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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>}}
{{DISPLAYTITLE:Vitamin K<sub>2</sub>}}
[[File:Menachinon.svg|thumb|class=skin-invert-image|General structure of vitamin K<sub>2</sub> (MK-n)]]
{{Underlinked|date=March 2013}}
'''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.
'''Vitamin K2''' (the menaquinones) is a group name for a family of related compounds, generally subdivided into short-chain menaquinones (with MK-4 as the most important member) and the long-chain menaquinones, of which MK-7, MK-8 and MK-9 are nutritionally the most recognized.


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>
== Forms ==
{{main|Vitamin K}}
All K vitamins are similar in structure: they share a “[[quinone]]” ring, but differ in the saturation and number of the attached carbon and hydrogen atoms (called “side chains”).<ref>Shearer MJ.2003 in Physiology. Elsevier Sciences LTD. 6039-45.</ref> The length is indicated in the name of the particular menaquinone chain (e.g., MK-4 means that four molecular units - called isoprene units - are attached to the main ring) and influences their transport to different target tissues.


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" />
[[File:Vitamin K structures.jpg|thumb|center|400px|Vitamin K structures. MK-4 and MK-7 are both subtypes of K<sub>2</sub>.]]


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>
== Mechanism of action ==
The [[mechanism of action]] of vitamin K2 is similar to vitamin K1. 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 carboxylation of the vitamin K-dependent proteins [i.e., : conversion of peptide-bound glutamic acid (Glu) to γ-carboxy glutamic acid (Gla)].


== Description ==
[[File:Carboxylation reaction vitamin K cycle.png|thumb|center|500px|Carboxylation reaction - 'Vitamin K cycle']]
{{See also|Vitamin K}}
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.
[[Carboxylation]] of vitamin K-dependent proteins, known as Gla-proteins, is important and serves as a recycling pathway to recover vitamin K from its epoxide metabolite (KO) for reuse in carboxylation. Several human Gla-containing proteins synthesized in several different types of tissues have been discovered:

* Coagulation factors (II, VII, IX, X), as well as anticoagulation proteins (C, S, Z). These Gla-proteins are synthesized in the liver and play an important role in blood homeo-stasis.
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.
* Osteocalcin. This non-collagenous protein is secreted by osteoblasts and plays an essential role in the formation of mineral in bone.
[[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 ==
{{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]]

[[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.
* [[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.
* 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. Their 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 ==
== 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
=== Bone density ===
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>
It has been suggested that vitamin K2 may play an important role in maintaining healthy levels of [[bone mineral density]] (BMD). However, data on the subject is inconclusive - some clinical trials show no improvement of BMD after vitamin K supplementation. First indications came from patients with femoral neck fractures, who demonstrated an extremely low level of circulating vitamin K. The strong association between vitamin K2 deficiency and impaired bone health was later proved by both laboratory and clinical studies. It has been found that vitamin K deficiency results in a decreased level of active osteocalcin, which in turn increases the risk for fragile bones.<ref>Booth SL, Broe KE, Peterson JW, Cheng DM, Dawson-Hughes B, Gundberg CM, Cupples LA, Wilson PW, Kiel DP. Associations between K vitamins biochemical measures and bone mineral density in men and women. J Clin Endocrinol Metab. 2004;89(10):4904-9</ref><ref>Knapen MH, Nieuwenhuijzen Kruseman AC, Wouters RS, Vermeer C. Correlation of serum osteocalcin fractions with bone mineral density in women during the first 10 years after menopause. Calcif Tissue Int. 1998;63(5):375-9.</ref> Research also showed that vitamin K2, but not K1 in combination with calcium and vitamin D can decrease bone turnover.<ref>Schurgers LJ,Knapen MH, Vermeer C. K vitamins2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Int. Congr. Series 2007; 179-187</ref> Moreover, a study performed by Knapen et al. clearly demonstrated that vitamin K2 is essential for the maintenance of bone strength in postmenopausal women, and was the factor for improving bone mineral content and femoral neck width.<ref>Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007;18(7):963-72</ref>


=== Utilisation ===
More arguments supporting the unique function of vitamin K2 came from Japan. The Japanese population seems to be at lower risk for bone fractures compared to European and American citizens. This finding would be paradoxical, if levels of calcium consumption were the only factor determining bone density. However, Japanese studies published in 2006 and 2008 link Japan's greater levels of BMD to that country's widespread consumption of [[Nattō|natto]], a traditional breakfast dish made of fermented soybeans. 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. Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and K vitamins.Eur J Epidemiol. 2008;23(3):219-25.</ref><ref>Ikeda Y, Iki M, Morita A, Kajita E, Kagamimori S, Kagawa Y, Yoneshima H. Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. J Nutr. 2006;136(5):1323-8.</ref>
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 ==
Even more striking is the research finding, reported in 2001, that there seems to be an inverse correlation between the amount of natto consumed, in different regions of Japan, and the number of hip fractures. In regions of the country where natto is not part of the daily diet, hip fractures are more common.<ref>Kaneki et al, “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.” Nutrition 2001, 17(4): 315-21.
{{more citations needed section|date=July 2019}}
</ref>
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>


=== Heart calcification ===
== 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}}
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 K2 deficiency, which leads to significant impairment in biological function of MGP, the most potent inhibitor of vascular calcification presently known.
Fortunately, animal research showed that vascular calcification might not only be prevented, but even reversed by increasing the daily intake of vitamin K2.<ref>Schurgers LJ, Spronk HM, Soute BA, et al. Regression of warfarin-induced medial elastocal¬cinosis by high intake of K vitamins in rats. Blood. 2007</ref> The strongly protective effect of K2 and not vitamin K1 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 JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134(11):3100-5.</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 K2 (MK-7 through MK-9) are the most important for efficiently preventing excessive calcium accumulation in the arteries.<ref>Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT A high menaquinone reduces the incidence of coronary heart disease in women. Nutr Metab Cardiovasc Dis. 2009 van Summeren MJ, van Coeverden SC, Schurgers LJ, Braam LA, Noirt F, Uiterwaal CS, Kuis W, Vermeer C. K vitamins status is associated with childhood bone mineral content.Br J Nutr. 2008;1-7.</ref>


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>
== Vitamin K2 and children’s health ==
Laboratory experiments, population-based studies, and clinical trials tightly link better vitamin K status to the attainment of strong and healthy bones. The beneficial role of vitamin K in children was confirmed by van Summeren et al.<ref>van Summeren MJ, van Coeverden SC, Schurgers LJ, Braam LA, Noirt F, Uiterwaal CS, Kuis W, Vermeer C. K vitamins status is associated with childhood bone mineral content.Br J Nutr. 2008;1-7.</ref> that revealed a strong positive association between vitamin K status and bone mineral content. Findings from previous studies indicated also that additional vitamin K intake may improve bone geometry and positively influence the gain in bone mass. In a study of 223 healthy girls (11–12 years), O’Connor et al.<ref>O'Connor E, Mølgaard C, Michaelsen KF, Jakobsen J, Lamberg-Allardt CJ, Cashman KD. Serum percentage undercarboxylated osteocalcin, a sensitive measure of K vitamins status, and its relationship to bone health indices in Danish girls. Br J Nutr. 2007;97(4):661-6.</ref> found a positive relation between vitamin K status and bone mineral density.


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>
Children have much higher bone metabolism than adults, so they need K vitamins in significantly larger quantities. Results from a number of studies suggest however a pronounced vitamin K deficiency in bone. In the majority of examined children, a marked elevation of undercarboxylated osteocalcin was observed, indicative for a poor K vitamin status.<ref>van Summeren M, Braam L, Noirt F, Kuis W, Vermeer C. Pronounced elevation of undercarboxylated osteocalcin in healthy children. Pediatr Res. 2007;61(3):366-70.</ref> A similar observation was made by Kalkwarf et al. showing the interdependence between vitamin K status and bone turnover.<ref>Kalkwarf HJ, Khoury JC, Bean J, Elliot JG. K vitamins, bone turnover, and bone mass in girls. Am J Clin Nutr. 2004t;80(4):1075-80.</ref> This research underlined that the requirement for K vitamins may be higher than the current recommendation, which was set in accordance only with coagulation needs.


== Dietary sources ==
== Absorption profile of different K vitamins ==
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}})
Vitamin K is absorbed along with dietary fat from the small intestine and transported by chylomi-crons in the circulation. 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 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 K1 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 K1 and MK-4. Accumulation of vitamin K in extra-hepatic tissues has direct relevance to vitamin K functions not related to haemostasis.<ref>Martin J. Shearer, Paul Newman. Metabolism and cell biology of vitamin K. Thromb Haemost 2008</ref>


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>
== Dietary sources and adequate intake ==
In 2012, Canadian health writer Denise Rheume-Bleue suggested the Recommended Daily Allowance (RDA) for K vitamins (range of 80-120 mcg) might be too low.<ref>Denise Rheume-Bleue, ''Vitamin K2 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 K2 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>
Highest concentrations of vitamin K1 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 K1 intake is provided by vegetables, the majority by green leafy vegetables. National surveys reveal that K1 intakes are very wide. Intakes determined by weighed-dietary Intakes are similar in mainland Britain to the USA with average intakes of around 70–80 μg/d, 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 K1, ~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>


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]].
== Dietary intake sources ==
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>
Vitamin K2 is preferred by the extra-hepatic tissues (bone, cartilage and vasculature) and is of bacterial origin. Scientific discussions are ongoing as to what extent K2 produced by our intestinal bacteria contributes to our daily vitamin K2 needs. If, however, intestinal bacterial supply was enough to supplement all tissues needing K2, we would not find high fractions of undercarboxylated Gla-proteins in human studies.
Natural K2 is also found in bacterial fermented foods, like mature cheeses and curd. The MK-4 form of K2 is often found in relatively small quantities in meat and eggs.
However, the richest source of Natural K2 is the traditional Japanese dish 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):315-21.</ref> made of fermented soybeans, which provides an unusually rich source of Natural K2 as long-chain MK-7: its consumption in Japan has been linked to significant improvement in K vitamin's status and bone health in many studies. Unfortunately, the intensive smell and “controversial” taste make this soyfood a less attractive source of Natural K2 for Westerners' taste buds.


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.
== Other sources ==
Accumulating evidence suggests that Western society is affected by subclinical deficiency of vitamin K. Moreover, it has been scientifically proven that for optimal bone and vascular health, relatively high in-takes of vitamin K are required. {{fact|date=March 2013}}
The synthetic (and less effective) short-chain vitamin K1 is commonly used in food supplements. In case of vitamin K2, the most popular forms are MK-4 and MK-7.


Supplement companies sell nattō extract reportedly standardized with regard to K<sub>2</sub> content, in capsule form.{{citation needed|date=February 2019}}
== Vitamin K deficiency ==
There are two kinds of vitamin K deficiency: acute and chronic. Widely recognized, acute deficiency is characterized by unusual bleeding from gums, nose, or the gastrointestinal tract. Consequences can be severe, including internal clogging, strokes, lung damage, and death caused by immoderate blood loss.
Newborn infants are at increased risk for acute vitamin K deficiency, because vitamin K is not transported sufficiently across the placenta, and the newborn gut is sterile at the beginning. Thus, there are no bacteria to produce the required amount of vitamin K.
Vitamin K deficiency may also occur with the use anticoagulant drugs (i.e., warfarin or other coumarins), prolonged use of antibiotics, gallbladder disease, and Crohn’s disease. Chronic vitamin K deficiency is less obvious than acute deficiency. It is actually more dangerous because there are no alarming symptoms and the results - impairments in bone, cardiovascular health, and other disease of aging – might be severe.
It had been long believed that vitamin K deficiency is rare. Requirements could be easily met via diet and microbial biosynthesis by bacteria living in the gut. However, recent scientific data show that the amount of vitamin K is not as abundant in the diet as once thought. Even a well-balanced diet might not provide vitamin K in the amounts sufficient for satisfying the body’s needs. This is especially concerning given that, according to researcher CJ Prynne, mean dietary intake of vitamin K is currently significantly lower than it was 50 years ago, while the daily consumption of vitamin K has gradually decreased since 1950.<ref>Prynne CJ, Thane CW, Prentice A, Wadsworth ME. Intake and sources of phylloquinone (vitamin K(1)) in 4-year-old British children: comparison between 1950 and the 1990s. Public Health Nutr. 2005;8(2):171-80.</ref>


=== Analysis of foods ===
This shortage can be partly explained by alterations in food composition (people eat much less green-leafy vegetables, which are rich in vitamin K1) and different preparation practices. Food used to be made in the presence of various bacteria species (synthesizing vitamin K2). Now, sterile conditions introduced by international standards of food manufacturing stop microorganisms, including beneficial flora, from multiplying and penetrating the human body.
Dietary patterns have also changed over decades. For example, children in 1950 derived around 15% of their vitamin K intake from fats and oil sources and 55% from vegetables (excluding potatoes). In the 1990s, 35% came from fats and oils, and just 30% from vegetables.
Moreover, it was shown that all K vitamins are absorbed from the gastrointestinal tract in the small intestine. Bacterial colonies producing menaquinones are located in the colon (large intestine), where the bile salts required for vitamin K uptake are not present. As stated earlier, the efficacy of intestinal vitamin K absorption might be questionable. Further, the presently used Recommended Dietary Intake for vitamin K might be too low The need for complete activation of coagulation factors is satisfied, but it's not enough to fulfill all of vitamin K's benefits.


{| class="wikitable"
== Vitamin K status ==
! Food
Measurement techniques:
! Vitamin K<sub>2</sub> (μg per 100&nbsp;g <br /> or μg/100 ml)<ref name="Schurgers 2000" />{{rp|Table 2}}
* Food frequency questionnaires to determine vitamin K intake. Disadvantage = Rough estimates
! Proportion of compounds
* Circulating vitamin K levels
|-
* Biomarker to reflect vitamin K sufficiency
| [[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 ==
High-performance liquid chromatography is the technique to measure the level of vitamin K in the blood. Disadvantage = However, circulating vitamin K levels correspond to the daily intake of green-leafy vegetables, cheeses, etc.
{{multiple issues|section=y|
The best way to evaluate vitamin K efficiency is to determine the decrease in the circulating undercarboxylated form of the vitamin K-dependent proteins in the blood (e.g., the level of carboxylated osteocalcin or MGP).
{{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 antagonist]]s are therefore advised not to consume diets rich in K vitamins.{{citation needed|date=February 2019}}
== Anticoagulants and K2 supplementation ==
Recent studies found a clear association between long-term 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.


== In other organisms ==
Anticoagulant therapy is usually instituted to avoid life-threatening diseases and a high vitamin K intake interferes with the anticoagulant effect. Patients on coumarin treatment 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.
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>
== An overdose problem – does it exist? ==
There is no known toxicity associated with high doses of menaquinones (vitamin K2).
Individuals taking anticoagulant medications, such as warfarin (coumarins) should consult their doctor before taking Vitamin K2.
Unlike the other fat-soluble vitamins, vitamin K is not stored in any significant quantity in the liver; therefore toxic level is not a described problem. Taking too much of any vitamin or nutritional supplement is not recommended.
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 K1 or K2”.
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 K2.


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>
==References==

== See also ==
* [[Vitamin K]]
* [[Phytomenadione|Vitamin K<sub>1</sub>]]
* [[Menadione|Vitamin K<sub>3</sub>]]

== References ==
{{Reflist}}
{{Reflist}}


==External links==
*[http://www.vitak.com/ Vitak BV - a research company with a long expertise in all aspects of vitamin K and vitamin K-dependent proteins.]
*[http://www.vitamink2.org/ VitaminK2.org - an International Community founded to explore and understand the emerging role of Natural Vitamin K2 in human health.]
{{vitamin}}
{{vitamin}}


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

[[de:Vitamin K2]]
[[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

[edit]
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

[edit]

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

[edit]

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

[edit]

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

[edit]

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

[edit]

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

[edit]

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

[edit]

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

[edit]

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

[edit]

References

[edit]
  1. ^ a b c d Myneni VD, Mezey E (November 2017). "Regulation of bone remodeling by vitamin K2". Oral Diseases. 23 (8): 1021–1028. doi:10.1111/odi.12624. PMC 5471136. PMID 27976475.
  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.
  3. ^ Sato T, Schurgers LJ, Uenishi K (November 2012). "Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women". Nutrition Journal. 11 (93): 93. doi:10.1186/1475-2891-11-93. PMC 3502319. PMID 23140417.
  4. ^ Kang, Min-Ji; Baek, Kwang-Rim; Lee, Ye-Rim; Kim, Geun-Hyung; Seo, Seung-Oh (2022-03-03). "Production of Vitamin K by Wild-Type and Engineered Microorganisms". Microorganisms. 10 (3): 554. doi:10.3390/microorganisms10030554. ISSN 2076-2607. PMC 8954062. PMID 35336129.
  5. ^ Shearer, Martin J.; Newman, Paul (March 2014). "Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis". Journal of Lipid Research. 55 (3): 345–362. doi:10.1194/jlr.R045559. ISSN 0022-2275. PMC 3934721. PMID 24489112.
  6. ^ Vermeer C, Braam L (2001). "Role of K vitamins in the regulation of tissue calcification". Journal of Bone and Mineral Metabolism. 19 (4): 201–6. doi:10.1007/s007740170021. PMID 11448011. S2CID 28406206.
  7. ^ Suttie JW (1995). "The importance of menaquinones in human nutrition". Annual Review of Nutrition. 15: 399–417. doi:10.1146/annurev.nu.15.070195.002151. PMID 8527227.
  8. ^ Weber P (October 2001). "Vitamin K and bone health". Nutrition. 17 (10): 880–7. doi:10.1016/S0899-9007(01)00709-2. PMID 11684396.
  9. ^ Shearer, M. J. (2003). Physiology. Elsevier Sciences. pp. 6039–6045.
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  13. ^ Institute of Medicine, Panel on Micronutrients (2001). "5. Vitamin K". Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academies Press. ISBN 0-309-07279-4. NBK222299.
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  19. ^ Pucaj K, Rasmussen H, Møller M, Preston T (September 2011). "Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7". Toxicology Mechanisms and Methods. 21 (7): 520–32. doi:10.3109/15376516.2011.568983. PMC 3172146. PMID 21781006.
  20. ^ Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL (January 2006). "Vitamin K contents of meat, dairy, and fast food in the U.S. diet". Journal of Agricultural and Food Chemistry. 54 (2): 463–7. doi:10.1021/jf052400h. PMID 16417305.
  21. ^ a b c Schurgers LJ, Vermeer C (November 2000). "Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations". Haemostasis. 30 (6): 298–307. doi:10.1159/000054147. PMID 11356998. S2CID 84592720. Foods purchased in and around Maastricht (Netherlands) – Table 2. Mean of K vitamins (μg/100 g or μg/100 ml)
  22. ^ Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M (2000). "Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals". Journal of Bone and Mineral Metabolism. 18 (4): 216–22. doi:10.1007/s007740070023. PMID 10874601. S2CID 24024697.
  23. ^ Kaneki M, Hodges SJ, Hedges SJ, Hosoi T, Fujiwara S, Lyons A, et al. (April 2001). "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". Nutrition. 17 (4): 315–21. doi:10.1016/s0899-9007(00)00554-2. PMID 11369171.
  24. ^ "On the Trail of the Elusive X-Factor: Vitamin K2 Revealed".
  25. ^ Rocchi R, Zwinkels J, Kooijman M, Garre A, Smid EJ (February 2024). "Development of novel natto using legumes produced in Europe". Heliyon. 10 (5): e26849. Bibcode:2024Heliy..1026849R. doi:10.1016/j.heliyon.2024.e26849. PMC 10923668. PMID 38463896.
  26. ^ a b c Vermeer, Cees; Raes, Joyce; van 't Hoofd, Cynthia; Knapen, Marjo H. J.; Xanthoulea, Sofia (2018). "Menaquinone Content of Cheese". Nutrients. 10 (4): 446. doi:10.3390/nu10040446. PMC 5946231. PMID 29617314.
  27. ^ Fu X, Harshman SG, Shen X, Haytowitz DB, Karl JP, Wolfe BE, Booth SL (June 2017). "Multiple Vitamin K Forms Exist in Dairy Foods". Current Developments in Nutrition. 1 (6): e000638. doi:10.3945/cdn.117.000638. PMC 5998353. PMID 29955705.
  28. ^ a b c d e f g Rhéaume-Bleue, Kate (August 27, 2013). Vitamin K2 and the Calcium Paradox: How a Little-Known Vitamin Could Save Your Life. Harper. pp. 66–67. ISBN 978-0-06-232004-9.
  29. ^ Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ (1999). "Changes in bone density after exposure to oral anticoagulants: a meta-analysis". Osteoporosis International. 9 (5): 441–8. doi:10.1007/s001980050169. PMID 10550464. S2CID 12494428.
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