Vitamin K structures. MK-4 and MK-7 are both subtypes of K2.
|Use||Vitamin K deficiency, Warfarin overdose|
|Biological target||Gamma-glutamyl carboxylase|
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation (K from koagulation, Danish for "coagulation") or for controlling binding of calcium in bones and other tissues. The complete synthesis involves final modification of these so-called "Gla proteins" by the enzyme gamma-glutamyl carboxylase that uses vitamin K as a cofactor. The presence of uncarboxylated proteins indicates a vitamin K deficiency. Carboxylation allows them to bind (chelate) calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Research suggests that deficiency of vitamin K may also weaken bones, potentially contributing to osteoporosis, and may promote calcification of arteries and other soft tissues.
Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) derivatives. Vitamin K includes two natural vitamers: vitamin K1 (phylloquinone) and vitamin K2 (menaquinone). Vitamin K2, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms. The two most studied ones are menaquinone-4 (MK-4) and menaquinone-7 (MK-7).
Vitamin K1 is made by plants, and is found in highest amounts in green leafy vegetables, because it is directly involved in photosynthesis. It is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K2 in the form of MK-4 (known as menaquinone). Bacteria in the gut flora can also convert K1 into MK-4. All forms of K2 other than MK-4 can only be produced by bacteria, which use these during anaerobic respiration. Vitamin K3 (menadione), a synthetic form of vitamin K, was used to treat vitamin K deficiency, but because it interferes with the function of glutathione, it is no longer used this way.
Average diets are usually not lacking in vitamin K, and primary deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include those who suffer from liver damage or disease (e.g. alcoholics), cystic fibrosis, or inflammatory bowel diseases, or have recently had abdominal surgeries. Secondary vitamin K deficiency can occur in people with bulimia, those on stringent diets, and those taking anticoagulants. Other drugs associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanisms are still unknown. Vitamin K deficiency has been defined as a vitamin K-responsive hypoprothrombinemia which increase prothrombin time and thus can result in coagulopathy, a bleeding disorder. Symptoms of K1 deficiency include anemia, bruising, nosebleeds and bleeding of the gums in both sexes, and heavy menstrual bleeding in women.
Coronary heart disease is associated with lower levels of K2. Vitamin K2 (as menaquinones MK-4 through MK-10) intake level is inversely related to severe aortic calcification and all-cause mortality.
Long-term use of vitamin K antagonists as anticoagulation therapy was associated with lower cancer incidence.
The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin K in 1998. The IOM does not distinguish between K1 and K2 – both are counted as vitamin K. At that time, sufficient information was not available to establish EARs and RDAs for vitamin K. In instances such as these, the board sets Adequate Intakes (AIs), with the understanding that at some later date, AIs will be replaced by more exact information. The current AIs for adult women and men ages 19 and up are 90 and 120 μg/day, respectively. AI for pregnancy is 90 μg/day. AI for lactation is 90 μg/day. For infants up to 12 months, the AI is 2.0–2.5 μg/day; for children ages 1–18 years the AI increases with age from 30 to 75 μg/day. As for safety, the IOM sets tolerable upper intake levels (known as ULs) for vitamins and minerals when evidence is sufficient. Vitamin K has no UL, as human data for adverse effects from high doses are inadequate. Collectively, the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes.
The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in United States. For women and men over age 18 the AI is set at 70 μg/day. AI for pregnancy is 70 μg/day, and for lactation 70 μg/day. For children ages 1–17 years, the AIs increase with age from 12 to 65 μg/day. Japan set AIs for adult women at 65 μg/day and for men at 75 μg/day. The EFSA and Japan AIs are lower than the U.S. RDAs. EFSA and Japan also reviewed safety and concluded—as had the United States—that there was insufficient evidence to set an UL for vitamin K.
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percentage of Daily Value (%DV). For vitamin K labeling purposes, 100% of the Daily Value was 80 μg, but as of May 27, 2016, it was revised upwards to 120 μg, to bring it into agreement with the AI. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower food sales. During the six months following the 1 January 2020 compliance date the FDA planned to work cooperatively with manufacturers to meet the new Nutrition Facts label requirements, and not to focus on enforcement. A table of the old and new adult Daily Values is provided at Reference Daily Intake.
According to the Global Fortification Data Exchange, vitamin K deficiency is so rare that no countries require that foods be fortified. The World Health Organization does not have recommendations on vitamin K fortification.
|Kale, cooked||1⁄2 cup||265||Parsley, raw||1⁄4 cup||246|
|Spinach, cooked||1⁄2 cup||444||Spinach, raw||1 cup||145|
|Collards, cooked||1⁄2 cup||418||Collards, raw||1 cup||184|
|Swiss chard, cooked||1⁄2 cup||287||Swiss chard, raw||1 cup||299|
|Mustard greens, cooked||1⁄2 cup||210||Mustard greens, raw||1 cup||279|
|Turnip greens, cooked||1���2 cup||265||Turnip greens, raw||1 cup||138|
|Broccoli, cooked||1 cup||220||Broccoli, raw||1 cup||89|
|Brussels sprouts, cooked||1 cup||219||Endive, raw||1 cup||116|
|Cabbage, cooked||1⁄2 cup||82||Green leaf lettuce||1 cup||71|
|Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force.|
While these plant sources are high in vitamin K1, the tight binding to thylakoid membranes in chloroplasts makes it less bioavailable, whether raw or cooked, compared to the vitamin in a dietary supplement.
Vitamin K is also part of the suggested treatment regime for poisoning by rodenticide (coumarin poisoning). Vitamin K treatment may only be necessary in people who deliberately have consumed large amounts of rodenticide or have consumed an unknown amount of rodenticide. Patients are given oral vitamin K1 to prevent the negative effects of rodenticide poisoning, and this dosing must sometimes be continued for up to nine months in cases of poisoning by "superwarfarin" rodenticides such as brodifacoum. Oral Vitamin K1 is preferred over other vitamin K1 routes of administration because it has fewer side effects.
Vitamin K is given as an injection to newborns to prevent vitamin K deficiency bleeding (VKDB). The blood clotting factors of newborn babies are roughly 30–60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts, i.e., lack of intestinal bacteria to synthesize vitamin K. Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at 0.25–1.7%, with a prevalence of 2–10 cases per 100,000 births. Human milk contains 1–4 μg/L of vitamin K1, while infant formula can contain up to 100 μg/L. Late onset VKDB, with onset 2 to 12 weeks after birth, can be a consequence of exclusive breastfeeding, especially if there was no preventive treatment. Median prevalence of late onset VKDB was 35 cases per 100,000 live births in infants who had not received prophylaxis at birth.
Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalization, brain damage, and death. Intramuscular injection, typically given shortly after birth, is more effective in preventing vitamin K deficiency bleeding than oral administration, which calls for weekly dosing up to three months of age.
Managing warfarin therapy
The proper anticoagulant action of the anticoagulant drug warfarin is a function of vitamin K intake and drug dose, and due to differing absorption must be individualized for each patient. Vitamin K is a treatment for bleeding events caused by overdose of the drug. The vitamin can be administered by mouth, intravenously or subcutaneously. Oral vitamin K is used in situations when a person's International normalised ratio (INR) is greater than 10 but there is no active bleeding.
Treating coumarin (rodenticide) poisoning
Coumarin is used in the pharmaceutical industry as a precursor reagent in the synthesis of a number of synthetic anticoagulant pharmaceuticals. One subset, 4-hydroxycoumarins, act as vitamin K antagonists. They block the regeneration and recycling of vitamin K. Some of the 4-hydroxycoumarin anticoagulant class of chemicals are designed to have high potency and long residence times in the body, and these are used specifically as second generation rodenticides ("rat poison"). Death occurs after a period of several days to two weeks, usually from internal hemorrhaging. For humans, and for animals that have consumed either the rodenticide or rats poisoned by the rodenticide, treatment is prolonged administration of large amounts of vitamin K.
No known toxicity is associated with high doses of the phylloquinone (vitamin K1) or menaquinone (vitamin K2) forms of vitamin K, so no tolerable upper intake level (UL) has been set. However, vitamin K1 has been associated with severe adverse reactions such as bronchospasm and cardiac arrest when given intravenously as opposed to orally.
Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K2 (as MK-4) and even up to 135 mg per day (45 mg three times daily) of K2 (as MK-4), showed no increase in blood clot risk.
Unlike the safe natural forms of vitamin K1 and vitamin K2 and their various isomers, a synthetic form of vitamin K, vitamin K3 (menadione), is demonstrably toxic at high levels. The U.S. FDA has banned this form from over-the-counter sale in the United States because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.
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The structure of phylloquinone, Vitamin K1, is marked by the presence of a phytyl group. The structures of menaquinones are marked by the polyisoprenyl side chain present in the molecule that can contain four to 13 isoprenyl units.
The three synthetic forms of vitamin K are vitamins K3 (menadione), K4, and K5, which are used in many areas, including the pet food industry (vitamin K3), and to inhibit fungal growth when sprayed on foods (vitamin K5).
Conversion of vitamin K1 to vitamin K2
Vitamin K2 (menaquinone) includes several subtypes. The two most studied ones are menaquinone-4 (menatetrenone, MK-4) and menaquinone-7 (MK-7). The MK-4 form of vitamin K2 is produced by conversion of vitamin K1 in the testes, pancreas, and arterial walls. While major questions still surround the biochemical pathway for this transformation, the conversion is not dependent on gut bacteria, as it occurs in germ-free rats and in parenterally administered K1 in rats. In fact, tissues that accumulate high amounts of MK-4 have a remarkable capacity to convert up to 90% of the available K1 into MK-4. There is evidence that the conversion proceeds by removal of the phytyl tail of K1 to produce menadione as an intermediate, which is then condensed with an activated geranylgeranyl moiety (see also prenylation) to produce vitamin K2 in the MK-4 (menatetrenone) form.
Vitamin K1 (phylloquinone), the precursor of most vitamin K in nature, is an important chemical in green plants, where it functions as an electron acceptor in photosystem I during photosynthesis. For this reason, vitamin K1 is found in large quantities in the photosynthetic tissues of plants (green leaves, and dark green leafy vegetables such as romaine lettuce, kale, and spinach), but it occurs in far smaller quantities in other plant tissues (roots, fruits, etc.). Iceberg lettuce contains relatively little. The function of phylloquinone in plants appears to have no resemblance to its later metabolic and biochemical function (as "vitamin K") in animals, where it performs a completely different biochemical reaction.
Vitamin K (in animals) is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate (Gla) residues. The modified residues are often (but not always) situated within specific protein domains called Gla domains. Gla residues are usually involved in binding calcium, and are essential for the biological activity of all known Gla proteins.
17 human proteins with Gla domains have been discovered; they play key roles in the regulation of three physiological processes:
- Blood coagulation: prothrombin (factor II), factors VII, IX, and X, and proteins C, S, and Z
- Bone metabolism: osteocalcin, also called bone Gla protein (BGP), matrix Gla protein (MGP), periostin, and Gla-rich protein (GRP).
- Vascular biology: growth arrest-specific protein 6 (Gas6)
- Unknown functions: proline-rich γ-carboxyglutamyl proteins (PRGPs) 1 and 2, and transmembrane γ-carboxy glutamyl proteins (TMGs) 3 and 4.
Vitamin K is absorbed through the jejunum and ileum in the small intestine. The process requires bile and pancreatic juices. Estimates for absorption are on the order of 80% for vitamin K1 in its free form - as a dietary supplement - but much lower when present in foods. For example, the absorption of vitamin K from kale and spinach - foods identified as having a high vitamin K content - are on the order of 4% to 17%. Less information is available for absorption of vitamin K2 from foods. The intestinal membrane protein Niemann-Pick C1-like 1 (NPC1L1) mediates cholesterol absorption. Animal studies show that it also factors into absorption of vitamins E and K1. The drug ezetimibe inhibits NPC1L1 causing a reduction in cholesterol absorption in humans, and in animal studies, also reduces vitamin E and vitamin K1 absorption. An expected consequence would be that administration of ezetimibe to people who take warfarin (a vitamin K antagonist) would potentiate the warfarin effect. This has been confirmed in humans.
Function in animals
The function of vitamin K2 in the animal cell is to add a carboxylic acid functional group to a glutamate (Glu) amino acid residue in a protein, to form a gamma-carboxyglutamate (Gla) residue. This is a somewhat uncommon posttranslational modification of the protein, which is then known as a "Gla protein". The presence of two −COOH (carboxylic acid) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate calcium ions. The binding of calcium ions in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called vitamin K-dependent clotting factors discussed below.
Within the cell, vitamin K undergoes electron reduction to a reduced form called vitamin K hydroquinone, catalyzed by the enzyme vitamin K epoxide reductase (VKOR). Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called gamma-glutamyl carboxylase or the vitamin K-dependent carboxylase. The carboxylation reaction only proceeds if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time. The carboxylation and epoxidation reactions are said to be coupled. Vitamin K epoxide is then reconverted to vitamin K by VKOR. The reduction and subsequent reoxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle. Humans are rarely deficient in vitamin K because, in part, vitamin K2 is continuously recycled in cells.
Warfarin and other 4-hydroxycoumarins block the action of VKOR. This results in decreased concentrations of vitamin K and vitamin K hydroquinone in tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of clotting suppression, warfarin treatment must be carefully monitored to avoid overdose.
The following human Gla-containing proteins ("Gla proteins") have been characterized to the level of primary structure: blood coagulation factors II (prothrombin), VII, IX, and X, anticoagulant protein C and protein S, and the factor X-targeting protein Z. The bone Gla protein osteocalcin, the calcification-inhibiting matrix Gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs), the function of which is at present unknown. Gas6 can function as a growth factor to activate the Axl receptor tyrosine kinase and stimulate cell proliferation or prevent apoptosis in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.
Gla proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood-clotting system. In some cases, activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.
Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus. These snails produce a venom containing hundreds of neuroactive peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain two to five Gla residues.
Methods of assessment
An increase in prothrombin time, a coagulation assay, has been used as an indicator of vitamin K status, but it lacks sufficient sensitivity and specificity for this application. Serum phylloquinone (K1) is the most commonly used marker of vitamin K status. Concentrations <0.15 µg/L are indicative of deficiency. Disadvantages include exclusion of the other vitamin K vitamers and interference from recent dietary intake. Vitamin K is required for the gamma-carboxylation of specific glutamic acid residues within the Gla domain of the 17 vitamin K-dependent proteins (VKDPs). Thus, a rise in uncarboxylated VKDPs is an indirect but sensitive and specific marker for vitamin K deficiency. If uncarboxylated prothrombin is being measured, this "Protein induced by Vitamin K Absence/antagonism (PIVKA-II)" is elevated in vitamin K deficiency. The test is used to assess risk of vitamin K deficient bleeding in newborn infants. Osteocalcin is a VKDP involved in calcification of bone tissue. The ratio of uncarboxylated osteocalcin to carboxylated osteocalcin (ucOC/OC) increases with vitamin K deficiency. Vitamin K2 has been shown to lower ucOC/OC and improved lumbar vertebrae bone mineral density. Matrix Gla Protein (MGP) is another VKDP. To become biologically active, MGP must undergo vitamin K dependent phosphorylation and carboxylation. Elevated plasma concentration of dephosphorylated, uncarboxylated MGP (dp-ucMGP) is indicative of vitamin K deficiency. Elevated dp-ucMGP is associated with vascular calcification. Meta-analyses showed that in adults, elevated dp-ucMGP was associated with an increased risk of all-cause mortality and cardiovascular mortality.
Function in bacteria
Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K2 (MK-7 up to MK-11), but not vitamin K1 (phylloquinone). In these bacteria, menaquinone transfers two electrons between two different small molecules, during oxygen-independent metabolic energy production processes (anaerobic respiration). For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, passes two electrons to menaquinone. The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate converts the molecule to succinate or nitrite plus water, respectively.
Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except the final electron acceptor is not molecular oxygen, but fumarate or nitrate. In aerobic respiration, the final oxidant is molecular oxygen (O2), which accepts four electrons from an electron donor such as NADH to be converted to water. E. coli, as facultative anaerobes, can carry out both aerobic respiration and menaquinone-mediated anaerobic respiration.
In 1929, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet. He initially replicated experiments reported by scientists at the Ontario Agricultural College (OAC). McFarlane, Graham and Richardson, working on the chick feed program at OAC, had used chloroform to remove all fat from chick chow. They noticed that chicks fed only fat-depleted chow developed hemorrhages and started bleeding from tag sites. Dam found that these defects could not be restored by adding purified cholesterol to the diet. It appeared that – together with the cholesterol – a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K. Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K1 and K2) published in 1939. Several laboratories synthesized the compound(s) in 1939.
For several decades, the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg).
The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.
The precise function of vitamin K was not discovered until 1974, when three laboratories isolated the vitamin K-dependent coagulation factor prothrombin (factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that, while warfarin-treated cows had a form of prothrombin that contained 10 glutamate (Glu) amino acid residues near the amino terminus of this protein, the untreated cows contained 10 unusual residues that were chemically identified as γ-carboxyglutamate (Gla). The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.
The risk of osteoporosis, assessed via bone mineral density and fractures, was not affected by lower vitamin K food consumption or by people on warfarin therapy - a vitamin K antagonist. There is not enough evidence to support a claim that vitamin K supplementation benefits bone health.
Adequate intake of vitamin K2 is associated with the inhibition of arterial calcification and stiffening, but there have been few interventional studies and no good evidence that vitamin K supplementation is of any benefit in the primary prevention of cardiovascular disease. One 10-year population study, the Rotterdam Study, did show a clear and significant inverse relationship between the highest intake levels of menaquinone (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese) and cardiovascular disease and all-cause mortality in older men and women.
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