ミトミシン生物合成におけるヒドロキシキノンOメチル化

Sabine Grüschow¹, Leng-Chee Chang, Yingqing Mao

¹Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.

Journal of the American Chemical Society

|April 28, 2007

まとめ

MmcRメチルトランスフェラーゼは,メトキシ基を加えることでミトミシンAとBの生成に不可欠です. このメチル化ステップは,重要な化学療法薬であるミトミシンCの生物合成に不可欠です.

科学分野:

バイオケミストリーバイオケミストリー
分子生物学は分子生物学である.
自然製品バイオシンセシス自然製品バイオシンセシス

背景:

ミトミシン (Mitomycin) は,がん治療に使用される生物還元活性化DNAアルキル化剤である.
ミトマイシンの細胞毒性は,キノンの置換物によって影響される彼らの電気化学的可能性に依存します.
ミトマイシンAとBのキノンメトキシ群は,その活性には極めて重要です.

研究の目的:

ミトミシンAとBのキノンメトキシ群の生物発生を調査する.
ミトマイシン生成におけるmmcRメチルトランスフェラーゼ遺伝子の役割を決定する.
ミトミシンCバイオシンセシスのための7-Oメチル化の必要性を明らかにする.

主な方法:

遺伝子消去研究:MMcRが削除されたStreptomyces lavendulae菌株をエンジニアリングした.
メタボライト分析:野生型および変異株の培養抽出物を分析した.
酵素測定:クローン化および過剰発現したMmcRメチルトランスフェラーゼを in vitroメチル化研究のために.

主要な成果:

mmcRの削除は,ミトマイシンA,B,Cの生産を廃止した.
変異株で観察された7-デメチルミトミシンAとBの蓄積.
MmcRは,7-hydroxymitomycinsの7-O-メチル化をin vitroで触媒化し,前駆物質が供給されたときにミトミシン生産を回復しました.

結論:

MmcRメチルトランスフェラーゼは,ミトマイシンAとBの7メトキシ群を形成する際に直接的な触媒的役割を果たします.
7-Oメチル化は,臨床薬剤であるミトミシンCの生物合成の前提条件である.
ミトミシンバイオシンセシスの理解は,新しいDNAアルキル化剤の開発の洞察を提供します.

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