Elucidation of the mechanism of intracellular phosphatidylinositol trafficking by the Phs1 family

• Project/Area Number: 20687008
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Functional biochemistry
• Research Institution: Hokkaido University
• Principal Investigator: KIHARA Akio Hokkaido University, 大学院・薬学研究院, 教授 (50333620)
• Co-Investigator(Renkei-kenkyūsha): SASSA Takayuki 北海道大学, 大学院・薬学研究院, 講師 (20342793) ; OBARA Keisuke 北海道大学, 大学院・薬学研究院, 助教 (30419858)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥25,480,000 (Direct Cost: ¥19,600,000、Indirect Cost: ¥5,880,000); Fiscal Year 2010: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2009: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2008: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
• Keywords: 脂質 / 代謝 / 細胞内輸送 / 脂肪酸 / 極長鎖脂肪酸 / スフィンゴ脂質 / 遺伝子 / タンパク質 / ホスファチジルイノシトール / 脂質輸送 / 生体膜 / 縮合酵素 / アシルCoA / 3-ヒドロキシアシルCoA脱水酵素

Research Abstract

Phs1 is a 3-hydroxyacyl-CoA dehydratase involved in the elongation of very long-chain fatty acids (VLCFAs). We demonstrated here that Phs1 regulates sphingolipid synthesis and phosphatidylinositol transport through interacting with proteins involved in lipid metabolism and vesicular transport. We also succeeded in identifying mammalian homologs of Phs1, HACD1-4. By revealing substrate specificities of enzymes catalyzing the rate-limiting step of the VLCFA elongation, we have elucidated the entire VLCFA pathways in mammals. Moreover, we obtained some knowledge about relationship between VLCFA elongation and certain disorders.

Research Products

• [Journal Article] ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. (2010)
  • Author(s): Ohno, Y., Suto, S., Yamanaka, M., Mizutani, Y., Mitsutake, S., Igarashi, Y., Sassa, T., Kihara, A.
  • Journal Title: Proc.Natl.Acad.Sci.USA 107 Pages: 18439-18444
  • NAID: 120002934261
  • Peer Reviewed
• [Journal Article] Hetero-oligomeric interactions of an ELOVL4 mutant protein : implications in the molecular mechanism of Stargardt-3 macular dystrophy. (2010)
  • Author(s): Okuda, A., Naganuma, T., Ohno, Y., Abe, K., Yamagata, M., Igarashi, Y., Kihara, A.
  • Journal Title: Mol.Vis. 16 Pages: 2438-2445
  • Peer Reviewed
• [Journal Article] Characterization of HACD1 K64Q mutant found in arrhythmogenic right ventricular dysplasia patients. (2010)
  • Author(s): Konishi, H., Okuda, A., Ohno, Y., Kihara, A.
  • Journal Title: J.Biochem. 148 Pages: 617-622
  • NAID: 10027879523
  • Peer Reviewed
• [Journal Article] 脂肪酸の多彩な代謝,生理機能と関連疾患 (2010)
  • Author(s): 木原章雄
  • Journal Title: 生化学 82 Pages: 591-605
  • NAID: 10026607547
• [Journal Article] ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis (2010)
  • Author(s): Ohno Y, Kihara A, et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 107 Pages: 18439-18444
  • NAID: 120002934261
  • Peer Reviewed
• [Journal Article] Hetero-oligomeric interactions of an ELOVL4 mutant protein : implications in the molecular mechanism of Stargardt-3 macular dystrophy (2010)
  • Author(s): Okuda A, Kihara A, et al.
  • Journal Title: Mol.Vision Volume: 16 Pages: 2438-2445
  • Peer Reviewed
• [Journal Article] Characterization of HACD1 K64Q mutant found in arrhythmogenic right ventricular dysplasia patients (2010)
  • Author(s): Konishi H, Kihara A, et al.
  • Journal Title: J.Biochem. Volume: 148 Pages: 617-622
  • NAID: 10027879523
  • Peer Reviewed
• [Journal Article] Ceramide biosynthesis in keratinocyte and its role in skin function. (2009)
  • Author(s): Mizutani, Y., Mitsutake, S., Tsuji, K., Kihara, A., Igarashi, Y.
  • Journal Title: Biochimie 91 Pages: 784-790
  • Peer Reviewed
• [Journal Article] Ceramide biosynthesis in keratinocyte and its role in skin function (2009)
  • Author(s): Mizutani Y.
  • Journal Title: Biochimie VOL.91 Pages: 784-790
  • Peer Reviewed
• [Journal Article] Membrane topology and essential amino acid residues of Phs1, a 3-hydroxyacyl-CoA dehydratase involved in very long-chain fatty acid elongation. (2008)
  • Author(s): Kihara, A., Sakuraba, H., Ikeda, M., Denpoh, A., Igarashi, Y.
  • Journal Title: J.Biol.Chem. 283 Pages: 11199-11209
  • Peer Reviewed
• [Journal Article] Characterization of four mammalian 3-hydroxyacyl-CoA dehydratases involved in very long-chain fatty acid synthesis. (2008)
  • Author(s): Ikeda, M., Kanao, Y., Yamanaka, M., Sakuraba, H., Mizutani, Y., Igarashi, Y., Kihara, A.
  • Journal Title: FEBS Lett. 582 Pages: 2435-2440
  • Peer Reviewed
• [Journal Article] 2-Hydroxy-ceramide synthesis by ceramide synthase family : enzymatic basis for the preference of FA chain length. (2008)
  • Author(s): Mizutani, Y., Kihara, A., Chiba, H., Tojo, H., Igarashi, Y.
  • Journal Title: J.Lipid Res. 49 Pages: 2356-2364
  • Peer Reviewed
• [Journal Article] Membrane topology and essential amino acid residues of Phsl, a 3-hydroxyacylCoA dehydratase involved in very long-chain fatty acid elongation (2008)
  • Author(s): Kihara A.
  • Journal Title: The Journal of Biological Chemistry 283 Pages: 11199-11209
  • Peer Reviewed
• [Journal Article] Characterization of four mammalian 3-hydroxyacyl-CoA dehydratases involved in very long-chain fatty acid synthesis (2008)
  • Author(s): Ikeda M.
  • Journal Title: FEBS Letter 582 Pages: 2435-2440
  • Peer Reviewed
• [Journal Article] 2-Hydroxy-ceramide synthesis by ceramide synthase family : enzymatic basis for the preference of FA chain length (2008)
  • Author(s): Mizutani Y.
  • Journal Title: Journal of Lipid Resarch 49 Pages: 2356-2364
  • Peer Reviewed
• [Presentation] 脂肪酸伸長因子ELOVL6の生化学的解析 (2011)
  • Author(s): 永沼達郎
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: ツインメッセ静岡(静岡県)
  • Year and Date: 2011-03-29
• [Presentation] Elongation of C24 fatty acids by ELOVL1 and C24 sphingolipid synthesis by CerS2 are closely linked (2010)
  • Author(s): 大野祐介
  • Organizer: 第33回日本分子生物学会年会/第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2010-12-09
• [Presentation] C24アシルCoAの産生とC24セラミド合成による制御機構 (2010)
  • Author(s): 木原章雄
  • Organizer: 第3回セラミド研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2010-11-12
• [Presentation] C24アシルCoAの産生とC24セラミド合成による制御機構 (2010)
  • Author(s): 木原章雄
  • Organizer: 第3回セラミド研究会学術集会
  • Place of Presentation: 東京大学(東京都)(招待講演)
  • Year and Date: 2010-11-12
• [Presentation] 極長鎖脂肪酸の代謝経路と調節機構 (2010)
  • Author(s): 木原章雄
  • Organizer: 神戸大学医学部グローバルCOE学術講演会
  • Place of Presentation: 神戸大学(兵庫県)(招待講演)
  • Year and Date: 2010-10-19
• [Presentation] Specificity of elongation of saturated, very long-chain fatty acids provides a link to C24 sphingolipid synthesis. (2010)
  • Author(s): Kihara, A.
  • Organizer: The 27th Naito Conference on Membrane Dynamics and Lipid Biology [I]
  • Place of Presentation: Sapporo
  • Year and Date: 2010-06-30
• [Presentation] Specificity of elongation of saturated, very long-chain fatty acids provides a link to C24 sphingolipid synthesis (2010)
  • Author(s): Kihara, A.
  • Organizer: The 27th Naito Conference on Membrane Dynamics and Lipid Biology [I]
  • Place of Presentation: ガトーキングダム札幌(北海道)(招待講演)
  • Year and Date: 2010-06-30
• [Presentation] 極長鎖脂肪酸伸長酵素ELOVLの機能およびスフィンゴ脂質合成調節機構の解明 (2010)
  • Author(s): 大野祐介
  • Organizer: 日本薬学会北海道支部例会第134回例会
  • Place of Presentation: 札幌コンベンションセンター(北海道)
  • Year and Date: 2010-05-08
• [Presentation] Synthesis of very long-chain fatty acid and its relationship to sphingolipid metabolism. (2009)
  • Author(s): Kihara, A., Igarashi, Y.
  • Organizer: 50th International Conference on the Bioscience of Lipids
  • Place of Presentation: Regensburg, Germany
  • Year and Date: 2009-09-04
• [Presentation] Synthesis of very long-chain fatty acid and its relationship to sphingolipid metabolism (2009)
  • Author(s): Kihara A.
  • Organizer: 50^<th> International Conference on the Bioscience of Lipids
  • Place of Presentation: Regensburg(ドイツ)
  • Year and Date: 2009-09-04
• [Presentation] 脂質非対称変化による酵母スフィンゴイド塩基トランスロカーゼ発現誘導の分子機構 (2008)
  • Author(s): 木原章雄
  • Organizer: 第31回日本分子生物学会年会/第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸)
  • Year and Date: 2008-12-11
• [Presentation] 細胞膜脂質非対称感知システムによるスフィンゴイド塩基トランスロカーゼRsb1の発現誘導機構 (2008)
  • Author(s): 木原章雄
  • Organizer: 第176回酵母細胞研究会例会
  • Place of Presentation: アサヒビール(株)本社 (東京)
  • Year and Date: 2008-12-08
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