Vitamin K base

The dioxetane rearranges to an epoxide that has a strongly basic alkoxide ion called a vitamin K base. 

The vitamin K base is a strong enough base to remove a proton from the y-carbon of glutamate. 

The glutamate carbanion adds to CO2 to form y-carboxyglutamate, and the protonated vitamin K base (a hydrate) loses water, forming vitamin K epoxide. 

Biochemical Reactions. The quinones in biological systems play varied and important roles (21,22). In insects they are used for defense purposes, and the vitamin K family members, eg, vitamin [11104-38-4] (32) and vitamin [11032-49-8] (33), which are based on 2-meth5l-l,4-naphthoquiaone, are blood-clotting agents (see Vitamins, vitamin k). 

The classical method for the determination of vitamin K is based on the clotting time of a vitamin K-deficient chick. It is relatively easy to produce a hemorraghic state ia chicks (17). Vitamin K-deficient tats have also been used for this assay (18). Owiag to the development of modem chromatographic techniques, this method of analysis has been supplanted by other methodology. 

In a novel approach to vitamin K, Hoffmann-La Roche has exploited the potential acidity at C-3 as a means to attach the side chain of vitamin (36). Menadione was reacted with cyclopentadiene to yield the Diels-Alder adduct. The adduct is treated with base and alkylated at C-3 with phytyl chloride. A retro Diels-Alder reaction yields vitamin K. Process improvements in this basic methodology have been claimed by Japanese workers (37). 

Work in the mid-1970s demonstrated that the vitamin K-dependent step in prothrombin synthesis was the conversion of glutamyl residues to y-carboxyglutamyl residues. Subsequent studies more cleady defined the role of vitamin K in this conversion and have led to the current theory that the vitamin K-dependent carboxylation reaction is essentially a two-step process which first involves generation of a carbanion at the y-position of the glutamyl (Gla) residue. This event is coupled with the epoxidation of the reduced form of vitamin K and in a subsequent step, the carbanion is carboxylated (77—80). Studies have provided thermochemical confirmation for the mechanism of vitamin K and have shown the oxidation of vitamin KH2 (15) can produce a base of sufficient strength to deprotonate the y-position of the glutamate (81—83). 

The fact that pentacarbonyl carbene complexes react with enynes in a chemo-selective and regiospecific way at the alkyne functionality was successfully applied in the total synthesis of vitamins of the Kj and K2 series [58]. Oxidation of the intermediate tricarbonyl(dihydrovitamin K) chromium complexes with silver oxide afforded the desired naphthoquinone-based vitamin K compounds 65. Compared to customary strategies, the benzannulation reaction proved to be superior as it avoids conditions favouring (E)/(Z)-isomerisation within the allylic side chain. The basic representative vitamin K3 (menadione) 66 was synthesised in a straightforward manner from pentacarbonyl carbene complex 1 and propyne (Scheme 38). 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

Increased bilirubin levels are caused due to the intake of large doses of such drugs as chloroquine, vitamin K, sulpha-drugs, tetracyclines, paracetamol, nicotinic acid and monoamine oxidase inhibitors (e.g., iproniazid RP 1.0 nialamide RP 1.8 isocarboxazid RP 3.1 phenelzine RP 18 pheniprazine RP31 and tranylcypromine RP 45), where RP designates the Relative Potency based on the tiyptamine potentiation test. The elevated levels are due to hepatic injury, and... 

Animals fed spoiled sweet clover were prone to fatal haemorrhages. The canse was traced to the presence of dicoumarol. This compound interferes with the effects of vitamin K in blood coagulation, the blood loses its ability to clot, and minor injnries can lead to severe internal bleeding. Synthetic dicoumarol has been nsed as an oral blood anticoagnlant in the treatment of thrombosis, where the risk of blood clots becomes life threatening. It has since been snperseded by warfarin, a synthetic development based on the natnral prodnct. 

Among the vitamin K vitamers, only phylloquinone is accounted for routine food analysis. Furthermore infant formulas, both milk-based and soy protein-based, are supplemented with a synthetic preparation of phylloquinone (the only form admitted) [403], which usually contain about 10% of the biologically inactive ctT-isomer [497]. 

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.

Some results. Rapid kinetic methods have revealed that enzymes often combine with substrates extremely quickly,60 with values of k] in Eq. 9-14 falling in the range of 106 to 108 M 1 s . Helix-coil transitions of polypeptides have relaxation times of about 10-8 s, but renaturation of a denatured protein may be much slower. The first detectable structural change in the vitamin A-based chromophore of the light-operated proton pump bacteriorhodopsin occurs in - 5 x 10 8 s, while a proton is pumped through the membrane in... 

Biochemical Reactions. The quinones in biological systems play varied and important roles. In insects they are used for defense purposes, and the vitamin K family members, which are based on 2-methyl-... 

The fat-soluble vitamins comprise vitamins A, D, E, and K, whose biological activities are attributed to a number of structurally related compounds known as vitamers. Also included are those carotenoids that are precursors of vitamin A. Recommended dietary allowances (RDAs) based on human epidemiological and experimental animal studies have been published in the United States for vitamins A, D, E, and K (1). Other countries and international bodies have compiled similar recommendations. In the United States and Canada, fluid milk is supplemented by law with vitamin D to a level of 400 international units per quart (10 /zg/0.95 L) to meet the RDA of 10 p%. Other commodities, such as margarine, milk products, ready-to-eat breakfast cereals, and dietetic foods, are commonly supplemented with vitamins A, D, and E. Except for infant formulas, vitamin K is not added to foods. The addition of vitamins to a particular processed food is intended to provide a specific proportion of the RDA. 

Enzymatic hydrolysis is a nondestructive alternative to saponification for removing triglycerides in vitamin K determinations. For the simultaneous determination of vitamins A, D, E, and K in milk- and soy-based infant formulas and dairy products fortified with these vitamins (81), an amount of sample containing approximately 3.5-4.0 g of fat was digested for 1 h with lipase at 37°C and at pH 7.7. This treatment effectively hydrolyzed the glycerides, but only partially converted retinyl palmitate and a-tocopheryl acetate to their alcohol forms vitamin D and phyllo-quinone were unaffected. The hydrolysate was made alkaline in order to precipitate the fatty acids as soaps and then diluted with ethanol and extracted with pentane. A final water wash yielded an organic phase containing primarily the fat-soluble vitamins and cholesterol. 

AOAC official method 992.27. Trans-vitamin K, (phylloquinone) in ready-to-feed milk-based infant formula. Liquid chromatographic method. In MP Bueno, ed. Official Methods of Analysis of AOAC International. 16th ed. Arlington, VA AOAC International, 1995, p. 50-6-50-8. 

A simple and effective chemical method was developed for quantitatively reducing quinones, based on their reaction with metallic zinc and zinc ions [248]. Comparison of this method with conventional electrochemical reduction [249-252] revealed the chemical method to be considerably superior. A reduction reaction of vitamin Kj and other quinones in the presence of Zn° and Zn2+ eliminates the need to apply large negative potentials and may also be performed in the absence of any applied electrochemical potential. Some quinones used, such as UQ-10, menadione, and vitamin K, of the menaquinone series (MKs 4-10) could all be reduced to their corresponding hydroquinones in these conditions. 

There are some well-described deficiency syndromes, the well-established therapeutic use of vitamin K antagonists as oral anticoagulants and the well-known positive effects of pantothenic acid on skin hydration/moisturization and wound healing, which apparently lacks scientific solid base. Apart from that there are not many studies available on the treatment of dermatological disorders with these vitamins, either systemically or topically. Even less is known about transdermal penetration, stability, and formulation dependencies of possible topical applications. 

Table 6.1 lists the water-soluble vitamins with their structures and coenzyme forms. Certain portions of the coenzymes are especially important in their biological activities, and they are indicated by arrows. For example, in case of coenzyme A, a thiol ester is formed between its -SH residue and the acyl group being transferred. And in the case of pyridoxal phosphate, its carbonyl residue forms a Schiff base with the amino group of the amino acid that is being decarboxylated. Fat-soluble vitamins (Table 6.2) are also transformed into biologically active substances. However, with the possible exception of vitamin K, these do not operate as prosthetic groups or cosubstrates in specific enzyme reactions. 

Vitamin K, menadione, Q 1 Hx02 (Figure 6.10), which is found in spinach and cabbage and a wide range of other foods and acts as a blood clotter. Warfrin, sometimes administered as a blood thinner , works by disrupting the activity of vitamin K. Vitamin K is also mostly produced by intestinal bacteria. There are some variations of the structure for four similar vitamin K molecules all based upon the structure shown. 

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