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File:Phylloquinone structure.svg
File:Menaquinone.svg

Vitamin K (K from "Koagulations-Vitamin" in German, Danish, Swedish and Norwegian[1]) denotes a group of lipophilic, hydrophobic vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation. Chemically they are 2-methyl-1,4-naphthoquinone derivatives.

Vitamin K2 (menaquinone, menatetrenone) is normally produced by bacteria in the intestines, and dietary deficiency is extremely rare unless the intestines are heavily damaged, are unable to absorb the molecule, or due to decreased production by normal flora, as seen in broad spectrum antibiotic use[How to reference and link to summary or text].

Chemical structureEdit

All members of the vitamin K group of vitamins share a methylated naphthoquinone ring structure, and vary in the aliphatic side chain attached at the 3-position (see figure 1). Phylloquinone (also known as vitamin K1) invariably contains in its side chain four isoprenoid residues, one of which is unsaturated.

Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids.

It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.

PhysiologyEdit

Vitamin K is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate residues (abbreviated Gla-residues). The modified residues are situated within specific protein domains called Gla domains. Gla-residues are usually involved in binding calcium. The Gla-residues are essential for the biological activity of all known Gla-proteins.[2]

At this timeTemplate:Dated maintenance category 14 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:

Recommended amountsEdit

The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) of Vitamin K for a 25-year old male is 120 micrograms/day. In 2002 it was found that to get maximum carboxylation of osteocalcin, one may have to take up to 1000 mcg of Vitamin K1. Like other liposoluble vitamins [vitamins A, D, E], vitamin K is stored in the fat tissue of the human body. Although allergic reaction is possible, there is no known toxicity associated with high doses of the phylloquinone (vitamin K1) or menaquinone (vitamin K2) forms of vitamin K and therefore no Tolerable Upper Intake Level (UL) have been set.[6]

Sources of Vitamin KEdit

Vitamin K is found chiefly in leafy green vegetables such as spinach, swiss chard, and Brassica (e.g. cabbage, kale, cauliflower, broccoli, and brussels sprouts); some fruits such as avocado and kiwifruit are also high in Vitamin K. By way of reference, two tablespoons of parsley contain 153% of the recommended daily amount of vitamin K.[7]. Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large caloric consumption to meet the USDA recommended levels.[8]

Phylloquinone (vitamin K1) is the major dietary form of vitamin K.
Menaquinone-4 and Menaquinone-7 (vitamin K2) are found in meat, eggs, dairy [9] and natto[10]. MK-4 is synthesized by animal tissues, the rest (mainly MK-7) are synthesized by bacteria during fermentation. In natto 0% of vitamin K is from MK-4 and in cheese 2-7%.[11]

Role in disease / deficiencyEdit

Main article: Vitamin K deficiency

Vitamin K-deficiency may occur by disturbed intestinal uptake (such as would occur in a bile duct obstruction), by therapeutic or accidental intake of vitamin K-antagonists or, very rarely, by nutritional vitamin K deficiency.

Use on newborn babiesEdit

Template:Unencyclopedic In some countries, Vitamin K is routinely given to newborn babies, orally or by injection. Vitamin K is used as prophylactic measure to prevent late-onset haemorrhagic disease (HDN). As HDN is relatively rare, some parents decline Vitamin K protocol for their newborn; most pediatricians, however, highly recommend the prophylactic dose for adequate protection. Newborns have the right amount of Vitamin K in their bodies at about eight days of age, unless HDN runs in your family, Vitamin K injections are not necessary. If you still feel it is needed, you may use an oral Vitamin K, which does not harm the newborn in any way.Template:Nonspecific

BiochemistryEdit

DiscoveryEdit

In 1929, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.[12] After several weeks, the animals developed hemorrhages and started bleeding. 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.[13] Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on Vitamin K. Several laboratories synthesized the compound in 1939.[14]

For several decades the vitamin K-deficient chick model was the only method of quantitating 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). [15] 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.[16]

Function in the cellEdit

The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al.[17], Nelsestuen et al.[18], and Magnusson et al.[19]) 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 amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues which were chemically identified as gamma-carboxyglutamate, or 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 biochemistry of how Vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world. Within the cell, Vitamin K undergoes electron reduction to a reduced form of Vitamin K (called Vitamin K hydroquinone) by the enzyme Vitamin K epoxide reductase (or VKOR).[20] Another enzyme then oxidizes Vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase[21][22] or the Vitamin K-dependent carboxylase. The carboxylation reaction will only proceed 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 reactions. Vitamin K epoxide is then re-converted to Vitamin K by the Vitamin K epoxide reductase. These two enzymes comprise the so-called Vitamin K cycle.[23] One of the reasons why Vitamin K is rarely deficient in a human diet is because Vitamin K is continually recycled in our cells.

Warfarin and other coumarin drugs block the action of the Vitamin K epoxide reductase.[24] This results in decreased concentrations of Vitamin K and Vitamin K hydroquinone in the 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 suppression of the clotting, Warfarin treatment must be carefully monitored to avoid over-dosing. See Warfarin.

Gla-proteinsEdit

At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and 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 that activates the Axl receptor tyrosine kinase and stimulates cell proliferation or prevents 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. Remarkably, 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.[25] These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2-5 Gla residues.[26]

Function in BacteriaEdit

Many bacteria, such as Escherichia coli found in the large intestine, can synthesize Vitamin K2 (menaquinone),[27] but not Vitamin K1 (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called anaerobic respiration.[28] 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, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate will convert the molecule to succinate or nitrite + water, respectively. Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except that the final electron acceptor is not molecular oxygen, but say 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.) Escherichia coli can carry out aerobic respiration and menaquninone-mediated anaerobic respiration.

CarcinogenicityEdit

Vitamin K substances are IARC Group 3 carcinogens. One study conducted in the United Kingdom in 1970 found a nearly two-fold increase of leukaemia in children administered synthetic Vitamin K1 phytomenadione intramuscularly[29], but later studies have failed to find whether Vitamin K is carcinogenic or not.[30][31][32][33]

ReferencesEdit

  1. Dam, Henrik (1935), "[http://www.biochemj.org/bj/029/1273/0291273.pdf The Antihaemorrhagic Vitamin Of The Chick]", Biochemical Journal XXIX (82): 1273–1285, http://www.biochemj.org/bj/029/1273/0291273.pdf 
  2. Furie B, Bouchard BA, Furie BC (Mar 1999). Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid. Blood 93 (6): 1798–808.
  3. Mann KG (1999). Biochemistry and physiology of blood coagulation. Thromb. Haemost. 82 (2): 165–74.
  4. Price PA (1988). Role of vitamin-K-dependent proteins in bone metabolism. Annu. Rev. Nutr. 8: 565–83.
  5. Berkner KL, Runge KW (2004). The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J. Thromb. Haemost. 2 (12): 2118–32.
  6. Higdon Vitamin K. Linus Pauling Institute, Oregon State University. URL accessed on 2008-04-12.
  7. Nutrition Facts and Information for Parsley, raw
  8. Nutrition facts, calories in food, labels, nutritional information and analysis – NutritionData.com
  9. Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL (January 2006). Vitamin k contents of meat, dairy, and fast food in the u.s. Diet. J. Agric. Food Chem. 54 (2): 463–7.
  10. Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M (2000). Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals. J. Bone Miner. Metab. 18 (4): 216–22.
  11. On the Trail of the Elusive X-Factor: Vitamin K2 Revealed.
  12. Dam, H. (1935). The Antihæmorrhagic Vitamin of the Chick.: Occurrence And Chemical Nature. Nature 135 (3417): 652–653.
  13. MacCorquodale, D. W., Binkley, S. B.; Thayer, S. A.; Doisy, E. A. (1939). On the constitution of Vitamin K1. Journal of the American Chemical Society 61: 1928–1929.
  14. Fieser, L. F. (1939). Synthesis of Vitamin K1. Journal of the American Chemical Society 61: 3467–3475.
  15. Dam, Henrik (December 12, 1946). The discovery of vitamin K, its biological functions and therapeutical application. Nobel Prize lecture
  16. Warner, E. D., Brinkhous, K. M.; Smith, H. P. (1938). . Proceedings of the Society of Experimental Biology and Medicine 37: 628.
  17. Stenflo J, Fernlund P, Egan W, Roepstorff P., Vitamin K-dependent modifications of glutamic acid residues in prothrombin, Proceedings of the National Academy of Sciences, USA, 1974, 71:2730–3. PMID 4528109
  18. Nelsestuen GL, Zytkovicz TH, Howard JB., The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin, Journal of Biological Chemistry, 1974, 249(19):6347-50. PMID 4214105
  19. Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A, Primary structure of the vitamin K-dependent part of prothrombin. FEBS Letters, 1974, 44(2):189-93. PMID 4472513
  20. Oldenburg J, Bevans CG, Muller CR, Watzka M, Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle, Antioxidants and Redox Signaling, 2006, 8(3-4):347-53. Review. PMID 16677080
  21. Suttie JW, Vitamin K-dependent carboxylase, Annual Review of Biochemistry,1985, 54:459-77. Review. PMID 3896125
  22. Presnell SR, Stafford DW, The vitamin K-dependent carboxylase, Thrombosis and Haemostasis, 2002, 87(6):937-46. Review. PMID 12083499
  23. Stafford DW, The vitamin K cycle, Journal of Thrombosis Haemostasis, 2005, (8):1873-8. Review. PMID 16102054
  24. Whitlon DS, Sadowski JA, Suttie JW, Mechanisms of coumadin action: significance of vitamin K epoxide reductase inhibition, Biochemistry, 1978, 17:1371–7. PMID 646989
  25. Terlau H, Olivera BM. Conus venoms: a rich source of novel ion channel-targeted peptides, Physiological Reviews, 2004, 84(1):41-68. Review. PMID 14715910
  26. Buczek O, Bulaj G, Olivera BM, Conotoxins and the posttranslational modification of secreted gene products, Cell and Molecular Life Sciences, 2005, 62(24):3067-79. Review. PMID:16314929
  27. Bentley, R, Meganathan, R., Biosynthesis of Vitamin K (menaquinone) in Bacteria, Bacteriological Reviews, 1982, 46(3):241-280. Review.
  28. Haddock, BA, Jones, CW, Bacterial Respiration, Bacteriological Reviews, 1977, 41(1):74-99. Review.
  29. Vitamin K: controversy? what controversy?
  30. (2003) Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn. Pediatrics 112 (1 Pt 1): 191–2.
  31. Fear NT, Roman E, Ansell P, Simpson J, Day N, Eden OB (2003). Vitamin K and childhood cancer: a report from the United Kingdom Childhood Cancer Study. Br. J. Cancer 89 (7): 1228–31.
  32. von Kries R (1999). Oral versus intramuscular phytomenadione: safety and efficacy compared. Drug Saf 21 (1): 1–6.
  33. IARC Monograph volume 76. URL accessed on 2008-03-07.


External links Edit


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Template:Enzyme cofactors

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