Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme

Abstract

Vitamin K occurs in the natural world in several forms, including a plant form, phylloquinone (PK), and a bacterial form, 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 (refs 4-8). This occurs either directly within certain tissues or by interconversion to menadione (K(3)), followed by prenylation to MK-4 (refs 9-12). No previous study has sought to identify the human enzyme responsible for MK-4 biosynthesis. Previously we provided evidence for the conversion of PK and K(3) into MK-4 in mouse cerebra. However, the molecular mechanisms for these conversion reactions are unclear. Here we identify a human MK-4 biosynthetic enzyme. We screened the human genome database for prenylation enzymes and found UbiA prenyltransferase containing 1 (UBIAD1), a human homologue of Escherichia coli prenyltransferase menA. We found that 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. Converted MK-4-d(7) was chemically identified by (2)H-NMR analysis. MK-4 biosynthesis by UBIAD1 was not affected by the vitamin K antagonist warfarin. UBIAD1 was localized in endoplasmic reticulum and ubiquitously expressed in several tissues of mice. 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.

Anti-Inflammatory Actions of Vitamin K

“…It is unclear if this was due to a direct effect on the joint tissue as a latter study using menadione-epoxide in the same model was also found to have a significant anti-inflammatory activity [70]. Alternative explanation for these effects includes the possible conversion of these menadione and menadione-epoxide molecules into vitamin K2, as menaquinone-4, through the action of UBIAD1 [68]. This would be consistent with lapine caecal bacterial conversion due to known coprophagy in this species (see chapter by O'Neil et al, in this volume).…”

“…Research that started in the 1990s demonstrated that menadione was an important derivative from vitamin K1 that was converted in the rat to make the vitamin K2 congener menaquinone-4 [64][65][66][67]. The enzyme responsible for the conversion of menadione to menaquinone-4, UBIAD1 [68] has a wide distribution across species and likely plays a significant role in the vitamin K status of many animals (see chapter by O'Neil et al, this volume).…”

Effects of Vitamin D, K1, and K2 Supplementation on Bone Formation by Osteoblasts In Vitro: A Meta-analysis

“…Vitamin K 1 is synthesized by plants, while vitamin K 2 is produced by bacteria [10]. Vitamin K 2 is also synthesized in certain vertebrate tissue through the conversion of vitamin K 1 or phylloquinone into menaquinone-4, a form of vitamin K 2 , using the enzyme UbiA prenyltransferase containing 1 (UBIAD1; [11]). Vitamin K functions as a cofactor for the enzyme gammacarboxylase, which carboxylates glutamic acid and results in its conversion to gamma-carboxyglutamic acid [10].…”

Menaquinone‐4 Enhances Steroidogenesis in Testis Derived Tumor Cells Via the Elevation of cAMP Level

“…MK-4 is not commonly synthesized by bacteria and is instead alkylated from menadione, which is supplemented in animal feeds to increase vitamin K levels. In most organs, MK-4 is converted from dietary vitamin K1 and other menaquinones [1,2] via a process catalyzed by UbiA prenyltransferase domain containing protein 1 [3]. Furthermore, MK-4 is prescribed as a therapeutic agent for osteoporosis and to prevent fractures in Japan [4].…”