Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme
Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme
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DOI：
10.1038/nature09464
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发表时间：
2010-11-04
期刊：
影响因子：
64.8
通讯作者：
Okano, Toshio
中科院分区：
文献类型：
--
作者：
Nakagawa, Kimie;Hirota, Yoshihisa;Okano, Toshio
维生素K在自然界中以几种形式存在，包括植物形式叶绿醌（PK）和细菌形式甲基萘醌（MK）。在包括人类在内的许多物种中，PK是肝脏维生素K含量的次要成分，大多数肝脏维生素K含量包含长链MK。甲基萘醌-4（MK-4）普遍存在于肝外组织中，在人类和大鼠的脑、肾脏和胰腺中浓度特别高（1 - 3）。已经一致显示PK内源性转化为MK-4（参考文献4 - 8）。这或者直接发生在某些组织中，或者通过相互转化为甲萘醌（K-3），然后异戊烯化为MK-4（参考文献9 - 12）。以前没有研究试图确定负责MK-4生物合成的人类酶。之前，我们提供了小鼠大脑中PK和K3转化为MK-4的证据（13）。然而，这些转化反应的分子机制尚不清楚。在这里，我们确定了人类MK-4生物合成酶。我们筛选了人类基因组数据库中的异戊二烯化酶，发现了UbiA异戊二烯基转移酶1（UBIAD 1），这是大肠杆菌异戊二烯基转移酶menA的人类同源物。我们发现，针对UBIAD 1基因的短干扰RNA抑制了人细胞中氘标记维生素K衍生物转化为氘标记MK-4（MK-4-d（7））。我们证实，UBIAD 1基因编码MK-4生物合成酶，通过其在感染UBIAD 1杆状病毒的昆虫细胞中表达和将氘标记的维生素K衍生物转化为MK-4-d（7）。转化的MK-4-d（7）通过H-2-NMR分析进行化学鉴定。维生素K拮抗剂华法林不影响UBIAD 1合成MK-4。UBIAD 1定位于内质网，并在小鼠的几种组织中广泛表达。我们的研究结果表明，UBIAD 1是一种人类MK-4生物合成酶;这一鉴定将允许对维生素K摄入量和骨骼健康做出更有效的决定。
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(1-3). 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 K3 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 H-2-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.