||This article needs more medical references for verification or relies too heavily on primary sources. (November 2015)|
|Use||Vitamin K deficiency|
|Biological target||Gamma-glutamyl carboxylase|
Vitamin K is a group of structurally similar, fat-soluble vitamins the human body requires for complete synthesis of certain proteins that are prerequisites for blood coagulation that the body needs for controlling binding of calcium in bones and other tissues. The vitamin K-related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Low levels of vitamin K also weaken bones and 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 and vitamin K2. 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.
Vitamin K1, also known as phylloquinone, phytomenadione, or phytonadione, is synthesized by plants, and is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis. It may be thought of as the "plant" form of vitamin K. 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.
Bacteria in the gut flora can also convert K1 into vitamin K2. In addition, bacteria typically lengthen the isoprenoid side chain of vitamin K2 to produce a range of vitamin K2 forms, most notably the MK-7 to MK-11 homologues of vitamin K2. All forms of K2 other than MK-4 can only be produced by bacteria, which use these forms in anaerobic respiration. The MK-7 and other bacterially derived forms of vitamin K2 exhibit vitamin K activity in animals, but MK-7's extra utility over MK-4, if any, is unclear and is a matter of investigation.
Three synthetic types of vitamin K are known: vitamins K3, K4, and K5. Although the natural K1 and all K2homologues and synthetic K4 and K5 have proven nontoxic, the synthetic form K3 (menadione) has shown toxicity.
Discovery of vitamin K1
Vitamin K1 was identified in 1929 by Danish scientist Henrik Dam when he investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet. After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. A second compound—together with the cholesterol—apparently 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.
Conversion of vitamin K1 to vitamin K2 in animals
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 (menatetrione) form.
Vitamin K2 (menaquinone) includes several subtypes. The two subtypes most studied are menaquinone-4 (menatetrenone, MK-4) and menaquinone-7 (MK-7).
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 (vitamin K5).
Vitamin K1, the precursor of most vitamin K in nature, is a stereoisomer of phylloquinone, 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.
At this time, 17 human proteins with Gla domains have been discovered, and 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 the recently discovered Gla-rich protein (GRP).
- Vascular biology: growth arrest-specific protein 6 (Gas6)
- Unknown function: proline-rich g-carboxy glutamyl proteins (PRGPs) 1 and 2, and transmembrane g-carboxy glutamyl proteins (TMGs) 3 and 4.
Like other lipid-soluble vitamins (A, D, E), vitamin K is stored in the fat tissue of the human body.
Absorption and dietary need
Previous theory held that dietary deficiency is extremely rare unless the small bowel was heavily damaged, resulting in malabsorption of the molecule. Another at-risk group for deficiency were those subject to decreased production of K2 by normal intestinal microbiota, as seen in broad spectrum antibioticuse. Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics. Diets low in vitamin K also decrease the body's vitamin K concentration. Those with chronic kidney disease are at risk for vitamin K deficiency, as well as vitamin D deficiency, and particularly those with the apoE4 genotype. Additionally, in the elderly there is a reduction in vitamin K2production.
Dietary Reference Intake
The Food and Nutrition Board of the U.S. Institute of Medicine updated an estimate of what constitutes an Adequate Intake (AI) for vitamin K in 2001. At that time there was not sufficient evidence to set the more rigorous Estimated Average Requirement (EAR) or Recommended Dietary Allowance (RDA) given for most of the essential vitamins and minerals. The current AIs for vitamin K for women and men ages 18 and up are 90 μg/day and 120 μg/day, respectively. AI for pregnancy and lactation is 90 μg/day. For infants up to 12 months the AI is 2.0-2.5 μg/day. and for children ages 1–18 years the AI increases with age from 30 to 75 μg/day. As for safety, the FNB also sets Tolerable Upper Intake Levels (known as ULs) for vitamins and minerals when evidence is sufficient. In the case of vitamin K no UL is set, as evidence for adverse effects is not sufficient. Collectively EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes. The European Food Safety Authority reviewed the same safety question and did not set an UL.
For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin K labeling purposes 100% of the Daily Value was 80 μg, but as of May 2016 it has been revised to 120 μg. A table of the pre-change adult Daily Values is provided at Reference Daily Intake. Food and supplement companies have until July 28, 2018 to comply with the change.