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専用のポリケチド合成モジュールによって触媒化されたビニロゲスの鎖の分岐

Tom Bretschneider¹, Joel B Heim, Daniel Heine

¹Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena 07745, Germany.

|September 20, 2013

まとめ

科学者たちは,ポリケチドで枝分かれした炭素鎖を作り出す新しい細菌酵素モジュールを発見し,薬剤発見の可能性を拡大しました. この新しいメカニズムは,既知の経路とは異なるもので,強力な抗がんおよび抗真菌化合物の活性には極めて重要です.

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.
合成生物学合成生物学とは

背景:

モジュラーポリケチド合成酵素 (PKSs) は,複雑なポリケチドを生成するために不可欠であり,その多くは抗感染性および抗腫瘍薬のリードとして機能する.
現在のPKSの研究は主に線形骨組みの組み立てに焦点を当て,ポリケチド化合物の構造的多様性を制限しています.
PKS経路の合理的な工学は,新薬の類似品を生成するために不可欠です.

研究の目的:

独特の連鎖分岐能力を持つBurkholderia rhizoxinicaからの新しいPKSモジュールを調査する.
この非正規のポリケチド組成のメカニズムとその構造的基礎を解明する.
ポリケチドの構造的多様性を生み出すために,この発見の影響を調査する.

主な方法:

PKSモジュールの試験管内再構成.
キードメインのX線結晶学.
サイト・ダイレクト・ミュータゲネシス実験.
中間の状態の分析. 中間の状態の分析.

主要な成果:

マイケル型アセチル添加を行うことができる新しいPKSモジュールが特定され,ポリケチド鎖の枝を形成しました.
ケトシンタゼドメインは,この分岐活動に不可欠であると特定されました.
交配的に結合された中間状態は,鎖アルキル化のための新しいメカニズムを明らかにし,テルペノイドのような分岐とは異なる.
この非法定的な改変は,強力な抗真菌剤であるリゾキシンの生物活性に不可欠である.

結論:

この研究は,新しいPKSモジュールとメカニズムを明らかにし,ポリケチドアセンブリの生物合成の範囲を拡大しています.
この発見は,PKS経路を合理的に設計し,治療の可能性のある新しいポリケチド構造を作成するための基礎を提供します.
提案されたビニロゲス分岐反応は,ケトシンタゼ分岐-アシル-キャリア-タンパク質アーキテクチャを持つPKSモジュールの統一モデルを提供します.

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