Vitamin epoxidation

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 epoxide of vitamin K is involved in the regeneration of the anticoagulant vitamin (a naphthoquinone) from the active hydroquinone form (81JA5939). 

Woodward-Eschenmoser method, 4, 431-440 neo-Vitamin B,2, 4, 421 Vitamin C — see Ascorbic acid Vitamin E — see a-Tocopherol Vitamin K epoxide, 7, 119 synthesis, 1, 439 Vitamins heterocyclic... 

In contrast to the formation and calcification of bones, vitamin K seems to lower the risk of aortic calcification. The mechanisms for these antagonistic effects is not known but a participation of osteocalcin (expressed in artherosclerotic plaques) as well as of matrix Gla protein (MGP) are discussed. In addition, the vitamin K epoxide reductase complex seems to be involved [5]. 

Spronk HM (2006) Vitamin K epoxide reductase complex and vascular calcification is this the important link between vitamin K and the arterial vessel wall Circulation 113 1550-1552... 

Goodstadt, L. and Ponting, C.P. (2004). Vitamin K epoxide reductase homology, active site and catalytic mechanism. Trends in Biochemical Science 29, 289-292. 

Robertson, H.M. (2004). Genes encoding vitamin K epoxide reductase are present in Drosophila and trypanosomatid protists. Genetics 168,1077-1080. 

Vitamin K is the cofactor for the carboxylation of glutamate residues in the post-synthetic modification of proteins to form the unusual amino acid y-carboxygluta-mate (Gla), which chelates the calcium ion. Initially, vitamin K hydroquinone is oxidized to the epoxide (Figure 45-8), which activates a glutamate residue in the protein substrate to a carbanion, that reacts non-enzymically with carbon dioxide to form y-carboxyglut-amate. Vitamin K epoxide is reduced to the quinone by a warfarin-sensitive reductase, and the quinone is reduced to the active hydroquinone by either the same warfarin-sensitive reductase or a warfarin-insensitive... 

It is assumed that in order to have vitamin A activity a molecule must have essentially one-half of its structure similar to that of (i-carotene with an added molecule of water at the end of the lateral polyene chain. Thus, P-carotene is a potent provitamin A to which 100% activity is assigned. An unsubstituted p ring with a Cii polyene chain is the minimum requirement for vitamin A activity. y-Car-otene, a-carotene, P-cryptoxanthin, a-cryptoxanthin, and P-carotene-5,6-epoxide aU have single unsubstimted rings. Recently it has been shown that astaxanthin can be converted to zeaxanthin in trout if the fish has sufficient vitamin A. Vitiated astaxanthin was converted to retinol in strips of duodenum or inverted sacks of trout intestines. Astaxanthin, canthaxanthin, and zeaxanthin can be converted to vitamin A and A2 in guppies. ... 

Carotene cleavage enzymes — Two pathways have been described for P-carotene conversion to vitamin A (central and eccentric cleavage pathways) and reviewed recently. The major pathway is the central cleavage catalyzed by a cytosolic enzyme, p-carotene 15,15-oxygenase (BCO EC 1.13.1.21 or EC 1.14.99.36), which cleaves p-carotene at its central double bond (15,15 ) to form retinal. Two enzymatic mechanisms have been proposed (1) a dioxygenase reaction (EC 1.13.11.21) that requires O2 and yields a dioxetane as an intermediate and (2) a monooxygenase reaction (EC 1.14.99.36) that requires two oxygen atoms from two different sources (O2 and H2O) and yields an epoxide as an intermediate. ... 

Examples of the use of dimethylsulfonium methylide and dimethylsulfoxonium methylide are listed in Scheme 2.21. Entries 1 to 5 are conversions of carbonyl compounds to epoxides. Entry 6 is an example of cyclopropanation with dimethyl sulfoxonium methylide. Entry 7 compares the stereochemistry of addition of dimethylsulfonium methylide to dimethylsulfoxonium methylide for nornborn-5-en-2-one. The product in Entry 8 was used in a synthesis of a-tocopherol (vitamin E). 

Menadione (vitamin K-3, 79) in ethanol in the presence of oxygen was placed in the sun for 10 min to give the 2,3-epoxide (80) [64]. This has been photolysed in micellar solutions to give two main products 2-hydroxy-3-methylnaphtho-quinone and 2,3-dihydro-2-hydroxy-2-methylnaphthoquinone [65]. Solid menadione left on a south-facing windowsill (in Texas ) for a month gave two photodimers the syn head-to-head and syn head-to-tail cyclobutanes. With UV... 

Figure 13 shows the structure and absolute configuration of (2R,3S)-(-) vitamin K3 epoxide. This epoxide, prepared in optically active form by us (70) in 1976, had been known as a racemate since 1939 (78). It has recently been implicated (79) in prothrombin biosynthesis (80). The absolute configuration as shown in Figure 13 is based on the work of Snatzke (76) and the absolute rotation is [ ]436 = — 124° (acetone) and [a] = 0° ( ) (acetone). 

T. M. Guenthner, D. Cai, R. Wallin, Co-Purification of Microsomal Epoxide Hydrolase with the Warfarin-Sensitive Vitamin Kx Oxide Reductase of the Vitamin K Cycle , Biochem. Pharmacol. 1998, 55, 169 - 175. 

The health impairing and toxic elfects of oxidation of lipids are due to loss of vitamins, polyenoic fatty acids, and other nutritionally essential components formation of radicals, hydroperoxides, aldehydes, epoxides, dimers, and polymers and participation of the secondary products in initiation of oxidation of proteins and in the Maillard reaction. Dilferent oxysterols have been shown in vitro and in vivo to have atherogenic, mutagenic, carcinogenic, angiotoxic, and cytotoxic properties, as well as the ability to inhibit cholesterol synthesis (Tai et ah, 1999 Wpsowicz, 2002). 

Nutritional factors may influence the toxicity of pesticides. Research in this area has primarily focused on the role of dietary proteins, particularly sulfur-containing amino acids, trace minerals, and vitamins A, C, D, and E. Studies in rats show that inadequate dietary protein enhances the toxicity of most pesticides but decreases, or fails to affect, the toxicity of a few. The results of these studies have shown that at one-seventh or less normal dietary protein, the hepatic toxicity of heptachlor is diminished as evidenced by fewer enzyme changes (Boyd 1969 Shakman 1974). The lower-protein diets may decrease metabolism of heptachlor to heptachlor epoxide. 

A -tritylaziridine-2-(5)-carboxaldehyde. The application of a novel, sequential, trans-acetalation oxonium ene cyclization has delivered a stereoselective synthesis of the C-aromatic taxane skeleton, and a combinatorial sequence of the regioselective propiolate-ene, catalytic enantioselective epoxidation and carbonyl-ene cyclization reactions has been used to complete the synthesis of the A-ring of a vitamin D hybrid analogue. 

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. 

---