| Project/Area Number |
17K08240
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Physical pharmacy
|
|---|
| Research Institution | Kumamoto University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2017-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
|
|---|
| Keywords | 酵素 / 蛋白質 / 薬剤耐性菌 / 阻害剤 / 構造機能解析 |
|---|
| Outline of Final Research Achievements |
Metallo-β-lactamase, an enzyme having two Zn(II) ions at the active site, hydrolyzes β-lactam agents. In this study, we investigated IMP-6, a single amino acid mutation (Ser196Gly near the active site) enzyme of IMP-1, which is frequently isolated in Japan. IMP-6 differed from IMP-1 in the inhibitory potency of thiol inhibitors.Therefore, we focused on the solution structure, inhibition mode against thiol inhibitors, and elimination rate constant of Zn(II) ions from the active site of IMP-6.
IMP-6 was structurally similar to IMP-1, and the inhibition mode was the same in both cases.However, the elimination rate constant of Zn(II) ions was found to be relatively high in the case of IMP-6.Based on these findings, it was concluded that a single amino acid mutation (Ser196Gly) of IMP-1 affects the ability to bind Zn(II) ions.
|
| Academic Significance and Societal Importance of the Research Achievements |
メタロ-β-ラクタマーゼ（MBL）酵素を産生する細菌は、薬剤耐性菌となり、ほとんどすべてのβ-ラクタム剤を加水分解してしまうことから、感染治療を困難にさせます。本研究では、MBLであるIMP-1とその一アミノ酸変異体であるIMP-6を対象として、IMP-1に対する阻害様式を構造的かつ機能的に検討しました。この比較により、一アミノ酸変異によって、活性中心にあるZn(II)イオンの結合能に影響を与えていることが分かりました。この影響は、他のMBLでも該当すると考えられ、IMP-1に対する阻害剤開発だけでなく、MBL全般の阻害剤開発に役立つと考えています。
|
