New Development of Vitamin K Research: Identification of Human Menaquinone-4 Biosynthetic Enzyme

Natural vitamin K is found in two forms: a plant form, phylloquinone (PK) and bacterial forms, menaquinones (MKs). In many species, including humans, PK is a minor constituent of hepatic vitamin K content, with most hepatic vitamin K content comprising long-chain MKs. Menaquinone-4 (MK-4) is ubiquitously present in extrahepatic tissues, with particularly high concentrations in the brain, kidney and pancreas of humans and rats. It has consistently been shown that PK is endogenously converted to MK-4. The molecular mechanisms for these conversion reactions have been unclear. To identify the MK-4 biosynthetic enzyme, we screened the human genome database for prenylation enzyme. We found UbiA prenyltransferase domain containing 1 (UBIAD1), a human homologue of Escherichia coli prenyltransferase menA. The short interfering RNA against the UBIAD1 gene inhibited the conversion of deuterium-labelled vitamin K derivatives into deuterium-labelled-MK-4 (MK-4-d(7)) in human cells. We confirmed that the UBIAD1 gene encodes an MK-4 biosynthetic enzyme through its expression and conversion of deuterium-labelled vitamin K derivatives into MK-4-d(7) in insect cells infected with UBIAD1 baculovirus. UBIAD1 was localized in endoplasmic reticulum. Our results show that UBIAD1 is a human MK-4 biosynthetic enzyme; this identification will permit more effective decisions to be made about vitamin K intake and bone health.