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Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme
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Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme
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Journal Article
Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme
2010
Overview
Key enzyme in vitamin K metabolism
Vitamin K, an important factor in blood clotting and bone metabolism, is present in the diet principally as phylloquinone (PK) from plants. One form of the vitamin, menaquinone-4 or MK-4, has a highly specific tissue distribution in the brain, kidney and pancreas in humans and in rats, suggestive of local synthesis from phylloquinone. An enzyme catalysing that synthesis has now been identified: UbiA prenyltransferase containing 1 (UBIAD1) is a human homologue of an
Escherichia coli
enzyme. Previously its function was unclear, although it is a candidate gene in Schnyder crystalline corneal dystrophy. The discovery of a human MK-4 enzyme able to biosynthesize the hormonally active form of vitamin K is of relevance to work on human vitamin K requirements and bone health.
These authors identify the human enzyme responsible for menaquinone-4 biosynthesis, a naturally occurring form of vitamin K. They find that
UbiA prenyltransferase containing 1
, a human homologue of a prenyltransferase gene from
Escherichia coli
, encodes an enzyme that can convert vitamin K derivatives into menaquinone-4.
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
1
,
2
,
3
. 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
13
. 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Biological and medical sciences
/ Cell metabolism, cell oxidation
/ Dimethylallyltranstransferase
/ E coli
/ Enzymes
/ Fundamental and applied biological sciences. Psychology
/ Humanities and Social Sciences
/ Humans
/ letter
/ Mice
/ Molecular and cellular biology
/ RNA, Small Interfering - genetics
/ RNA, Small Interfering - metabolism
/ Science
/ Studies
/ Vitamin K - antagonists & inhibitors
