Phylloquinone, biosynthesis

Biosynthesis of naphthoquinones lawsone and juglone starts, similarly to phylloquinone biosynthesis, from the shikimic acid metabolite chorismic acid, and proceeds via the intermediate l,4-dihydroxy-2-naphthoic acid. The precursor of alkannin is 4-hydroxybenzoic acid, which is another metabolite of... 

An example of a biological Friedel-Crafts reaction occurs during the biosynthesis of phylloquinone, or vitamin Kl( the human blood-clotting factor. Phylloquinone is formed by reaction of 1,4-dihydroxynaphthoic acid with phytyl diphosphate. Phytyl diphosphate first dissociates to a resonance-stabilized allylic carbocation, which then substitutes onto the aromatic ring in the typical way. Several further transformations lead to phylloquinone (Figure 16.10). 

Figure 16.10 Biosynthesis of phylloquinone (vitamin K-j) from 1,4-dihydroxynaphthoic acid. The key step that joins the 20-carbon phytyl side chain to the aromatic ring is a Friedel-Crafts-like electrophilic substitution reaction.

Human milk contains about 2 xg/L of vitamin K. Vitamin K denotes a group of compounds containing the 2-methyl-1,4-naphthoquinone chemical moiety. Phylloquinone is the plant form of the vitamin and is the most prevalent homologue in milk. The vitamin is required for the biosynthesis of prothrombin and many other essential blood-clotting factors (Jensen, 1992). 

Biosynthesis. The asymmetric incorporation of 4-(2 -carboxyphenyl-4-oxobu-tyrate [o-succinylbenzoate (211)] into phylloquinone by Zea mays has been reported. The incorporation of (211), via its coenzyme A thioester, into l,4-dihydroxy-2-naphthoic acid (212) and menaquinone has been studied in cell-free extracts of Mycobacterium phlei and Micrococcus luteus. The biosynthesis and metabolism of menaquinone-4 in the crab has been described. A soluble enzyme complex capable of converting 2-octaprenylphenol (213) into... 

CjiHioOs, Mr 222.20, mp. 135-137 °C. An intermediate in the biosynthesis of 1,4-dihydroxynaphthalene-2-carboxylic acid, which in turn is a precursor of alizarin(e), menaquinone (vitamin K3), and vitamin K] (phylloquinone). The biosynthesis proceeds from isochorismic acid and 2-oxoglutaric acid. 

This suspension culture of Morinda cells is being studied because the biosynthesis of anthraquinones and its glycosides can be triggered in the culture. Upon transfer of cells into darkness and a medium containing sucrose the chlorophyll decreases and the lipoquinones (including phylloquinone) disappear from the cells (Table 1). Simultaneously, anthraquinone pigments are formed (Fig. 4) and the cultured cells turn yellow and eventually red. Thus, in the suspension culture photoautotrophy correlates with lipoquinone synthesis while heterotrophy correlates with anthraquinone synthesis. This reflects the situation in the intact plants where lipoquinones are associated with chloroplast whereas anthraquinones occur in the roots. 

The fact that phylloquinone and anthraquinone biosynthesis share a common biosynthetic pathway in the initial steps raises two questions how is the metabolic shift... 

One of the open questions in anthraquinone biosynthesis is the nature of the branching compound X (Fig. 4). In vitamin K2 biosynthesis 1,4-dihydroxy-2 naphthoic acid (V) is involved (vide supra). It may also be an intermediate in phylloquinone s and anthraquinone biosynthesis. Feeding experiments established that anthraquinones in Rubia, Morinda and Galium >28,2 9 derived from shikimic acid, a-ketoglutaric acid and mevalonic acid with -succinylben-zoic acid being a key intermediate. Incorpo-... 

While the biosynthesis of vitamin Ki (phylloquinone) may proceed through 1,4-dihydroxy-2-naphthoic acid (DHNA) (V), > 9 an alternative route has been suggested (Fig. 

Therapy. The therapeutic importance of vitamin K has been extensively reviewed (Mount et al, 1982). Included in this class of chemicals is a group of naphthoquinone derivatives with anti-hemorrhagic characteristics. Natural vitamin K is composed of a series of phylloquinones and menaquinone derivatives of which vitamin and vitamin K2 are respective representatives. Vitamin K3, or menadione, is the synthetic water-soluble form which can be converted to the vitamin K2 derivatives in animals (Mount et al, 1982). The requirement for vitamin K (Table 5) is met by a combination of dietary intake (vitamin K ) and microbiolgical biosynthesis in the gut (vitamin K2). Vitamin which is stored in the liver, is the preferred therapeutic agent rather than the poorly stored menadione. 

Isochorismate is linked to the formation of o-hydroxybenzoic acid (salicylate), as well as 2,3-dihydroxybenzoic acid required for enterobactin biosynthesis (Scheme 11.87). Isochorismate is also a precursor to the vitamins K phylloquinone and mena-quinone (Scheme 11.88). 

Phylloquinone and menaquinone are derived from chorismic acid, which results from 3-phosphoenolpyruvic acid (a product of glycolysis) and D-erythrose 4-phosphate (a product of the pentose and Calvin cycles) as a starting compound for the biosynthesis of phenylalanine, tyrosine and tryptophan. It is transformed into iso-chorismic acid other carbon atoms are derived from 2-oxoglutaric acid. The side chain is provided by ph)4yl diphosphate or by polyprenyl diphosphates, which are formed from geranylgeranyl diphosphate. The final reaction is a methylation at C-2. 

Examination of some of the features of the biosynthesis of phylloquinones such as (9) in higher plants and of menaquinones (10) in bacteria has shown that the pol5qjrenyl chains and nuclear C methyl groups arise imexceptionally from (R)-mevalonic acid (11) and L-methionine respectively The aspect of biosynthesis which has commanded most attention is the building of the naphthoquinone nucleus from (—)-shikimic acid and almost all of the critical and pertinent observations upon this intriguing problem have been made in relation to menaquinones from bacterial sources. 

FIGURE 119.2 Proposed biosynthetic pathway of phylloquinone in Synechocystis sp. PCC 6803. The genes responsible for the biosynthesis of menaquinone were initially described in E. colt. The homologs of these genes were identified in the genome sequence of Synechocystis sp. PCC 6803, and menA, menB, menD, menE, and menG were confirmed by experiment. 

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