Vitamin K2

{{Short description|Group of vitamins and bacterial metabolites}} {{more medical citations needed|date=April 2015}} {{DISPLAYTITLE:Vitamin K₂}} thumb|class=skin-invert-image|General structure of vitamin K₂ (MK-n) '''Vitamin K₂''' 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 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.<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 K₂ 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 commonly found in animal products. 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."<ref name=pmid23140417>{{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 |article-number=93 |date=November 2012 |pmid=23140417 |pmc=3502319 |doi=10.1186/1475-2891-11-93 |doi-access=free}}</ref> The MK-4 in animal (including human) tissue is made from dietary plant vitamin K₁. This process can be accomplished by animal tissues alone, as it proceeds in germ-free rodents.<ref name="Shearer"/> * 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 |page=554 |doi=10.3390/microorganisms10030554 |pmid=35336129 |pmc=8954062 |issn=2076-2607 |doi-access=free}}</ref> They are bioavailable: oral consumption of MK-7 "significantly increases serum MK-7 levels and therefore may be of particular importance for extrahepatic tissues".<ref name=pmid23140417/> * 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.<ref name="Myneni-2017" />

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|date=March 2023}} it is no longer used for this purpose.<ref name="Myneni-2017" /> K₃ is now known to be a circulating intermediate in the animal production of MK-4: K₁ is absorbed into the gut and converted into blood K₃ and target tissues convert K₃ into 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>

== Description == {{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.<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.

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. center|thumb|400x400px|class=skin-invert-image|Vitamin K structures. MK-4 and MK-7 are both subtypes of K₂.

== 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" (i.e., in conversion of peptide-bound glutamic acid (glu) to γ-carboxyglutamic 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>

thumb|center|500px|class=skin-invert-image|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:<ref>{{cite web|title=Gene group: Gla domain containing|publisher=HUGO Gene Nomenclature Committee|access-date=9 May 2026|url=https://www.genenames.org/data/genegroup/#!/group/1250}}</ref>

* 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 == There is inconclusive clinical data whether specific vitamin K2 supplementation confers any beneficial effects compared to vitamin K1 which is the most common form in supplements.<ref name="Myneni-2017" /> ''In vitro'' studies show certain cellular effects of vitamin K2 in bone which are not observed with the K1 variant (including bone marrow stem cell (BMSC) proliferation, and stimulation of osteoblast differentiation).<ref name="Myneni-2017" /> The effects of vitamin K2 appear to be accentuated when combined with vitamin D and in the setting of osteoporosis.<ref name="Myneni-2017" />

Research suggests that vitamin K₂ (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>

== Absorption profile == {{more citations needed section|date=July 2019}} Vitamin K is absorbed along with dietary fat from the small intestine and transported by chylomicrons 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 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.<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 (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|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 K₂ for the carboxylation of osteocalcin in bone and 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 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|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 K₁ or K₂". 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 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|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|bibcode=2006JAFC...54..463E }}</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 K₂ 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 K₂ Revealed |access-date=2015-11-30 |archive-date=2016-02-27 |archive-url=https://web.archive.org/web/20160227003251/http://www.westonaprice.org/fat-soluble-activators/x-factor-is-vitamin-k2#fig4 |url-status=dead }}</ref>{{better source needed|date=February 2019}} 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.<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 |article-number=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 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|date=February 2019}}

=== Analysis of foods ===

{| class="wikitable" ! Food ! Vitamin K₂ (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 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&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 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&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 |article-number=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 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<ref name="Rheaume-Bleue 2013">{{cite book |last1=Rhéaume-Bleue |first1=Kate |title=Vitamin K₂ 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 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 == {{multiple issues|section=y| {{more citations needed section|date=February 2019}} {{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 antagonists are therefore advised not to consume diets rich in K vitamins.{{citation needed|date=February 2019}}

== 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.<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 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).<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>

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>

== See also == * Vitamin K * Vitamin K₁ * Vitamin K₃

== References == {{Reflist}}

{{vitamin}}

Category:Vitamin K Category:1,4-Naphthoquinones Category:Polyenes Category:Meroterpenoids