| Project/Area Number |
18K05326
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 37010:Bio-related chemistry
|
|---|
| Research Institution | Kurume University |
|---|
Principal Investigator |
Sato Hideaki 久留米大学, 医学部, 准教授 (60271996)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
杉島 正一 久留米大学, 医学部, 准教授 (30379292)
塚口 舞 (古澤舞) 久留米大学, 医学部, 助教 (40624094)
|
|---|
| Project Period (FY) |
2018-04-01 – 2021-03-31
|
| Project Status |
Completed (Fiscal Year 2020)
|
| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | ヘム生合成 / ポルフィリン生合成 / テトラピロール / Ｘ線結晶構造解析 / 酵素反応機構 / 結晶構造解析 / タンパク質間相互作用 |
|---|
| Outline of Final Research Achievements |
In the animal heme biosynthesis pathway catalyzed by eight enzymes, hydroxymethylbilane synthase (HMBS) that catalyzes the third step forms a product by sequentially condensing four molecules of substrate with dipyrromethane cofactor. In this study, in order to well-understand the construction of tetrapyrrole, the reaction mechanism of HMBS was investigated by structural biology techniques. Holo-HMBS and reaction intermediates (ES1 ~ ES4), in which 1 to 4 molecules of substrate are linked to the cofactor, were isolated, and crystal structures of holo-HMBS, ES2, and the complexes of them with a substrate derivative were analyzed. From the obtained crystal structures, the molecular mechanism of the HMBS reaction was considered. In particular, it was found that the construction of the pyrrole chain proceeds by repeating the condensation reaction at a single substrate-binding site.
|
| Academic Significance and Societal Importance of the Research Achievements |
ヘム生合成経路においてピロール環を含む基質4分子からテトラピロールを構築する酵素HMBSが、どのように基質を捕らえて連結していくのかについて、基質誘導体との複合体の立体構造に基づいて示すことができた。このHMBSの基質結合部位に基質誘導体が結合した複合体の立体構造は、本研究で初めて明らかになったものである。研究成果は、ヘム生合成が遺伝的に障害されてポルフィリン前駆体が蓄積するポルフィリン症の原因の理解につながるものと期待される。
|
