菌類のメロテルペノイド生物合成におけるヘテロジメの非ヘム鉄酵素
Xinyang Li1, Takayoshi Awakawa1,2, Takahiro Mori1,2,3
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Journal of the American Chemical Society
|December 9, 2021
まとめ
海洋真菌タラロミセス・パープレオゲヌスは,タラロミオリドと呼ばれる珍しい六環メロテルペノイドを生成します. 研究者は生物合成遺伝子クラスター (tlxA-J) を解明し,重要な酸化ステップを触媒する新しい非ヘム鉄 (NHI) 酵素ヘテロダイマーを発見した.
科学分野:
- 生物化学
- 自然製品化学
- 分子生物学
背景:
- タラロミオリドは,海洋キノコタラロミセス・パープレオゲヌスから分離された複雑な六環メロテルペノイドである.
- これらの化合物は,ユニークな (3R) -6 -ヒドロキシメレインと4,5 -セコドリマン基構造を特徴としています.
研究 の 目的:
- タラロミオリド産生を担う生物合成遺伝子群を特定し特徴づけること.
- 複合タラロミオリド構造の形成に伴う酵素メカニズムを解明する.
- 二次代謝物生物合成における非ヘム鉄 (NHI) 酵素ヘテロダイマーの新しい触媒的役割を調査する.
主な方法:
- アスペルギルスの推定生物合成遺伝子クラスター (tlxA-J) の異質表現.
- 単一の酵素と組み合わせた酵素の触媒作用を決定するインビトロ酵素測定
- CRISPR-Cas9ベースの遺伝子不活性化により 遺伝子機能を確認する.
- 酵素の構造と機能の関係を理解するために,X線構造分析と部位指向型変異.
主要な成果:
- 生物合成遺伝子クラスター tlxA-Jが特定され,機能的に特徴づけられました.
- NHI酵素のヘテロダイマーであるTlxJ-TlxIは,4,5-セコドリマンの骨格の形成を促進する重要なレトロアルドール反応を含む3つの酸化ステップを触媒することが判明した.
- 別のNHIヘテロダイマーであるTlxA-TlxCとTlxBは,最終製品を得るための,その後の水酸化とアセチル化段階に関与した.
- 構造分析により,TlxJ-TlxIヘテロダイマーの形成と触媒機構の洞察が得られた.
結論:
- この研究は,タラロミオリドの完全な生物合成経路を明らかにし,NHI酵素ヘテロダイマーの重要な役割を強調しています.
- これは2つのNHIタンパク質が二次代謝生物合成における触媒作用のための機能性ヘテロダイマーを形成することを示す最初の報告である.
- 二次代謝生物合成における機能性酸素酵素構造を作るための新しい方法論が確立された.
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