Mechanism of Metal Activation of Human Hematopoietic Prostaglandin D Synthase

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  • ヒト由来プロスタグランジンD合成酵素の金属イオン効果を考慮した阻害剤の開発
  • サイキン ノ ケンキュウ カラ ヒト ユライ プロスタグランジン D ゴウセイ コウソ ノ キンゾク イオン コウカ ノ メカニズム

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Abstract

We report the crystal structures of human hematopoietic prostaglandin (PG) D synthase bound to glutathione (GSH) and Ca2+ or Mg2+. Using GSH as a cofactor, prostaglandin D synthase catalyzes the isomerization of PGH2 to PGD2, a mediator for allergy response. The enzyme is a homodimer, and Ca2+ or Mg2+ increases its activity to - 150 % of the basal level, with half maximum effective concentrations of 400 μM for Ca2+ and 50 μM for Mg2+. In the Mg2+-bound form, the ion is octahedrally coordinated by six water molecules at the dimer interface. The water molecules are surrounded by pairs of Asp93, Asp96 and Asp97 from each subunit. Ca2+ is coordinated by five water molecules and an Asp96 from one subunit. The Asp96 residue in the Ca2+-bound form makes hydrogen bonds with two guanidium nitrogen atoms of Arg 14 in the GSH-binding pocket. Mg2+ alters the coordinating water structure and reduces one hydrogen bond between Asp96 and Arg14, thereby changing the interaction between Arg 14 and GSH. This effect explains a four-fold reduction in the Km of the enzyme for GSH. The structure provides insights into how Ca2+ or Mg2+ binding activates human hematopoietic PGD Synthase.

Journal

  • Nihon Kessho Gakkaishi

    Nihon Kessho Gakkaishi 45 (Supplement), 16-16, 2003

    The Crystallographic Society of Japan

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