference value]] for vitamin K or for K<sub>2</sub>. They have, however, published an [[Adequate Intake]] (AI) for vitamin K, but no value specifically for K<sub>2</sub>.{{Citation needed|date=August 2022}}

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).<ref>{{cite journal |vauthors=Booth SL, Suttie JW |title=Dietary intake and adequacy of vitamin K |journal=The Journal of Nutrition |volume=128 |issue=5 |pages=785–8 |date=May 1998 |pmid=9566982 |doi=10.1093/jn/128.5.785 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Schurgers LJ, Vermeer C |title=Differential lipoprotein transport pathways of K-vitamins in healthy subjects |journal=Biochimica et Biophysica Acta (BBA) - General Subjects |volume=1570 |issue=1 |pages=27–32 |date=February 2002 |pmid=11960685 |doi=10.1016/s0304-4165(02)00147-2}}</ref> This hypothesis is supported by the fact that {{citation needed span|text=the majority of the Western population exhibits a substantial fraction of undercarboxylated extra-hepatic proteins.|date=January 2017}} Thus, complete activation of [[coagulation factors]] is satisfied, but there does not seem to be enough vitamin K<sub>2</sub> for the carboxylation of [[osteocalcin]] in bone and [[Matrix gla protein|MGP]] in the vascular system.<ref>{{cite journal |vauthors=Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M, Dobnig H |title=Vascular calcification and osteoporosis--from clinical observation towards molecular understanding |journal=Osteoporosis International |volume=18 |issue=3 |pages=251–9 |date=March 2007 |pmid=17151836 |doi=10.1007/s00198-006-0282-z |s2cid=22800542}}</ref><ref>{{cite journal |vauthors=Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD |title=Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women |journal=Journal of Bone and Mineral Research |volume=6 |issue=11 |pages=1211–6 |date=November 1991 |pmid=1666807 |doi=10.1002/jbmr.5650061111 |s2cid=21412585}}</ref>

There is no known toxicity associated with high doses of menaquinones (vitamin K<sub>2</sub>). Unlike the other fat-soluble vitamins, vitamin K is not stored in any significant quantity in the [[liver]]. All data available {{as of|2017|lc=yes}} demonstrate that vitamin K has no adverse effects in healthy subjects.{{Citation needed|date=December 2019}} 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 K<sub>1</sub> or K<sub>2</sub>". Animal models involving rats, if generalisable to humans, show that MK-7 is well tolerated.<ref>{{cite journal |vauthors=Pucaj K, Rasmussen H, Møller M, Preston T |title=Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7 |journal=Toxicology Mechanisms and Methods |volume=21 |issue=7 |pages=520–32 |date=September 2011 |pmid=21781006 |pmc=3172146 |doi=10.3109/15376516.2011.568983}}</ref>

== Dietary sources ==
Apart from animal livers, the richest dietary source of menaquinones are fermented foods (from bacteria, not molds or yeasts); sources include [[cheese]]s 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|date=February 2019}} (Here and following it is noteworthy that most food assays measure only fully unsaturated menaquinones.{{citation needed|date=February 2019}})

MK-4 is synthesized by animal tissues and is found in meat, eggs, and dairy products.<ref name="pmid16417305">{{cite journal |vauthors=Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL |title=Vitamin K contents of meat, dairy, and fast food in the U.S. diet |journal=Journal of Agricultural and Food Chemistry |volume=54 |issue=2 |pages=463–7 |date=January 2006 |pmid=16417305 |doi=10.1021/jf052400h}}</ref> Cheeses have been found to contain MK-8 at 10–20&nbsp;μg per 100&nbsp;g and MK-9 at 35–55&nbsp;μg per 100&nbsp;g.<ref name="Shearer-2008" /> In one report, no substantial differences in MK-4 levels were observed between wild game, free-range animals, and factory farm animals.<ref name="Schurgers 2000">{{cite journal |vauthors=Schurgers LJ, Vermeer C |title=Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations |journal=Haemostasis |volume=30 |issue=6 |pages=298–307 |date=November 2000 |pmid=11356998 |doi=10.1159/000054147 |s2cid=84592720 |url=https://www.researchgate.net/publication/11980998 |quote=Foods purchased in and around Maastricht (Netherlands) – Table 2. Mean of K vitamins (μg/100 g or μg/100 ml)}}</ref>


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.<ref name="pmid10874601">{{cite journal |vauthors=Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M |title=Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals |journal=Journal of Bone and Mineral Metabolism |volume=18 |issue=4 |pages=216–22 |year=2000 |pmid=10874601 |doi=10.1007/s007740070023 |s2cid=24024697}}</ref>{{primary source inline|date=February 2019}} As of 2001, the richest known source of natural K<sub>2</sub> was [[nattō]] fermented using the nattō strain of ''[[Bacillus subtilis]]'',<ref>{{cite journal |vauthors=Kaneki M, Hodges SJ, Hedges SJ, Hosoi T, Fujiwara S, Lyons A, Crean SJ, Ishida N, Nakagawa M, Takechi M, Sano Y, Mizuno Y, Hoshino S, Miyao M, Inoue S, Horiki K, Shiraki M, Ouchi Y, Orimo H |display-authors=6 |title=Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk |journal=Nutrition |volume=17 |issue=4 |pages=315–21 |date=April 2001 |pmid=11369171 |doi=10.1016/s0899-9007(00)00554-2}}</ref> which is reportedly a good source of long-chain MK-7.{{citation needed|date=February 2019}} 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.{{Relevance inline|date=February 2019}}<ref>{{cite web |url=http://www.westonaprice.org/fat-soluble-activators/x-factor-is-vitamin-k2#fig4 |title=On the Trail of the Elusive X-Factor: Vitamin K<sub>2</sub> Revealed}}</ref>{{better source needed|date=February 2019}} Still it is unknown whether ''B. subtilis'' will produce K<sub>2</sub> using other legumes (e.g., [[chickpeas]], or [[lentils]]) or even ''B. subtilis'' fermented [[oatmeal]].
==Health effects==
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]].<ref name="pmid38463896">{{cite journal |vauthors=Rocchi R, Zwinkels J, Kooijman M, Garre A, Smid EJ |title=Development of novel natto using legumes produced in Europe |journal=Heliyon |date=February 2024 |volume=10 |issue=5 |pages=e26849 |pmid=38463896 |doi=10.1016/j.heliyon.2024.e26849 |doi-access=free |pmc=10923668 |bibcode=2024Heliy..1026849R}}</ref>


Food frequency questionnaire-derived estimates of relative intakes of vitamins K in one [[northern Europe]]an country suggest that for that population, about 90% of total vitamin K intakes are provided by K<sub>1</sub>, about 7.5% by MK-5 through MK-9 and about 2.5% by MK-4;{{citation needed|date=February 2019}} the intense smell and strong taste of nattō appear to make this soya food a less attractive source of K<sub>2</sub> for Western tastes.
===Bone density===
Vitamin K<sub>2</sub> deficiency results in a decreased level of active osteocalcin, which in turn increases the risk for fragile bones.<ref>Booth et al. (July 2, 2013) "Associations between Vitamin K Biochemical Measures and Bone Mineral Density in Men and Women", ''The Journal of Clinical Endocrinology & Metabolism'' Vol.89 No.10 pp.4904-9 {{doi|10.1210/jc.2003-031673}}</ref><ref>Knapen MH, Nieuwenhuijzen Kruseman AC, Wouters RS, Vermeer C. (Nov 1998) "Correlation of serum osteocalcin fractions with bone mineral density in women during the first 10 years after menopause", ''Calcified Tissue International'' Vol.63 No.5 pp.375-9, [[International Osteoporosis Foundation]] {{doi|10.1007/s002239900543}}</ref> Research also showed that vitamin K<sub>2</sub>, but not K<sub>1</sub> in combination with calcium and vitamin D can decrease bone turnover and that vitamin K<sub>2</sub> is essential for the maintenance of bone strength in postmenopausal women.<ref>[http://www.sciencedirect.com/science/article/pii/S0531513106005437 Schurgers LJ,Knapen MH, Vermeer C. Vitamin (March 2007) "K<sub>2</sub> supplementation improves hip bone geometry and bone strength indices in postmenopausal women",] ''International Congress Series'' Vol. 1297 pp. 179-187, Nutritional Aspects of Osteoporosis 2006. Proceedings of the 6th International Symposium on Nutritional Aspects of Osteoporosis, 4–6 May 2006, Lausanne, Switzerland</ref><ref>Knapen MH, Schurgers LJ, Vermeer C. (July 2007) "Vitamin K<sub>2</sub> supplementation improves hip bone geometry and bone strength indices in postmenopausal women", ''Osteoporosis International'' Vol.18 No.7 pp.963-72 {{doi| 10.1007/s00198-007-0337-9}}</ref>


Supplement companies sell nattō extract reportedly standardized with regard to K<sub>2</sub> content, in capsule form.{{citation needed|date=February 2019}}
The Japanese population seems to be at lower risk for bone fractures compared to European and American citizens. Studies link Japan's greater levels of BMD to that country's widespread consumption of [[Nattō|natto]]. Increased intake of MK-7 from natto seems to result in higher levels of activated osteocalcin and a significant reduction in fracture risk.<ref>Yaegashi Y, Onoda T, Tanno K, Kuribayashi T, Sakata K, Orimo H. (March 2008) "Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and vitamin K", ''European Journal of Epidemiology'' Vol. 23, Issue 3, pp 219-225 {{doi|10.1007/s10654-008-9225-7}}</ref><ref>[http://jn.nutrition.org/content/136/5/1323.full Ikeda et al. (May 2006) "Intake of Fermented Soybeans, ''Natto'', is Associated with Reduced Bone Loss in Postmenopausal Women: Japanese Population-Based Osteoporosis (JPOS) Study",] ''J Nutr.'' Vol.136 No.5 pp.1323-8.</ref><ref>[http://www.ncbi.nlm.nih.gov/pubmed/11369171 Kaneki et al. (Apr 2001) “Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K<sub>2</sub>: possible implications for hip-fracture risk”,] ''Nutrition'' Vol.17 No.4 pp.315-21
</ref>


===Heart calcification===
=== Analysis of foods ===
Patients suffering from osteoporosis were shown to have extensive calcium plaques, which impaired blood flow in the arteries. This simultaneous excess of calcium in one part of the body (arteries), and lack in another (bones) – which may occur even in spite of calcium supplementation – is known as the Calcium Paradox. The underlying reason is vitamin K<sub>2</sub> deficiency, which leads to significant impairment in biological function of [[Matrix gla protein|MGP]], the most potent inhibitor of vascular calcification presently known. Animal research showed that vascular calcification might not only be prevented, but even reversed by increasing the daily intake of vitamin K<sub>2</sub>.<ref>[ Schurgers et al. (April 01, 2007) "Regression of warfarin-induced medial elastocal-cinosis by high intake of K vitamins in rats",] ''Blood'' Vol.109 No.7 pp.2823-2831, American Society of Hematology {{doi|10.1182/blood-2006-07-035345}}</ref> The strongly protective effect of K<sub>2</sub> and not vitamin K<sub>1</sub> on cardiovascular health was confirmed by, among others, Geleijnse et al. in the Rotterdam Study (2004, see Figure 3) performed on a group of 4,800 subjects.<ref>[ Geleijnse et al. (Nov 1, 2004) "Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study",] ''J. Nutr.'' Vol.134 No.11 pp.3100-3105, The American Society for Nutritional Sciences</ref> Results of more than 10 years of follow-up were verified, also by Gast et al., who demonstrated that among K vitamins, the long-chain types of K<sub>2</sub> (MK-7 through MK-9) are the most important for efficiently preventing excessive calcium accumulation in the arteries.<ref>[ Gast et al. (Sep 2009) "A high menaquinone reduces the incidence of coronary heart disease in women",] ''Nutrition, Metabolism and Cardiovascular Diseases'' Vol.19 No.7 pp.504–510</ref><ref name=summeren>[ van Summeren et al. (Oct 2008) "Vitamin K status is associated with childhood bone mineral content",] ''[[British Journal of Nutrition]]'' Vo.100 No.4 pp.852-858 {{doi|10.1017/S0007114508921760}}</ref>


{| class="wikitable"
==Absorption profile of different K vitamins==
! Food
Vitamin K is absorbed along with dietary fat from the small intestine and transported by chylomicrons in the circulation. Most of vitamin K<sub>1</sub> 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 and HDL. MK-4 is carried by the same lipoproteins (TRL, LDL, and HDL) and cleared fast as well. The long-chain menaquinones are absorbed in the same way as vitamin K<sub>1</sub> and MK-4, but are efficiently redistributed by the liver in predominantly LDL (VLDL). 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 K<sub>1</sub> and MK-4. Accumulation of vitamin K in extra-hepatic tissues has direct relevance to vitamin K functions not related to hemostasis.<ref>Martin J. Shearer, Paul Newman. Metabolism and cell biology of vitamin K. Thromb Haemost 2008</ref>
! Vitamin K<sub>2</sub> (μg per 100&nbsp;g <br /> or μg/100 ml)<ref name="Schurgers 2000" />{{rp|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 cheese]]s (15 samples)
| 76.3
| 6% MK-4, 2% MK-5, 1% MK-6, 2% MK-7, 22% MK-8, 67% MK-9
|-
| [[Cheddar cheese|Cheddar]]
| 23.5 (235&nbsp;ng/g)<ref name="Vermeer_etal_2018" />
| (ng/g) 51.2 MK-4, 3.8 MK-6, 18.8 MK-7, 36.4 MK-8, 125 MK-9
|-
| [[Eel]]
| 63.1<ref name="Vermeer_etal_2018">{{cite journal |last1=Vermeer |first1=Cees |last2=Raes |first2=Joyce |last3=van 't Hoofd |first3=Cynthia |last4=Knapen |first4=Marjo H. J. |last5=Xanthoulea |first5=Sofia |year=2018 |title=Menaquinone Content of Cheese |journal=Nutrients |volume=10 |issue=4 |page=446 |doi=10.3390/nu10040446 |pmid=29617314 |pmc=5946231 |doi-access=free}}</ref>
| 100% MK-4
|-
| Eel
| 2.2<ref name="Schurgers 2000" />{{rp|Table 2}}
| 1.7 MK-4, 0.1 MK-6, 0.4 MK-7
|-
| [[Soft cheese]]s (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&nbsp;ng/g)<ref name="Vermeer_etal_2018" />
| (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){{dagger}}
| 38.1<ref name="Fu et al 2017">{{cite journal |vauthors=Fu X, Harshman SG, Shen X, Haytowitz DB, Karl JP, Wolfe BE, Booth SL |title=Multiple Vitamin K Forms Exist in Dairy Foods |journal=Current Developments in Nutrition |volume=1 |issue=6 |pages=e000638 |date=June 2017 |pmid=29955705 |pmc=5998353 |doi=10.3945/cdn.117.000638}}</ref>
| 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 cheese]]s (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<ref name="Rheaume-Bleue 2013">{{cite book |last1=Rhéaume-Bleue |first1=Kate |title=Vitamin K<sub>2</sub> and the Calcium Paradox: How a Little-Known Vitamin Could Save Your Life |date=August 27, 2013 |publisher=Harper |isbn=978-0-06-232004-9 |pages=66–67}}</ref>
| 100% MK-4
|-
| [[Butter]]
| 15.0
| 100% MK-4
|-
| Chicken liver (pan-fried)
| 12.6<ref name="Rheaume-Bleue 2013" />
| 100% MK-4
|-
| Chicken leg
| 8.5
| 100% MK-4
|-
| [[Ground beef]] (medium fat)
| 8.1<ref name="Rheaume-Bleue 2013" />
| 100% MK-4
|-
| Calf's liver (pan-fried)
| 6.0<ref name="Rheaume-Bleue 2013" />
| 100% MK-4
|-
| [[Hot dog]]
| 5.7<ref name="Rheaume-Bleue 2013" />
| 100% MK-4
|-
| [[Bacon]]
| 5.6<ref name="Rheaume-Bleue 2013" />
| 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 as food|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){{dagger}}
| 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<ref name="Rheaume-Bleue 2013" />
| 100% MK-4
|-
| [[Mackerel]]
| 0.4
| 100% MK-4
|-
| [[Skimmed milk]] [[yogurt]]
| 0.1
| 100% MK-8
|}
'''Notes:'''
* {{dagger}} – 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 ==
==Dietary sources and adequate intake==
{{multiple issues|section=y|
In 2012, Canadian health writer Kate Rhéaume-Bleue suggested the Recommended Daily Allowance (RDA) for K vitamins (range of 80-120&nbsp;µg) might be too low.<ref>Kate Rhéaume-Bleue, ''Vitamin K<sub>2</sub> and the Calcium Paradox.'' Mississaugua: Wiley, 2012, p. 74.</ref> Earlier suggestions in the scientific literature, which note that the RDA is based on hepatic (i.e. related to the liver) requirements only, date back as far as 1998.<ref>Booth SL, Suttie JW. Dietary intake and adequacy of K vitamins. J Nutr. 1998;128(5):785-8.</ref><ref>Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. 2002;1570(1):27-32.</ref> This hypothesis is supported by the fact that the majority of the Western population exhibits a substantial fraction of undercarboxylated extra-hepatic proteins. Thus, complete activation of coagulation factors is satisfied, but there doesn’t seem to be enough vitamin K<sub>2</sub> for the carboxylation of osteocalcin in bone and MGP in the vascular system.<ref>Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M, Dobnig H. Vascular calcification and osteoporosis--from clinical observation towards molecular understanding. Osteoporos Int. 2007;18(3):251-9.</ref><ref>Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD. Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J Bone Miner Res. 1991;6(11):1211-6.</ref>
{{more citations needed section|date=February 2019}}
Highest concentrations of vitamin K<sub>1</sub> are found in green leafy vegetables, but significant concentrations are also present in non-leafy green vegetables, several vegetable oils, fruits, grains and dairy. In Europe and the USA 60%, or more, of total vitamin K<sub>1</sub> intake is provided by vegetables, the majority by green leafy vegetables. National surveys reveal that K<sub>1</sub> intakes vary widely. Intakes determined by weighed-dietary Intakes are similar in mainland Britain to the USA with average daily intakes of around 70–80 μg, which is less than the adequate intake for vitamin K. Apart from animal livers, the richest dietary source of long-chain menaquinones are fermented foods (from bacteria not moulds or yeasts) typically represented by cheeses (MK-8, MK-9) in Western diets and natto (MK-7) in Japan. Food frequency questionnaire-derived estimates of relative intakes in the Netherlands suggest that ~90% of total vitamin K intakes are provided by K<sub>1</sub>, ~7.5 % by MK-5 through to MK-9 and ~ 2.5% by MK-4. Most food assays measure only fully unsaturated menaquinones; accordingly cheeses have been found to contain MK-8 at 10–20 μg/100g and MK-9 at 35–55 μg/100 g.<ref>Shearer N, Metabolism and cell biology of vitamin K. Thromb Haemost. 2008</ref>
{{primary sources|section|date=February 2019}}
}}
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.<ref>{{cite journal |vauthors=Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ |title=Changes in bone density after exposure to oral anticoagulants: a meta-analysis |journal=Osteoporosis International |volume=9 |issue=5 |pages=441–8 |year=1999 |pmid=10550464 |doi=10.1007/s001980050169 |s2cid=12494428}}</ref>


Furthermore, OAC is often linked to undesired soft-tissue calcification in both children and adults.<ref>{{cite journal |vauthors=Barnes C, Newall F, Ignjatovic V, Wong P, Cameron F, Jones G, Monagle P |title=Reduced bone density in children on long-term warfarin |journal=Pediatric Research |volume=57 |issue=4 |pages=578–81 |date=April 2005 |pmid=15695604 |doi=10.1203/01.pdr.0000155943.07244.04 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Hawkins D, Evans J |title=Minimising the risk of heparin-induced osteoporosis during pregnancy |journal=Expert Opinion on Drug Safety |volume=4 |issue=3 |pages=583–90 |date=May 2005 |pmid=15934862 |doi=10.1517/14740338.4.3.583 |s2cid=32013673}}</ref> 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.<ref>{{cite journal |vauthors=Schurgers LJ, Aebert H, Vermeer C, Bültmann B, Janzen J |title=Oral anticoagulant treatment: friend or foe in cardiovascular disease? |journal=Blood |volume=104 |issue=10 |pages=3231–2 |date=November 2004 |pmid=15265793 |doi=10.1182/blood-2004-04-1277 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Koos R, Mahnken AH, Mühlenbruch G, Brandenburg V, Pflueger B, Wildberger JE, Kühl HP |title=Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography |journal=The American Journal of Cardiology |volume=96 |issue=6 |pages=747–9 |date=September 2005 |pmid=16169351 |doi=10.1016/j.amjcard.2005.05.014}}</ref> 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.<ref>{{cite journal |vauthors=Zieman SJ, Melenovsky V, Kass DA |title=Mechanisms, pathophysiology, and therapy of arterial stiffness |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=25 |issue=5 |pages=932–43 |date=May 2005 |pmid=15731494 |doi=10.1161/01.atv.0000160548.78317.29 |doi-access=}}</ref><ref>{{cite journal |vauthors=Raggi P, Shaw LJ, Berman DS, Callister TQ |title=Prognostic value of coronary artery calcium screening in subjects with and without diabetes |journal=Journal of the American College of Cardiology |volume=43 |issue=9 |pages=1663–9 |date=May 2004 |pmid=15120828 |doi=10.1016/j.jacc.2003.09.068 |doi-access=}}</ref> [[Anticoagulant therapy]] is usually instituted to avoid life-threatening diseases, and high vitamin K intake interferes with anticoagulant effects.{{citation needed|date=February 2019}} Patients on [[warfarin]] (Coumadin) or being treated with other [[vitamin K antagonist]]s are therefore advised not to consume diets rich in K vitamins.{{citation needed|date=February 2019}}
==Dietary intake sources==


== In other organisms ==
Natural K2 is found in cheese, curd, animal liver and bacterial fermented foods, like sauerkraut and natto <ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC500743/?page=1</ref>. The MK-4 form of K2 is often found in relatively small quantities in meat and eggs. The richest source of natural K2 is the traditional Japanese dish [[Nattō|natto]]<ref>Kaneki M, Hodges SJ, Hosoi T, Fujiwara S, Lyons A, Crean SJ, Ishida N, Nakagawa M, Takechi M, Sano Y, Mizuno Y, Hoshino S, Miyao M, Inoue S, Horiki K, Shiraki M, Ouchi Y, Orimo H; ''Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of K vitamins2: possible implications for hip-fracture risk''; Nutrition; 2001; 17(4): 315-321.</ref> made of fermented soybeans and ''[[Bacillus subtilis]]'', which provides an unusually rich source of K<sub>2</sub> as long-chain MK-7: its consumption in [[Northern Japan]] has been linked to significant improvement in K vitamin's status and bone health in many studies. The intense smell and strong taste, however, make this soyfood a less attractive source of K<sub>2</sub> for Westerners' tastes. Supplement food companies sell nattō extract, standardized for K<sub>2</sub> content, in capsules.
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.<ref>{{cite journal |vauthors=Walther B, Karl JP, Booth SL, Boyaval P |title=Menaquinones, bacteria, and the food supply: the relevance of dairy and fermented food products to vitamin K requirements |journal=Advances in Nutrition |volume=4 |issue=4 |pages=463–73 |date=July 2013 |pmid=23858094 |pmc=3941825 |doi=10.3945/an.113.003855}}</ref>


Variations in biosynthetic pathways mean that bacteria also produce analogues of vitamin K<sub>2</sub>. For example, MK9<sub>(II-H)</sub>, 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<sub>(II-H)</sub> form seems to be more biologically active than ''trans'' MK9<sub>(II-H)</sub>.<ref>{{cite journal |last1=Dunphy |first1=Patrick J |last2=Gutnick |first2=David L |last3=Phillips |first3=Philip G |last4=Brodie |first4=Arnold F |title=A New Natural Naphthoquinone in Mycobacterium phlei |journal=Journal of Biological Chemistry |date=January 1968 |volume=243 |issue=2 |pages=398–407 |doi=10.1016/S0021-9258(18)99307-5 |doi-access=free}}</ref> However, with human enzymes, the naturally abundant ''trans'' form is more efficient.<ref>{{cite journal |last1=Cirilli |first1=I |last2=Orlando |first2=P |last3=Silvestri |first3=S |last4=Marcheggiani |first4=F |last5=Dludla |first5=PV |last6=Kaesler |first6=N |last7=Tiano |first7=L |title=Carboxylative efficacy of trans and cis MK7 and comparison with other vitamin K isomers. |journal=BioFactors |date=September 2022 |volume=48 |issue=5 |pages=1129–1136 |doi=10.1002/biof.1844 |pmid=35583412 |pmc=9790681}}</ref>
==Anticoagulants and K<sub>2</sub> supplementation==
Recent studies found a clear association between long-term [[anticoagulant|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/bone mineral content, osteopenia, and increased serum levels of undercarboxylated osteocalcin.<ref>Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ 3rd. Changes in bone density after exposure to oral anticoagulants: a meta-analysis.Osteoporos Int. 1999;9(5):441-8.</ref> Bone mineral density was significantly lower in stroke patients with long-term warfarin treatment compared to untreated patients and osteopenia was probably an effect of warfarin-interference with vitamin K recycling.<ref>Sato Y, Honda Y, Kunoh H, Oizumi K. Long-term oral anticoagulation reduces bone mass in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Stroke. 1997;28(12):2390-4.</ref>
Furthermore, OAC is often linked to an undesired soft-tissue calcification in both children and adults.<ref>Barnes C, Newall F, Ignjatovic V, Wong P, Cameron F, Jones G, Monagle P. Reduced bone density in children on long-term warfarin. Pediatr Res. 2005;57(4):578-81.</ref><ref>Hawkins D, Evans J. Minimising the risk of heparin-induced osteoporosis during pregnancy. Expert Opin Drug Saf. 2005;4(3):583-90</ref> 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.<ref>Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998;18(9):1400-7.</ref> Also in humans on OAC treatment, two-fold more arterial calcification was found as compared to patients not receiving vitamin K antagonists.<ref>Schurgers LJ, Aebert H, Vermeer C, Bültmann B, Janzen J. Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood. 2004 15;104(10):3231-2.</ref><ref>Koos R, Mahnken AH, Mühlenbruch G, Brandenburg V, Pflueger B, Wildberger JE, Kühl HP. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol. 2005;96(6):747-9.</ref> 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.<ref>Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932-43.</ref><ref>Raggi P, Shaw LJ, Berman DS, Callister TQ. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. J Am Coll Cardiol. 2004;43(9):1663-9.</ref> Coumarins, by interfering with vitamin K metabolism, might also lead to an excessive calcification of cartilage and tracheobronchial arteries.


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.<ref>{{cite journal |last1=Hojo |first1=K |last2=Watanabe |first2=R |last3=Mori |first3=T |last4=Taketomo |first4=N |title=Quantitative measurement of tetrahydromenaquinone-9 in cheese fermented by propionibacteria. |journal=Journal of Dairy Science |date=September 2007 |volume=90 |issue=9 |pages=4078–83 |doi=10.3168/jds.2006-892 |pmid=17699024 |doi-access=free}}</ref>
Anticoagulant therapy is usually instituted to avoid life-threatening diseases and a high vitamin K intake interferes with the anticoagulant effect. Patients on [[warfarin]] (Coumadin) treatment, or treatment with other [[vitamin K antagonist]] drugs, are therefore advised not to consume diets rich in K vitamins. However, the latest research proposed to combine vitamins K with OAC to stabilize the INR (International normalized ratio, a laboratory test measure of blood coagulation).


==Toxicity==
== See also ==
* [[Vitamin K]]
There is no upper toxicity associated with of menaquinones (vitamin K<sub>2</sub>). Individuals taking anticoagulant medications, such as warfarin (coumarins) should consult their doctor before taking Vitamin K<sub>2</sub>. All data available at this time 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 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 K<sub>1</sub> or K<sub>2</sub>”. A point of concern is however the potential interference of K vitamins with OAC treatment. Individuals taking anticoagulant medications, such as warfarin (coumarins) should consult their doctor before taking Vitamin K<sub>2</sub>. Animal models involving rats, if generalizable to humans, show that MK-7 is well-tolerated.<ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172146/ Pucaj et al. (Sep 2011) "Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7",] ''Toxicology Mechanisms and Methods'' Vol.21 No.7 pp.520–532</ref>
* [[Phytomenadione|Vitamin K<sub>1</sub>]]
* [[Menadione|Vitamin K<sub>3</sub>]]


==References==
== References ==
{{Reflist|30em}}
{{Reflist}}


{{vitamin}}
{{vitamin}}


[[Category:Vitamins]]
[[Category:Vitamin K]]
[[Category:Vitamin K]]
[[Category:1,4-Naphthoquinones]]
[[Category:Polyenes]]
[[Category:Meroterpenoids]]

Latest revision as of 09:10, 12 November 2024

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 tissue 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 regard to K2 content, in capsule form.[citation needed]

Analysis of foods

[edit]
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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  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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