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J.Health Sci., 56(6), 623-631, 2010
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New Developments in Research on Vitamin K Biosynthesis
Kimie Nakagawa*
Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
Phylloquinone (PK) is a major form of dietary vitamin K; however, the most prevalent form of vitamin K in humans and animals is menaquinone-4 (MK-4). Despite its high concentrations, the origin of MK-4 is yet to be defined. It is postulated that PK is converted into MK-4 and accumulates in extrahepatic tissues. To clarify this, PK with a deuterium-labelled 2-methyl-1,4-naphthoquinone ring was administered orally to mice and their cerebra were collected for deuterium (D) NMR and liquid chromatography (LC)-MS/MS analyses. We identified labelled MK-4 formed by conversion of the given PK, and this conversion occurred following oral or enteral administration but not parenteral or intracerebroventrical administration. Through the oral route, PK with the deuterium-labelled side chain in addition to the labelled 2-methyl-1,4-naphthoquinone was clearly converted into labelled MK-4 with a non-deuterium-labelled side chain, implying that PK was converted into MK-4 via the removal of an integral side chain. Our results suggest that cerebral MK-4 originates from PK intake, comprising the release of menadione (K3) from PK in the intestine followed by prenylation of K3 into MK-4 in the intestine or other tissues. We recently demonstrated that deuterium-labelled PK (PK-d7) and deuterium-labelled K3 (K3-d8) are converted to deuterium-labelled MK-4 (MK-4-d7) in human osteoblast-like MG-63 cells. Moreover, we identified that the side chain substrate involved in the conversion of PK or K3 to MK-4 is geranylgeranyl diphosphate deriving from the mevalonate pathway. Therefore, MK-4 biosynthesis likely plays an important role in biological functions of the brain and bones.
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