| Project/Area Number |
24550201
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Chemistry related to living body
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| Research Institution | Kurume University |
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Principal Investigator |
SATO Hideaki 久留米大学, 医学部, 准教授 (60271996)
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| Co-Investigator(Kenkyū-buntansha) |
NOGUCHI Masato 帝京大学, 福岡医療技術学部, 教授 (10124611)
HIGASHIMOTO Yuichiro 久留米大学, 医学部, 教授 (40352124)
HARADA Jiro 久留米大学, 医学部, 講師 (10373094)
TSUKAGUCHI Mai 久留米大学, 医学部, 助教 (40624094)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | ヘム生合成 / 結晶構造解析 / 酵素反応速度論解析 / 酵素-阻害剤複合体 / テトラピロール / ポルフィリン生合成 / 生化学 / 酵素反応速度論 / ポルフィリン / 酵素反応 / 阻害剤 |
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| Outline of Final Research Achievements |
Hydroxymethylbilane synthase (HMBS) and uroporphyrinogen III synthase, respectively, is the third and fourth enzyme in the heme biosynthetic pathway in animals. HMBS has a dipyrromethane cofactor at its active site and catalyzes the sequential condensation of four porphobilinogen (PBG) molecules to form a linear tetrapyrrole, hydroxymethylbilane. To elucidate the catalytic mechanism of HMBS in detail, the enzyme kinetic study of HMBS was carried out with a certain substrate analog (X-PBG). The X-PBG inhibited the HMBS reaction in a noncompetitive manner with Ki of 5 micro-M. Further, we determined the crystal structure of HMBS in complex with X-PBG, which revealed that X-PBG sits in the vicinity of the dipyrromethane cofactor. Especially, the aminomethyl group of X-PBG was found near the distal pyrrole ring of the cofactor. These results imply at least that X-PBG can prevent the condensation of the first PBG molecule with the distal pyrrole ring of the cofactor in HMBS.
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