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mmonly 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 34 vitamin k is required for the gamma carboxylation of specific glutamic acid residues within the gla domain of the 17 vitamin k dependent proteins thus a rise in uncarboxylated versions of these proteins 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 34 osteocalcin is involved in calcification of bone tissue the ratio of uncarboxylated osteocalcin to carboxylated osteocalcin increases with vitamin k deficiency vitamin k2 has been shown to lower this ratio and improve lumbar vertebrae bone mineral density 35 matrix gla protein must undergo vitamin k dependent phosphorylation and carboxylation elevated plasma concentration of dephosphorylated uncarboxylated mgp is indicative of vitamin k deficiency 36 synthetic forms edit some synthetic compounds also have vitamin k activity in humans one synthetic drug with vitamin k activity still used in developed countries the uk is menadiol sodium diphosphate unlike natural vitamin k it is water soluble and can be absorbed without the help of bile salts 37 side effects edit no known toxicity is associated with high oral doses of the vitamin k 1 or vitamin k 2 forms of vitamin k so regulatory agencies from us japan and european union concur that no tolerable upper intake levels needs to be set 5 8 9 however vitamin k 1 has been associated with severe adverse reactions such as bronchospasm and cardiac arrest when given intravenously the reaction is described as a nonimmune mediated anaphylactoid reaction with incidence of 3 per 10 000 treatments the majority of reactions occurred when polyoxyethylated castor oil was used as the solubilizing agent 38 non human uses edit menadione a natural 39 compound sometimes referred to as vitamin k 3 is used in the pet food industry because once consumed it is converted to vitamin k 2 40 the us food and drug administration has banned this form from sale as a human dietary supplement because overdoses have been shown to cause allergic reactions hemolytic anemia and cytotoxicity in liver cells 2 4 amino 2 methyl 1 naphthol is a synthetic menadione analog often called vitamin k 5 it has been used as a medicine for vitamin k deficiency research with k 5 suggests it may inhibit fungal growth in fruit juices 41 chemistry edit vitamin k 1 phylloquinone both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain phylloquinone has a phytyl side chain vitamin k 2 menaquinone in menaquinone the side chain is composed of a varying number of isoprenoid residues the most common number of these residues is four since animal enzymes normally produce menaquinone 4 from plant phylloquinone the structure of phylloquinone vitamin k 1 is marked by the presence of a phytyl sidechain 5 vitamin k 1 has an e trans double bond responsible for its biological activity and two chiral centers on the phytyl sidechain 42 vitamin k 1 appears as a yellow viscous liquid at room temperature due to its absorption of violet light in the uv visible spectra obtained by ultraviolet visible spectroscopy 43 the structures of menaquinones vitamin k 2 are marked by the polyisoprenyl side chain present in the molecule that can contain four to 13 isoprenyl units mk 4 is the most common form 5 the large size of vitamin k 1 gives many different peaks in mass spectroscopy most of which involve derivatives of the naphthoquinone ring base and the alkyl side chain 44 a sample of phytomenadione for injection also called phylloquinone conversion of vitamin k 1 to vitamin k 2 edit main article vitamin k 2 in animals the mk 4 form of vitamin k 2 is produced by conversion of vitamin k 1 in the testes pancreas and arterial walls 20 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 45 and in parenterally administered k 1 in rats 46 47 there is evidence that the conversion proceeds by removal of the phytyl tail of k 1 to produce menadione also referred to as vitamin k 3 as an intermediate which is then prenylated to produce mk 4 48 physiology edit in animals vitamin k 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 49 seventeen 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 50 bone metabolism osteocalcin matrix gla protein mgp 51 periostin 52 and gla rich protein 53 54 vascular biology matrix gla protein growth arrest specific protein 6 gas6 55 unknown functions proline rich γ carboxyglutamyl proteins 1 and 2 and transmembrane γ carboxy glutamyl proteins 3 and 4 56 absorption edit 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 k 1 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 regardless of whether raw or cooked 4 less information is available for absorption of vitamin k 2 from foods 4 5 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 k 1 57 the same study predicts potential interaction between sr bi and cd36 proteins as well 57 the drug ezetimibe inhibits npc1l1 causing a reduction in cholesterol absorption in humans and in animal studies also reduces vitamin e and vitamin k 1 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 57 biochemistry edit function in animals edit this section is missing information about invertebrates please expand the section to include this information further details may exist on the talk page january 2021 cyclic mechanism of action of vitamin k vitamin k hydroquinone vitamin k epoxide in both cases r represents the isoprenoid side chain vitamin k is distributed differently within animals depending on its specific homologue vitamin k 1 is mainly present in the liver heart and pancreas while mk 4 is better represented in the kidneys brain and pancreas the liver also contains longer chain homologues mk 7 to mk 13 58 the function of vitamin k 2 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 59 within the cell vitamin k participates in a cyclic process the vitamin undergoes electron reduction to a reduced form called vitamin k hydroquinone quinol catalyzed by the enzyme vitamin k epoxide reductase vkor 60 another enzyme then oxidizes vitamin k hydroquinone to allow carboxylation of glu to gla this enzyme is called gamma glutamyl carboxylase 61 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 restored to vitamin k by vkor the reduction and subsequent reoxidation of vitamin k coupled with carboxylation of glu is called the vitamin k cycle 62 humans are rarely deficient in vitamin k because in part vitamin k 2 is continuously recycled in cells 63 warfarin and other 4 hydroxycoumarins block the action of vkor 24 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 underdose and overdose 25 gamma carboxyglutamate proteins edit main article gla domain 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 and the four transmembrane gla proteins the function of which is at present unknown the gla domain is responsible for high affinity binding of calcium ions ca 2 to gla proteins which is often necessary for their conformation and always necessary for their function 59 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 64 another interesting class of invertebrate gla containing proteins is synthesized by the fish hunting snail conus geographus 65 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 the gla modification signal is different from the vertebrate gla domain 66 function in plants and cyanobacteria edit vitamin k 1 is an important chemical in green plants including land plants and green algae and some species of cyanobacteria where it functions as an electron acceptor transferring one electron in photosystem i during photosynthesis 67 for this reason vitamin k 1 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 1 but it occurs in far smaller quantities in other plant tissues 6 67 detection of vkorc1 homologues active on the k 1 epioxide suggest that k 1 may have a non redox function in these organisms in plants but not cyanobacteria knockout of this gene show growth restriction similar to mutants lacking the ability to produce k 1 68 function in other bacteria edit many bacteria including escherichia coli found in the large intestine can synthesize vitamin k 2 mk 7 up to mk 11 69 but not vitamin k 1 in the vitamin k 2 menaquinone synthesizing bacteria menaquinone transfers two electrons between two different small molecules during oxygen independent metabolic energy production processes anaerobic respiration 70 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 as 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 70 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 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 70 history edit in 1929 danish scientist henrik dam investigated the role of cholesterol by feeding chickens a cholesterol depleted diet 71 he initially replicated experiments reported by scientists at the ontario agricultural college 72 mcfarlane graham and richardson working on the chick feed program at oac 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 73 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 was 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 74 dam and doisy shared the 1943 nobel prize for medicine for their work on vitamin k 1 and k 2 published in 1939 several laboratories synthesized the compound s in 1939 75 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 76 the first published report of successful treatment with vitamin k of life thr...
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