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

Kimie Nakagawa, Yoshihisa Hirota, Natsumi Sawada, Naohito Yuge, Masato Watanabe, Yuri Uchino, Naoko Okuda, Yuka Shimomura, Yoshitomo Suhara, Toshio Okano

研究成果: Article

154 引用 (Scopus)

抄録

Vitaming 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 vitamingK content, with most hepatic vitamingK 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 4g-8). This occurs either directly within certain tissues or by interconversion to menadione (K 3), followed by prenylation to MK-4 (refs 9g-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 vitamingK 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 vitamingK 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 vitamingK 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 vitamingK intake and bone health.

元の言語English
ページ(範囲)117-121
ページ数5
ジャーナルNature
468
発行部数7320
DOI
出版物ステータスPublished - 2010 11 4
外部発表Yes

ASJC Scopus subject areas

  • General

これを引用

Nakagawa, K., Hirota, Y., Sawada, N., Yuge, N., Watanabe, M., Uchino, Y., ... Okano, T. (2010). Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature, 468(7320), 117-121. https://doi.org/10.1038/nature09464

Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. / Nakagawa, Kimie; Hirota, Yoshihisa; Sawada, Natsumi; Yuge, Naohito; Watanabe, Masato; Uchino, Yuri; Okuda, Naoko; Shimomura, Yuka; Suhara, Yoshitomo; Okano, Toshio.

:: Nature, 巻 468, 番号 7320, 04.11.2010, p. 117-121.

研究成果: Article

Nakagawa, K, Hirota, Y, Sawada, N, Yuge, N, Watanabe, M, Uchino, Y, Okuda, N, Shimomura, Y, Suhara, Y & Okano, T 2010, 'Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme', Nature, 巻. 468, 番号 7320, pp. 117-121. https://doi.org/10.1038/nature09464
Nakagawa K, Hirota Y, Sawada N, Yuge N, Watanabe M, Uchino Y その他. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature. 2010 11 4;468(7320):117-121. https://doi.org/10.1038/nature09464
Nakagawa, Kimie ; Hirota, Yoshihisa ; Sawada, Natsumi ; Yuge, Naohito ; Watanabe, Masato ; Uchino, Yuri ; Okuda, Naoko ; Shimomura, Yuka ; Suhara, Yoshitomo ; Okano, Toshio. / Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. :: Nature. 2010 ; 巻 468, 番号 7320. pp. 117-121.
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abstract = "Vitaming 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 vitamingK content, with most hepatic vitamingK 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 4g-8). This occurs either directly within certain tissues or by interconversion to menadione (K 3), followed by prenylation to MK-4 (refs 9g-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 vitamingK 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 vitamingK 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 vitamingK 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 vitamingK intake and bone health.",
author = "Kimie Nakagawa and Yoshihisa Hirota and Natsumi Sawada and Naohito Yuge and Masato Watanabe and Yuri Uchino and Naoko Okuda and Yuka Shimomura and Yoshitomo Suhara and Toshio Okano",
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AU - Nakagawa, Kimie

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AU - Yuge, Naohito

AU - Watanabe, Masato

AU - Uchino, Yuri

AU - Okuda, Naoko

AU - Shimomura, Yuka

AU - Suhara, Yoshitomo

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N2 - Vitaming 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 vitamingK content, with most hepatic vitamingK 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 4g-8). This occurs either directly within certain tissues or by interconversion to menadione (K 3), followed by prenylation to MK-4 (refs 9g-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 vitamingK 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 vitamingK 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 vitamingK 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 vitamingK intake and bone health.

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