Vitamin K

Vitamin K comprises a number of fat-soluble naphthoquinone derivatives, with vitamin Ki (phylloquinone) (Figure 4.50) being of plant origin whilst the vitamins K2 (menaquinones) are produced by microorganisms. Dietary vitamin K1 is obtained from almost any green vegetable, whilst a significant amount of vitamin K2 is produced by the intestinal microflora. As a result, vitamin K deficiency is rare. Deficiencies are usually the result of malabsorption of the vitamin, which is lipid soluble. Vitamin K1 (phytomenadione) or the water-soluble menadiol phosphate (Figure 4.57) may be employed as supplements. Menadiol is oxidized in the body to the quinone, which is then alkylated, e.g. with geranylgeranyl diphosphate, to yield a metabolically active product.

Vitamin K is involved in normal blood clotting processes, and a deficiency would lead to haemorrhage. Blood clotting requires the carboxylation of glutamate residues in the protein prothrombin, generating bidentate ligands that allow the protein to bind to other factors. This carboxylation requires carbon dioxide, molecular oxygen, and the reduced quinol form of vitamin K (Figure 4.57). During the carboxylation, the reduced vitamin K suffers epoxidation, and vitamin K is subsequently regenerated by reduction. Anticoagulants such as dicoumarol and warfarin (see page 144) inhibit this last reduction step. However, the polysaccharide anticoagulant heparin (see page 477) does not interfere with vitamin K metabolism, but acts by complexing with blood clotting enzymes.

vitamin K

menadiol phosphate reductase

menadiol phosphate

reductase

Vitamin And Blood Clotting

CO2H prothrombin

H Nn

vitamin K epoxide

Figure 4.57

vitamin K epoxide

Figure 4.57

CO2H prothrombin

H Nn

-co2h

CO2H

OSB, and 1,4-dihydroxynaphthoic acid, or its diketo tautomer, have been implicated in the biosynthesis of a wide range of plant naphthoquinones and anthraquinones. There are parallels with the later stages of the menaquinone sequence shown in Figure 4.55, or differences according to the plant species concerned. Some of these pathways are illustrated in Figure 4.58. Replacement of the carboxyl function by an isoprenyl substituent is found to proceed via a disubstituted intermediate in Catalpa (Bignoniaceae) and

Streptocarpus (Gesneriaceae), e.g. catalponone (compare Figure 4.56), and this can be transformed to deoxylapachol and then menaquinone-1 (Figure 4.58). Lawsone is formed by an oxidative sequence in which hydroxyl replaces the carboxyl. A further interesting elaboration is the synthesis of an anthraquinone skeleton by effectively cycliz-ing a dimethylallyl substituent on to the naph-thaquinone system. Rather little is known about how this process is achieved but many examples are known from the results of labelling studies.

,CO2H

1,4-dihydroxy-naphthoic acid

CO2H

1,4-dihydroxy-naphthoic acid

CO2H

CO2H

catalponone O

deoxylapachol O

menaquinone-1 O

catalponone O

deoxylapachol O

menaquinone-1 O

CO2H

OH

lucidin

alizarin

Figure 4.58

lucidin

alizarin

Figure 4.58

Some of these structures retain the methyl from the isoprenyl substituent, whilst in others this has been removed, e.g. alizarin from madder (Rubia tinctorum; Rubiaceae), presumably via an oxidation - decarboxylation sequence. Hydroxylation, particularly in the terpenoid-derived ring, is also a frequent feature.

Some other quinone derivatives, although formed from the same pathway, are produced by dimethylallylation of 1,4-dihydroxynaphthoic acetate / malonate

acetate / malonate

OH O OH emodin

OH O OH

aloe-emodin

OH O OH emodin

OH O OH

aloe-emodin

Shikimate / 2-oxoglutarate / isoprenoid

alizarin

lucidin

alizarin

lucidin acid at the non-carboxylated carbon. Obviously, this is also a nucleophilic site and alkylation here is mechanistically sound. Again, cyclization of the dimethylallyl to produce an anthraquinone can occur, and the potently mutagenic lucidin from Galium species (Rubiaceae) is a typical example. The hydroxylation patterns seen in the anthraquinones in Figure 4.58 should be compared with those noted earlier in acetate/malonate-derived structures (see page 63). Remnants of the alternate oxygenation pattern are usually very evident in acetate-derived anthraquinones (Figure 4.59), whereas such a pattern cannot easily be incorporated into typical shikimate/2-oxoglutarate/isoprenoid structures. Oxygen sub-stituents are not usually present in positions fitting the polyketide hypothesis.

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