ポリケチドおよび非リボソームペプチド抗生物質:モジュラリティと汎用性

Christopher T Walsh¹

¹Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. christopher_walsh@hms.harvard.edu

Science (New York, N.Y.)

|March 20, 2004

まとめ

テーラーリング酵素は,生物学的活性ポリケチド (PK) と非リボソームペプチド (NRP) の自然産物の形成を誘導する. これらの酵素を再プログラムすることで,新しい抗生物質への道が開けます.

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.
自然製品化学自然製品化学

背景:

ポリケチド (PK) とノンリボソームペプチド (NRP) は,大型で多分子な酵素複合体によって合成される複雑な自然産物です.
遺伝子のクラスターによってコード化された,テーラーリング酵素は,生物学的活動に不可欠な構造的修正を導入します.
これらの改変には,サイクル化,酸化,クロスリンクなどがあり,多様な分子構造を生み出します.

研究の目的:

PKとNRPの天然製品の生物合成における裁縫酵素の役割を解明する.
新しい抗生物質の発見のためにこれらの酵素経路を再プログラムする可能性を調査する.

主な方法:

PKとNRPの組み立てラインと関連する裁縫酵素をコードする遺伝子クラスターの分析.
サイクル化と酸化反応の酵素メカニズムを調査する.
酵素のモジュール性と基質の許容性のバイオ情報分析.

主要な成果:

テーラーリング酵素は,PKとNRPのバイオシンセシス,ヘテロサイクライゼーション (シアゾール,オクサゾール) とマクロサイクライゼーションを含むサイクライゼーションの制約を導入します.
組み立て直後の酵素酸化により,複雑で相互に繋がった構造が形成されます.
証拠は,モジュラリティと酵素の許容性が経路の再プログラミングを可能にすることを示唆しています.

結論:

裁縫酵素は,PKとNRPの天然製品の生物活性構造を生成するために不可欠です.
これらの生物合成経路の固有のモジュラリティと柔軟性は,強化された特性を持つ新しい抗生物質の設計の機会を提供します.

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