Abstract
UbiA prenyltransferase domain containing 1 (UBIAD1) is a novel vitamin K2 biosynthetic enzyme screened and identified from the human genome database. UBIAD1 has recently been shown to catalyse the biosynthesis of Coenzyme Q10 (CoQ10) in zebrafish and human cells. To investigate the function of UBIAD1 in vivo, we attempted to generate mice lacking Ubiad1, a homolog of human UBIAD1, by gene targeting. Ubiad1-deficient (Ubiad1 −/−) mouse embryos failed to survive beyond embryonic day 7.5, exhibiting small-sized body and gastrulation arrest. Ubiad1 −/− embryonic stem (ES) cells failed to synthesize vitamin K2 but were able to synthesize CoQ9, similar to wild-type ES cells. Ubiad1 +/− mice developed normally, exhibiting normal growth and fertility. Vitamin K2 tissue levels and synthesis activity were approximately half of those in the wild-type, whereas CoQ9 tissue levels and synthesis activity were similar to those in the wild-type. Similarly, UBIAD1 expression and vitamin K2 synthesis activity of mouse embryonic fibroblasts prepared from Ubiad1 +/− E15.5 embryos were approximately half of those in the wild-type, whereas CoQ9 levels and synthesis activity were similar to those in the wild-type. Ubiad1 −/− mouse embryos failed to be rescued, but their embryonic lifespans were extended to term by oral administration of MK-4 or CoQ10 to pregnant Ubiad1 +/− mice. These results suggest that UBIAD1 is responsible for vitamin K2 synthesis but may not be responsible for CoQ9 synthesis in mice. We propose that UBIAD1 plays a pivotal role in embryonic development by synthesizing vitamin K2, but may have additional functions beyond the biosynthesis of vitamin K2.
Highlights
Vitamin K is a cofactor for gamma-glutamyl carboxylase (GGCX), an enzyme that converts specific glutamic acid residues in several substrate proteins involved in blood coagulation and bone metabolism to gamma-carboxyglutamic acid (Gla) residues [1,2]
We found that Ubiad1-deficient (Ubiad12/2) mice uniformly died between embryonic day (E) 7.5 and E10.5 and that Ubiad12/2 mouse embryos failed to be rescued, but their embryonic lifespans were extended partially to term by oral administration of MK-4 or Coenzyme Q10 (CoQ10) to pregnant Ubiad1+/2 mice, indicating that UbiA prenyltransferase domain containing 1 (UBIAD1) plays a pivotal role in the embryonic development of mice
To disrupt Ubiad1, the targeting vector was designed to flank exon 1 with two loxP sequences, and a frameshift was generated by excision with Cre recombinase (Figure 1)
Summary
Vitamin K is a cofactor for gamma-glutamyl carboxylase (GGCX), an enzyme that converts specific glutamic acid residues in several substrate proteins involved in blood coagulation and bone metabolism to gamma-carboxyglutamic acid (Gla) residues [1,2]. Besides its role as a cofactor for GGCX, vitamin K is involved in the transcriptional regulation of the nuclear receptor SXR/PXR [3,4,5] and regulates PKA signalling in osteoblasts and hepatocellular carcinoma cells [6]. Vitamin K functions as a mitochondrial electron carrier during ATP production by the electron transport chain in Drosophila [7]. All forms of vitamin K share a common 2-methyl-1,4naphthoquinone nucleus, differing from one another in the length and degree of saturation of the aliphatic side chain at the 3 position. Menadione (MD) or vitamin K3 is a synthetic compound that lacks a side chain, it is believed to be biologically active by virtue of its conversion to MK-4 in the body [8]
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