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Vitamin K
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Vitamin K (K from "Koagulations-Vitamin" in German) 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 K1 is also known as phylloquinone or phytomenadione. 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.
There are three synthetic forms of vitamin K, vitamins K3, K4 and K5 which are used in many areas including the pet food industry (vitamin K3) and to inhibit fungal growth (vitamin K5)
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).
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Vitamin K (K from "Koagulations-Vitamin" in German) 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 K1 is also known as phylloquinone or phytomenadione. 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.
There are three synthetic forms of vitamin K, vitamins K3, K4 and K5 which are used in many areas including the pet food industry (vitamin K3) and to inhibit fungal growth (vitamin K5)
Chemical structure
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.
Physiology
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 often (but not always) 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.
14 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:
Recommended amounts
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. The Adequate Intake (AI) of this phytonutrient for adult women is 90 micrograms/day, for infants is 10-20 micrograms/day, for children and adolescents 15-100 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.
Toxicity
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. However, vitamin K3 (menadione) has been shown to be toxic. In fact, the FDA has banned this synthetic form of the vitamin from over-the-counter supplements as large doses have been shown to cause allergic reactions, hemolytic anemia and cytotoxicity in liver cells
Sources of Vitamin K
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.. Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large caloric consumption to meet the USDA recommended levels.
It is believed that phylloquinone's tight binding to the thylakoid membranes in the chloroplasts is the reason behind the poor bioavailability of vitamin K in green plants. For example, cooked spinach has a 4 percent bioavailability of phylloquinone. However when one adds butter to the spinach, the bioavailability increases to 13 percent due to fat's stimulating effect
Phylloquinone (vitamin K1) is the major dietary form of vitamin K.
Menaquinone-4 and Menaquinone-7 (vitamin K2) are found in meat, eggs, dairy and natto. 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%.
Role in disease / deficiency
Average diets are usually not lacking in vitamin K and primary vitamin K deficiency is rare in healthy adults. As previously mentioned, newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include individuals who suffer from liver damage or disease (i.e. Alcoholics), people with cystic fibrosis, inflammatory bowel diseases or those who have recently had abdominal surgeries. Groups which may suffer from secondary vitamin K deficiency include bulimics, those on stringent diets and those taking anti-coagulants. Other drugs which have been associated with vitamin K deficiency include salicylates, barbiturates and cefamandole, although the mechanism is still unknown.There is no difference between the sexes as both males and females are affected equally. Symptoms of deficiency include heavy menstrual bleeding in women, anemia, bruising, and bleeding of the gums or nose .
Biochemistry
Discovery
In 1929, Danish scientist Henrik Dam 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. 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. Several laboratories synthesized the compound in 1939.
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). 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.
Function in the cell
The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al., Nelsestuen et al., and Magnusson et al.) 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). Another enzyme then oxidizes Vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase 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. 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. 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.
Methods of Assessment
Prothrombin time test:
Measures the time required for blood to clot:
Blood sample mixed with citric acid and put in a fibrometer
Delayed clot formation indicates a deficiency
Unfortunately insensitive to mild deficiency as the values do not change until the concentration of prothrombin in the blood has declined by at least 50 percent
Plasma Phylloquinone:
Was found to be positively correlated with phylloquinone intake in elderly British women, but not men
However an article by Schurges et al. reported no correlation between FFQ and plasma phylloquinone
Urinary ?-carboxyglutamic acid:
Urinary Gla responds to changes in dietary Vitamin K intake
Several days are required before any change can be observed
In a study by Booth et al. increases of phylloquinone intakes from 100 ug to between 377-417 ug for 5 days did NOT induce a significant change
Response may be age-specific
Gla-proteins
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. 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.
Function in Bacteria
Many bacteria, such as Escherichia coli found in the large intestine, can synthesize Vitamin K2 (menaquinone), but not Vitamin K1 (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called 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, 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.
Vitamin K Injection in Newborns and Carcinogenicity
Newborn babies are also particularly at risk for vitamin K deficiency as the blood clotting factors of babies are roughly 30 to 60 percent that of adult values due to the reduced synthesis of precursor proteins and the sterility of their guts. Premature babies are at an even higher risk of this deficiency. Human milk contains between 1 and 4 micrograms/litre of vitamin K1, while formula derived milk can contain up to 100 micrograms/litre in supplemented formulas. Vitamin K2 concentrations in human milk appear to be much lower than those of vitamin K1. It is estimated that there is a 0.25 to 1.7 percent occurrence of vitamin K deficiency bleeding (VDKB) in the first week of the infant's life with a prevalence of 2-10 cases per 100,000 births . As a result, in the Committee on Nutrition of the American Academy of Pediatrics (AAP) recommended that 0.5 to 1.0 mg Vitamin K1 be administered to all newborns shortly after birth . Controversy arose in the early 1990’s regarding this practice when two studies were shown suggesting a relationship between parenteral administration of vitamin K and childhood cancer (14). However poor methods and small sample sizes led to the discredit of these studies and a review of the evidence published in 2000 by Ross and Davies found no link between the two .
Vitamin K and Bone Health
Recently vitamin K has also been lauded for its potential role in the increase of bone mass. Studies have proved that supplemental vitamin K promotes osteotrophic processes and slows osteoclastic processes via calcium bonding. In Japan, a form of vitamin K2 is recognized as a treatment for osteoporosis . However the long term effects and benefits are unknown and it remains controversial. Data from the 1998 Nurses Health Study found an inverse relationship between dietary vitamin K1 and the risk of hip fracture. After being given 110 micrograms/day of vitamin K, the main results showed that women who consumed lettuce one or more times per day had a significantly lower risk of hip fracture than women who consumed lettuce one or fewer times per week. In addition to this, high intakes of vitamin D but low intakes of vitamin K may still pose an increased risk of hip fracture hinting at a relationship between these two vitamins [Kanai, T. et al. Serum Vitamin K level and Bone Mineral Density in Postmenopausal Women. International Journal of Gynecology and Obstetrics; 1997; 56:25-30.].
Vitamin K and Alzheimer's Disease
Research into the antioxidant properties of vitamin K indicates that the concentration of vitamin K is lower in the circulation of carriers of the APOE4 gene and recent studies have shown its ability to inhibit cell death due to oxidation in nerve cells. It has been hypothesized that vitamin K may exude an effect on neuronal damage and that supplementation may hold benefits to treating this disease, although more research is necessary in this area
Vitamin K as a Beauty Product
A study published in the Journal of Cosmetic Dermatology examined the effect of applying a gel containing 2% vitamin K plus 0.1% retinol, vitamin E, and vitamin C. Fifty-seven adults with dark circles participated in this 8-week study and the results, while not a slam-dunk, weren't exactly discouraging either: 47% of the testers noted "fair to moderate" improvement in their dark circles. The majority of testers noticed no change, but the treatment was well-tolerated.
Vitamin K and Cancer
At the same time researchers in Japan were studying the role of vitamin K2 in the prevention of bone loss in females with liver disease, they discovered another possible effect of this phytonutrient. This two year study which involved 21 women with viral liver cirrhosis found that women in the supplement group were 90 percent less likely to develop liver cancer A German study performed on men with prostate cancer found a significant inverse relationship between vitamin K2 consumption and advanced prostate cancer
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