Int. J. Mol. Sci. 2011, 12(2), 1115-1132; doi:10.3390/ijms12021115
Article

Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity

Yoshiyuki Mizushina 1,2,* email, Jun Maeda 3 , Yasuhiro Irino 4 , Masayuki Nishida 3 , Shin Nishiumi 3 , Yasuyuki Kondo 3 , Kazuyuki Nishio 5 , Kouji Kuramochi 5 , Kazunori Tsubaki 5 , Isoko Kuriyama 1 , Takeshi Azuma 3 , Hiromi Yoshida 1,2  and Masaru Yoshida 3,4,6,* email
1 Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan 2 Cooperative Research Center of Life Sciences, Kobe-Gakuin University, Chuo-ku, Kobe, Hyogo 650-8586, Japan 3 Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Hyogo 650-0017, Japan 4 The Integrated Center for Mass Spectrometry, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Hyogo 650-0017, Japan 5 Graduate School of Life and Environmental Science, Kyoto Prefectural University, Sakyo-ku, Kyoto 606-8522, Japan 6 Division of Metabolomics Research, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Hyogo 650-0017, Japan
* Authors to whom correspondence should be addressed.
Received: 13 December 2010; in revised form: 21 January 2011 / Accepted: 8 February 2011 / Published: 10 February 2011
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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Abstract: Previously, we reported that vitamin K3 (VK3), but not VK1 or VK2 (=MK-4), inhibits the activity of human DNA polymerase γ (pol γ). In this study, we chemically synthesized three intermediate compounds between VK2 and VK3, namely MK-3, MK-2 and MK-1, and investigated the inhibitory effects of all five compounds on the activity of mammalian pols. Among these compounds, MK-2 was the strongest inhibitor of mammalian pols α, κ and λ, which belong to the B, Y and X families of pols, respectively; whereas VK3 was the strongest inhibitor of human pol γ, an A-family pol. MK-2 potently inhibited the activity of all animal species of pol tested, and its inhibitory effect on pol λ activity was the strongest with an IC50 value of 24.6 μM. However, MK-2 did not affect the activity of plant or prokaryotic pols, or that of other DNA metabolic enzymes such as primase of pol α, RNA polymerase, polynucleotide kinase or deoxyribonuclease I. Because we previously found a positive relationship between pol λ inhibition and anti-inflammatory action, we examined whether these compounds could inhibit inflammatory responses. Among the five compounds tested, MK-2 caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear. In addition, in a cell culture system using mouse macrophages, MK-2 displayed the strongest suppression of the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS). Moreover, MK-2 was found to inhibit the action of nuclear factor (NF)-κB. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of MK-2 in mice led to suppression of TNF-α production in serum. In conclusion, this study has identified VK2 and VK3 intermediates, such as MK-2, that are promising anti-inflammatory candidates.
Keywords: vitamin K; MK-2; DNA polymerase λ; enzyme inhibitor; anti-inflammation

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Cite This Article

MDPI and ACS Style

Mizushina, Y.; Maeda, J.; Irino, Y.; Nishida, M.; Nishiumi, S.; Kondo, Y.; Nishio, K.; Kuramochi, K.; Tsubaki, K.; Kuriyama, I.; Azuma, T.; Yoshida, H.; Yoshida, M. Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity. Int. J. Mol. Sci. 2011, 12, 1115-1132.

AMA Style

Mizushina Y, Maeda J, Irino Y, Nishida M, Nishiumi S, Kondo Y, Nishio K, Kuramochi K, Tsubaki K, Kuriyama I, Azuma T, Yoshida H, Yoshida M. Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity. International Journal of Molecular Sciences. 2011; 12(2):1115-1132.

Chicago/Turabian Style

Mizushina, Yoshiyuki; Maeda, Jun; Irino, Yasuhiro; Nishida, Masayuki; Nishiumi, Shin; Kondo, Yasuyuki; Nishio, Kazuyuki; Kuramochi, Kouji; Tsubaki, Kazunori; Kuriyama, Isoko; Azuma, Takeshi; Yoshida, Hiromi; Yoshida, Masaru. 2011. "Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity." Int. J. Mol. Sci. 12, no. 2: 1115-1132.

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