Vitamin K is a fat-soluble vitamin that comes in two forms: Vitamin K1 and Vitamin K2.
The members share a naphthoquinone ring and differ in the tail attached to it. Vitamin K1, phylloquinone, comes from plants and carries a saturated phytyl chain. Vitamin K2, the menaquinones, comes from bacteria and carries a chain of repeating isoprene units, the number of which gives each form its name (MK-4, MK-7, MK-9, up to MK-13). It is the tail that decides how long the molecule would stay in blood, which tissue it would reach, and which protein it would activate.
The Discovery: 1929 to 1943
“Henrik Dam’s discovery of Vitamin K”
Henrik Dam, at the University of Copenhagen, was studying whether animals could make their own cholesterol. He fed chicks a sterol-free diet. He discovered that the chicks could produce cholesterol, but they developed a severe, unexpected side effect: uncontrolled hemorrhaging (bleeding) under the skin, into muscles, and within the gastrointestinal tract. Dam attempted to cure the bleeding by adding purified cholesterol back into the chicks’ diet, but it had no effect. This proved that the bleeding was not caused by a lack of cholesterol. Over the following years Dam showed the missing fat was fat-soluble, distinct from vitamins A, D and E, and present in green leaves and hog liver fat. In 1835 he named it Koagulationsvitamin, vitamin K. Dam’s work established that Vitamin K is required for the liver to produce prothrombin, a crucial protein that allows blood to clot. For this groundbreaking discovery, Henrik Dam was awarded the 1943 Nobel Prize in Physiology or Medicine, sharing the honor with American biochemist Edward Doisy, who successfully isolated and determined the chemical structure of the vitamin.
Herbert Almquist (along with E.L. Robert Stokstad) at Berkeley reached similar conclusions around the same time, and noticed that fish meal left to putrefy became a potent source as well. They noticed that while fresh alfalfa was a great source, spoiled or putrefied fish meal also cured the bleeding defect in chicks. He deduced that bacteria were the producing factor.
This work directly led to the understanding that Vitamin K exists in multiple forms. Vitamin K1 (phylloquinone, found in green leaves/plants) and Vitamin K2 (menaquinones, synthesized by bacteria, like those in the putrefied fish meal or the human gut).
K2 Major Blind Spot
It was concluded that vitamin K’s only role was blood coagulation. Because the liver prioritizes blood clotting, it absorbs Vitamin K1 (phylloquinone) quickly to activate clotting factors, satisfying the old bleeding assay. This approach completely overshadowed Vitamin K2 (menaquinones) and vital extra-hepatic proteins like osteocalcin and matrix Gla protein (MGP), which require K2 to guide calcium into the bones and keep it out of the arteries. Even dietary recommendations were built on the blood clotting basis.
The mechanism arrived in 1974. Johan Stenflo in Sweden and Gary Nelsestuen in Minnesota independently identified a modified amino acid in prothrombin: y-carboxyglutamic acid, or Gla. Vitamin K was not a clotting factor here, it was the cofactor for an enzyme that adds a carboxyl group to specific glutamate residues, building a calcium-binding site into whatever protein carries them.
Paul Price at UC San Diego found the first answers. In 1976 his group characterised a Gla protein from bone, later called osteocalcin. In the early 1980s they isolated matrix Gla protein (MGP), expressed in cartilage and in the arterial wall.
The decisive experiment came in 1997, when Gerard Karsenty’s group deleted the MGP gene in mice and published it in Nature. The animals calcified their arteries and cartilage, and most died of aortic rupture within two months. MGP needs carboxylation, carboxylation needs vitamin K, and the liver has first claim on what circulates. A person with entirely normal clotting could still be running short where it counts.
Where Vitamin K2 Stands Now
Japan moved first clinically. Menatetrenone (MK-4 at 45 mg daily) has been prescribed there for osteoporosis since the mid-1990s, supported by Masataka Shiraki’s 2000 trial reporting sustained lumbar bone density and fewer fractures over two years.
The supplement category was built on a 2007 pharmacokinetics paper. Leon Schurgers and Cees Vermeer at Maastricht compared equal doses of K1 and MK-7 and found MK-7 reached higher serum levels, persisted for days rather than hours, and carboxylated osteocalcin in a way K1 did not. This single finding is why almost every commercial K2 supplement on store shelves today uses MK-7, and why scientists use a specific blood marker (dp-ucMGP) to track how well K2 protects your arteries.
However, the common advice that “K1 is just for blood clotting and K2 is for bones” isn’t entirely accurate.
In 2010, researchers made a surprising discovery. Kimie Nakagawa’s group showed that the human enzyme UBIADQ converts dietary K1 into MK-4 in tissue.
In 2001, Japanese scientists found that individuals living in eastern Japan who consume large amounts of natto, which is rich in MK-7, have much fewer cases of hip fractures than people living in the western part of the country.
Several years later, a famous study known as the Rotterdam Study was conducted on almost 5,000 individuals and revealed something similar about the cardiovascular system: those consuming menaquinones in the largest amount had reduced arterial calcification and decreased mortality rate due to heart diseases. At the same time, vitamin K1 provided no benefits for the heart.
The Conclusion
Vitamin K activates at least 17 Gla proteins, most outside the clotting cascade. MGP inhibits vascular calcification and needs vitamin K to do it, MK-7 outperforms K1 on half-life and tissue delivery, carboxylation status responds measurably to MK-7 dose. All of this is well established.
What is still open is that whether better carboxylation equates to reduced risk for fractures and cardiovascular incidents, in whom, in what dosage. Scientists are still debating whether tracking arterial calcium scores even gives us a reliable picture of real-world heart health, or how much MK-4 our bodies naturally craft from simple K1 compared to what we get directly from K2 supplements.
Henrik Dam discovered vitamin K simply because his laboratory chicks wouldn’t stop bleeding without it. Unraveling every biological switch that single cofactor flips has taken decades of relentless science, and the full picture is still being painted.
Frequently Asked Question
Who discovered vitamin K2?
Henrik Dam discovered vitamin K in 1939 and Edward Doisy’s laboratory isolated it in 1939 from putrefied fish meal. Dam and Doisy shared the 1943 Nobel Prize.
Why did it take so long for vitamin K2 to be studied separately from K1?
Early research focused on the coagulation system, where phylloquinone (K1) plays the dominant dietary role, so menaquinone (K2) was studied less as its own subject until the 2000s brought population studies specifically distinguishing the two.
References
Dam, H. (1943). The discovery of vitamin K, its biological functions and therapeutical application [Nobel lecture]. The Nobel Foundation. https://www.nobelprize.org/prizes/medicine/1943/dam/lecture/
Diederichsen, A., Lindholt, J., Möller, S., Øvrehus, K. A., Auscher, S., Lambrechtsen, J., Hosbond, S., Alan, D., Urbonaviciene, G., Becker, S., Fredgart, M. H., Hasific, S., Folkestad, L., Gerke, O., Rasmussen, L., Møller, J., Mickley, H., & Dahl, J. (2022). Vitamin K2 and D in patients with aortic valve calcification: A randomized double-blinded clinical trial. Circulation, 145, 1387–1397. https://doi.org/10.1161/CIRCULATIONAHA.121.057008
Geleijnse, J., Vermeer, C., Grobbee, D., Schurgers, L., Knapen, M., van der Meer, I. M., Hofman, A., & Witteman, J. (2004). Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study. The Journal of Nutrition, 134(11), 3100–3105. https://doi.org/10.1093/jn/134.11.3100
Kaneki, M., Hodges, S. J., Hosoi, T., Fujiwara, S., Lyons, A., Crean, S. J., Ishida, N., Nakagawa, M., Takechi, M., Sano, Y., Mizuno, Y., Hoshino, S., Miyao, M., Inoue, S., Horiki, K., Shiraki, M., Ouchi, Y., & Orimo, H. (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), 315–321. https://doi.org/10.1016/S0899-9007(00)00554-2
Knapen, M. H. J., Drummen, N. E., Smit, E., Vermeer, C., & Theuwissen, E. (2013). Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporosis International, 24(9), 2499–2507. https://doi.org/10.1007/s00198-013-2325-6
Li, T., Wang, Y., & Tu, W. (2023). Vitamin K supplementation and vascular calcification: A systematic review and meta-analysis of randomized controlled trials. Frontiers in Nutrition, 10, Article 1115069. https://doi.org/10.3389/fnut.2023.1115069
Luo, G., Ducy, P., McKee, M. D., Pinero, G. J., Loyer, E., Behringer, R. R., & Karsenty, G. (1997). Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature, 386(6620), 78–81. https://doi.org/10.1038/386078a0
Nakagawa, K., Hirota, Y., Sawada, N., Yuge, N., Watanabe, M., Uchino, Y., Okuda, N., Shimomura, Y., Suhara, Y., & Okano, T. (2010). Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature, 468(7320), 117–121. https://doi.org/10.1038/nature09464
Price, P. A., Otsuka, A. S., Poser, J. W., Kristaponis, J., & Raman, N. (1976). Characterization of a γ-carboxyglutamic acid-containing protein from bone. Proceedings of the National Academy of Sciences, 73(5), 1447–1451. https://doi.org/10.1073/pnas.73.5.1447
Rønn, S. H., Harsløf, T., Oei, L., Pedersen, S. B., & Langdahl, B. L. (2021). The effect of vitamin MK-7 on bone mineral density and microarchitecture in postmenopausal women with osteopenia, a 3-year randomized, placebo-controlled clinical trial. Osteoporosis International, 32(1), 185–191. https://doi.org/10.1007/s00198-020-05638-z
Schurgers, L., Teunissen, K., Hamulyák, K., Knapen, M., Vik, H., & Vermeer, C. (2007). Vitamin K-containing dietary supplements: Comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood, 109(8), 3279–3283. https://doi.org/10.1182/blood-2006-08-040709
Shiraki, M., Shiraki, Y., Aoki, C., & Miura, M. (2000). Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. Journal of Bone and Mineral Research, 15(3), 515–521. https://doi.org/10.1359/jbmr.2000.15.3.515
Stenflo, J., Fernlund, P., Egan, W., & Roepstorff, P. (1974). Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proceedings of the National Academy of Sciences, 71(7), 2730–2733. https://doi.org/10.1073/pnas.71.7.2730
Vossen, L. M., de Leeuw, P., Schurgers, L., Heuts, S., Adriaans, B., de Haan, C., van Varik, B., & Kroon, A. A. (2026). Two years of menaquinone-7 supplementation and coronary artery calcification: A randomized clinical trial. JAMA Cardiology. Advance online publication. https://doi.org/10.1001/jamacardio.2026.1279
