Vitamin K, structure

The vitamin K structure shown earlier is that of K, primarily found in green plants. Vitamin K2 contains from three to six isoprene units (depending on the source), each of which has a double bond. Isoprene, 2-methyl-1,4-butadiene, is found in polymerlike repetitive isoprenoid units in natural rubber, carotenoids, steroids, and smaller compounds... 

Figure 54.1 Warfarin and vitamin K. The dashed line in the vitamin K structure indicates a long hydrocarbon chain (20 carbon atoms in the side chain altogether). There is sufficient similarity in the ring structures of the two compounds for warfarin to act as a molecular mimic, thus counteracting the action of vitamin K (see Appendix 14).

Determination of structural features. The ultraviolet spectrum has been of value in the determination of the structure of several vitamins. Thus the presence of an a-naphthoquinone system in vitamin K was first detected by this means. Also the 4-methylthiazole and the 2 5-dimethyl-6-aminopyridine system was first identified in vitamin Bj (thiamine), a- and /3-Ionones can be distinguished since the former contains two conjugated chromophores and the latter three conjugated chromophores. 

The isoprene-derived molecule whose structure is shown here is known alternately as Coumarin and warfarin. By the former name, it is a widely prescribed anticoagulant. By the latter name, it is a component of rodent poisons. How can the same chemical species be used for such disparate purposes The key to both uses lies in its ability to act as an antagonist of vitamin K in the body. 

Therapeutic Function Anticoagulant, Vitamin K antagonist Chemical Name 3-(Q -acetonyl-p-nitrobenzyl)-4-hydroxycoumarin Common Name Nicoumalone Structural Formula ... 

Chemical Name 2-Methyl-3-(3,7,11,1 5-tetramethvl-2-hexadecenvD-1,4-naphthalenedione Common Name Vitamin K, phytomeanadion, phylloquinone Structural Formula ... 

The formulas of some ARs are given in Figure 11.1, where it can be seen that they have some structural resemblance to both dicoumarol and vitamin K in its quinone form. All possess quinone rings linked to unsubstituted phenyl rings. The phenyl rings of the rodenticides confer hydrophobicity, especially in the relatively large and complex molecules of brodifacoum and flocoumafen. The chemical properties of some ARs are given in Table 11.1... 

Warfarin and the second-generation superwarfarins are ARs that have a structural resemblance to dicoumarol and vitamin K. They act as vitamin K antagonists, thereby retarding or stopping the carboxylation of clotting proteins in the hepatic endoplasmic reticulum. The buildup of nonfunctional, undercarboxylated clotting proteins in the blood leads eventually to death by hemorrhaging. 

Ubiquinone or Q (coenjyme Q) (Figure 12-5) finks the flavoproteins to cytochrome h, the member of the cytochrome chain of lowest redox potential. Q exists in the oxidized quinone or reduced quinol form under aerobic or anaerobic conditions, respectively. The structure of Q is very similar to that of vitamin K and vitamin E (Chapter 45) and of plastoquinone, found in chloroplasts. Q acts as a mobile component of the respiratory chain that collects reducing equivalents from the more fixed flavoprotein complexes and passes them on to the cytochromes. 

Wood, J.M., Brown, D. G. The Chemistry of Vitamin Bj2-Enzymes. Vol. 11, pp. 47-105. Wuthrich, K. Structural Studies of Hemes and Hemoproteins by Nuclear Magnetic Resonance Spectroscopy. Vol. 8, pp. 53-121. 

Antioxidants in fruits and vegetables including vitamin C and (3-carotene reduce oxidative stress on bone mineral density, in addition to the potential role of some nutrients such as vitamin C and vitamin K that can promote bone cell and structural formation (Lanham-New 2006). Many fruits and vegetables are rich in potassium citrate and generate basic metabolites to help buffer acids and thereby may offset the need for bone dissolution and potentially preserve bone. Potassium intake was significantly and linearly associated with markers of bone turnover and femoral bone mineral density (Macdonald and others 2005). 

The last of the fat-soluble vitamins to be identified was vitamin K, found by Dam to be an anti-hemorrhagic factor for young chicks, distinct from vitamin C. Its structure was determined by Dam in collaboration with Karrer. Interest in the vitamin was intensified when it was discovered (Link, 1941) that dicoumarol, present in spoiled sweet clover, was the agent producing hypothrombinemia (giving prolonged blood-clotting time) in cattle. Since vitamin K is structurally similar to dicoumarol, the vitamin was presumptively implicated in thrombin formation. This has been fully substantiated by recent work on the role of vitamin K in the synthesis of prothrombin in the liver. 

The vitamin K requirement is met from the diet (vitamin Ki) and microorganisms in the intestine (vitamin K2). The richest dietary source of vitamin K is green leafy vegetables but it is also present in meat and dairy produce. The structural formulae of vitamin Ki (phylloquinone) and vitamin K2 (menaquinone) are given in Figure 15.15. It was discovered in 1929 by Henrik Dam in Copenhagen, who discovered that it was necessary for the clotting... 

Figure 15.15 Different forms of vitamin K and the structure of an antagonist, warfarin.

Oral anticoagulants. Structurally related to vitamin K, 4-hydroxycouma-rins act as false vitamin K and prevent regeneration of reduced (active) vitamin I< from vitamin K epoxide, hence the synthesis of vitamin K-dependent clotting factors. 

In normal individuals phytonadione and the menaquinones have no activity while in vitamin K deficiency the vitamin promotes the hepatic biosynthesis of factor II (prothrombin), factor VII, factor IX and factor X. Vitamin K functions as an essential cofactor for the enzymatic activation of precursors of these vitamin K dependent clotting factors. The quinone structure of the active form of vitamin K, i.e. reduced vitamin K or hydroquinone. 

Structural formulas of several oral anticoagulant drugs and of vitamin K. The carbon atom of warfarin shown at the asterisk is an asymmetric center. 

Coenzyme Q10 shares a structural similarity with vitamin K, and an interaction has been observed between coenzyme Q10 and warfarin. Coenzyme Q10 supplements may decrease the effects of warfarin therapy. This combination should be avoided or very carefully monitored. 

Figure 2 Molecular structures and IUPAC numbering scheme of organic cofactors occurring in photosynthetic reaction centres (bRC, PS I, PS II). (Bac-teriolpheophytin is the free base of (bacterio)chlorophyll plastoquinone (PQ) is found in PS If phylloquinone or vitamin K, ( VK,) in PS I many bacteria contain ubiquinone (UQ). Shown is also the amino acid tyrosine (Tyr, Y) that is redox active in PS II.

The protein complex of T. elongatus consists of 12 subunits that contain 96 Chi a and 22 carotenoid molecules, 3 [4Fe4S] centres and 2 phylloquinone (vitamin K,) molecules (for molecular structures see Fig. 2). The cofactors of the ET chain are arranged in two branches as pairs of molecules related by a pseudo-C2 axis. After light excitation an electron is donated from the primary donor P700, a pair of chlorophylls, to monomeric chlorophyll a (acceptor A0), phylloquinone (A() and the 3 iron-sulfur centres (F , Oa and B). It has been controversially discussed in the literature whether both highly symmetric pigment branches are... 

The structure of vitamin K is characterized by methylnaphthoquinone rings with a side chain at position 3. It exists naturally in two forms phylloquinone (vitamin Kt 6.13) occurs only in plants, while menaquinones (vitamin K2 6.14) are a family of compounds with a side chain consisting of between 1 and 14 isoprene units. Menaquinones are synthesized only by bacteria (which inhabit the human gastrointestinal tract and thus provide some of the vitamin K required by the body). Menadione (vitamin K3 6.15) is a synthetic compound with vitamin K activity. Unlike Kj and K2, menadione is water soluble and is not active until it is alkylated in vivo. 

The antiscurvy (antiscorbutic) activity was called vitamin C, and when its structure became known it was called ascorbic acid. The fat-soluble factor preventing rickets was designated vitamin D. By 1922, it was recognized that another fat-soluble factor, vitamin E, is essential for full-term pregnancy in the rat. In the early 1930s vitamin K and the essential fatty acids were added to the list of fat-soluble vitamins. Study of the human blood disorders "tropical macrocytic anemia" and "pernicious anemia" led to recognition of two more water-soluble vitamins, folic acid and vitamin B12. The latter is required in minute amounts and was not isolated until 1948. Have all the vitamins been discovered Rats can be reared on an almost completely synthetic diet. However, there is the possibility that for good health humans require some as yet undiscovered compounds in our diet. Furthermore, it is quite likely that we receive some essential nutrients that we cannot synthesize from bacteria in our intestinal tracts. An example may be the pyrroloquinoline quinone (PQQ).e... 

Another important family of quinones, related in structure to those already discussed, are the vitamins K (Fig. 15-24, Box 15-F). These occur naturally as two families. The vitamins K, (phylloquinones) have only one double bond in the side chain and that is in the prenyl unit closest to the ring. This suggests again the possibility of chromanol formation. In the vitamin K2 (menaquinone) series, a double bond is present in each of the prenyl units. A synthetic compound menadione completely lacks the polyprenyl side chain and bears a hydrogen in the corresponding position on the ring. Nevertheless, menadione serves as a synthetic vitamin K, apparently because it can be converted in the body to forms containing polyprenyl side chains. 

The most obvious effect of a deficiency in vitamin K in animals is delayed blood clotting, which has been traced to a decrease in the activity of prothrombin and of clotting factors VII, IX, and X (Chapter 12, Fig. 12-17). Prothrombin formed by the liver in the absence of vitamin K lacks the ability to chelate calcium ions essential for the binding of prothrombin to phospholipids and to its activation to thrombin. The structural differences between this abnormal protein and the normal prothrombin have been pinpointed at the N terminus of the 560 residue glycoprotein.e f Tryptic peptides from the N termini differed in electrophoretic mobility. As detailed in Chapter 12, ten residues within the first 33, which were identified as glutamate residues by the sequence analysis on normal prothrombin, are actually y-carboxyglutamate (Gla). The same amino acid is present near the N termini of clotting factors VII, IX, and X. 

VITAMIN K. Sometimes referred to as the antihemmorhagic vitamin, and. earlier in its development, the prothrombin factor or Koagulations-vitamin, vitamin Kis a substituted derivative of naphthoquinone and occurs in several forms. The designationphylloquinone. or Ki, refers to 2-methyl-3-phytyl-l,4 naphthoquinone the designations famoquinone and prertyl-menaquinone, or K2, refer to 2-difarnesyl-3-methyl-1, 4-naphthoquinone. Menadione, sometimes called oil-soluble vitamin K3, is 2-methyl-1,4-naphthoquinone. The structure of phylloquinone is ... 

Among other naturally occurring substances having quinone-type structures, one of the most important is the blood antihemorrhagic factor, vitamin K, which occurs in green plants and is a substituted 1,4-naphthalenedione ... 

The structure of vitamin Kj has been established by degradation and by synthesis. Surprisingly, the long alkyl side chain of vitamin K, is not necessary for its action in aiding blood clotting because 2-methyl-l,4-naphthoquinone is almost equally active on a molar basis. 

---