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lic 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 threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by smith warner and brinkhous 77 the precise function of vitamin k was not discovered until 1974 when prothrombin a blood coagulation protein was confirmed to be vitamin k dependent when the vitamin is present prothrombin has amino acids near the amino terminus of the protein as γ carboxyglutamate instead of glutamate and is able to bind calcium part of the clotting process 78 research edit osteoporosis edit vitamin k is required for the gamma carboxylation of osteocalcin in bone 79 the risk of osteoporosis assessed via bone mineral density and fractures was not affected for people on warfarin therapy a vitamin k antagonist 80 studies investigating whether vitamin k supplementation reduces risk of bone fractures have shown mixed results 4 79 81 82 cardiovascular health edit matrix gla protein is a vitamin k dependent protein found in bone but also in soft tissues such as arteries where it appears to function as an anti calcification protein in animal studies animals that lack the gene for mgp exhibit calcification of arteries and other soft tissues 4 in humans keutel syndrome is a rare recessive genetic disorder associated with abnormalities in the gene coding for mgp and characterized by abnormal diffuse cartilage calcification 83 these observations led to a theory that in humans inadequately carboxylated mgp due to low dietary intake of the vitamin could result in increased risk of arterial calcification and coronary heart disease 4 in meta analyses of population studies low intake of vitamin k was associated with inactive mgp arterial calcification 84 and arterial stiffness 85 86 lower dietary intakes of vitamin k 1 and vitamin k 2 were also associated with higher coronary heart disease 36 87 when blood concentration of circulating vitamin k 1 was assessed there was an increased risk in all cause mortality linked to low concentration 88 89 in contrast to these population studies a review of randomized trials using supplementation with either vitamin k 1 or vitamin k 2 reported no role in mitigating vascular calcification or reducing arterial stiffness the trials were too short to assess any impact on coronary heart disease or mortality 90 other edit population studies suggest that vitamin k status may have roles in inflammation brain function endocrine function and an anti cancer effect for all of these there is not sufficient evidence from intervention trials to draw any conclusions 4 from a review of observational trials long term use of vitamin k antagonists as anticoagulation therapy is associated with lower cancer incidence in general 91 there are conflicting reviews as to whether agonists reduce the risk of prostate cancer 92 93 references edit 1 2 3 4 5 6 7 8 9 fact sheet for health professionals vitamin k us national institutes of health office of dietary supplements 29 march 2021 retrieved 4 june 2025 1 2 3 4 5 6 7 8 9 10 11 12 13 vitamin k corvallis or micronutrient information center linus pauling institute oregon state university 2026 retrieved 4 june 2025 shearer mj okano t august 2018 key pathways and regulators of vitamin k function and intermediary metabolism annual review of nutrition 38 1 127 151 doi 10 1146 annurev nutr 082117 051741 issn 0199 9885 pmid 29856932 s2cid 207573643 1 2 3 4 5 6 7 8 9 10 11 bp marriott df birt va stallings aa yates eds 2020 vitamin k present knowledge in nutrition eleventh edition london united kingdom academic press elsevier pp 137 154 doi 10 1002 9781119946045 ch15 isbn 978 0 323 66162 1 1 2 3 4 5 6 7 institute of medicine us panel on micronutrients 2001 vitamin k dietary reference intakes for vitamin a vitamin k arsenic boron chromium copper iodine iron manganese molybdenum nickel silicon vanadium and zinc national academy press pp 162 196 doi 10 17226 10026 isbn 978 0 309 07279 3 pmid 25057538 1 2 3 4 5 6 usda national nutrient database for standard reference legacy vitamin k pdf u s department of agriculture agricultural research service 2018 archived from the original pdf on 17 october 2020 retrieved 27 september 2020 overview on dietary reference values for the eu population as derived by the efsa panel on dietetic products nutrition and allergies pdf european food safety authority 2017 1 2 3 sasaki s 2008 dietary reference intakes dris in japan asia pac j clin nutr 17 suppl 2 420 444 pmid 18460442 1 2 tolerable upper intake levels for vitamins and minerals pdf european food safety authority 2006 federal register may 27 2016 food labeling revision of the nutrition and supplement facts labels pdf p 33982 daily value reference of the dietary supplement label database dsld dietary supplement label database dsld archived from the original on 7 april 2020 retrieved 16 may 2020 changes to the nutrition facts label u s food and drug administration fda 27 may 2016 archived from the original on 18 may 2019 retrieved 16 may 2020 this article incorporates text from this source which is in the public domain industry resources on the changes to the nutrition facts label u s food and drug administration fda 21 december 2018 archived from the original on 4 september 2019 retrieved 16 may 2020 this article incorporates text from this source which is in the public domain map count of nutrients in fortification standards global fortification data exchange archived from the original on 11 april 2019 retrieved 3 september 2019 allen l de benoist b dary o et al 2006 guidelines on food fortification with micronutrients pdf world health organization who archived from the original pdf on 24 december 2006 retrieved 3 september 2019 1 2 tarvainen m fabritius m yang b march 2019 determination of vitamin k composition of fermented food food chem 275 515 522 doi 10 1016 j foodchem 2018 09 136 pmid 30724228 s2cid 73427205 1 2 3 4 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 1 2 3 4 5 6 7 8 mihatsch wa braegger c bronsky j et al july 2016 prevention of vitamin k deficiency bleeding in newborn infants a position paper by the espghan committee on nutrition pdf journal of pediatric gastroenterology and nutrition 63 1 123 129 doi 10 1097 mpg 0000000000001232 pmid 27050049 s2cid 4499477 1 2 elder sj haytowitz db howe j et al january 2006 vitamin k contents of meat dairy and fast food in the u s diet journal of agricultural and food chemistry 54 2 463 467 doi 10 1021 jf052400h pmid 16417305 1 2 shearer mj newman p october 2008 metabolism and cell biology of vitamin k thrombosis and haemostasis 100 4 530 547 doi 10 1160 th08 03 0147 pmid 18841274 s2cid 7743991 wong rs cheng g chan np et al january 2006 use of cefoperazone still needs a caution for bleeding from induced vitamin k deficiency am j hematol 81 1 76 doi 10 1002 ajh 20449 pmid 16369967 what is vitamin k deficiency bleeding 24 july 2023 retrieved 18 april 2024 sankar mj chandrasekaran a kumar p et al may 2016 vitamin k prophylaxis for prevention of vitamin k deficiency bleeding a systematic review j perinatol 36 suppl 1 s29 35 doi 10 1038 jp 2016 30 pmc 4862383 pmid 27109090 1 2 whitlon ds s...