癌に関連したIDH1変異は,2-ヒドロキシグルタレットを産生する
Lenny Dang1, David W White, Stefan Gross
1Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
Nature
|November 26, 2009
まとめ
サイトソリックイソシトラート脱水素酵素1 (IDH1) の変異により,新しい酵素機能が生まれます. この機能により,R(-) -2-ヒドロキシグルタレート (2HG) が生成され,これは脳がんの形成と進行を促す腫瘍代謝物質である.
科学分野:
- バイオケミストリー バイオケミストリー
- 腫瘍学 腫瘍学
- 分子生物学は分子生物学である.
背景:
- 細胞性イソシトラート脱水素酵素1 (IDH1) の変異は,ヒトの原発性脳がんに多く見られる.
- これらの変異は,IDH1活性部位にある単一のアミノ酸残基に影響を与え,その触媒的機能に影響を与えます.
研究 の 目的:
- 癌に関連したIDH1変異の機能的影響を調査する.
- IDH1変異が,グリオマゲネシスに関連した新しい酵素活性を与えるかどうかを決定する.
主な方法:
- 酵素活性アッセイは,基板変換を評価するためのものです.
- 変異したIDH1のメカニズムを解明するための構造研究.
- ヒトの膠原腫におけるR(-) -2-ヒドロキシグルタレート (2HG) 濃度の測定.
主要な成果:
- 癌に関連したIDH1変異は,ネオモルフな酵素活性をもたらします:アルファ-ケトグルタレートのNADPH依存的還元をR(-) -2-ヒドロキシグルタレート (2HG) にします.
- 構造分析は,変異したIDH1の活性部位の変化を明らかにし,酸化脱炭素化から還元合成への移行を説明します.
- 2HG濃度の上昇は,IDH1変異を有するヒトの悪性結晶腫で観察されました.
結論:
- グリオマのIDH1変異は,オンコメタボライト2HG.の産生につながります.
- 2HGの蓄積は,膠原腫の発症および悪性進行に寄与する.
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