膜アロステリーと独特の水性サイトは,酵素基板特異性を促進する

Varnavas D Mouchlis¹, Yuan Chen¹, J Andrew McCammon¹

¹Department of Chemistry and Biochemistry and Department of Pharmacology, School of Medicine , University of California , San Diego, La Jolla , California 92093-0601 , United States.

Journal of the American Chemical Society

|January 18, 2018

まとめ

リピドミクスと分子ダイナミクスは,独特のフォスフォリファースA2酵素特異性を明らかにします. 触媒の残留物ではなく,新しい防水結合部位が,これらの重要な酵素の基板の好みを決定する.

科学分野:

生物化学
分子生物学
構造生物学

背景:

リン酸塩A2 (PLA2) 酵素は,炎症や膜の改造を含む細胞プロセスに不可欠です.
PLA2の特異性を理解することは生物学的役割の多様性を解明する鍵です

研究の目的:

3つの主要なヒトPLA2酵素の基質特異性の分子基礎を解明する.
PLA2の活性を制御するユニークな結合相互作用と構造的決定因子を明らかにする.

主な方法:

リピドミクスを分子動態 (MD) シミュレーションと統合する.
酵素と基板の相互作用と結合モードの計算分析
ヒトのフォスフォリファースA2酵素の構造と結合に関する研究

主要な成果:

3つの主要なヒトPLA2に対して,予期せぬヘッドグループとアシル鎖の特異性を発見した.
各酵素に特異的な結合部位と結合界面を特定した.
分解された脂肪酸のヒドロホビック結合部位が,触媒残留物ではなく,酵素特異性を支配することを明らかにした.

結論:

MDシミュレーションは,PLA2の特異性に関する前例のない構造の洞察を提供します.
特定のPLA2酵素は,脂肪酸とフォスフォリピド基板に対して明確な好みを表し,その生物学的機能に影響を与えます.
細胞性PLA2はアラキドン酸を好み,カルシウム依存性PLA2はリノール酸を好み,分泌されたPLA2はリノール酸とリン酸塩を好む.

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