Mechanism of metal activation of human hematopoietic prostaglandin D synthase

被引:63
作者
Inoue, T
Irikura, D
Okazaki, N
Kinugasa, S
Matsumura, H
Uodome, N
Yamamoto, M
Kumasaka, T
Miyano, M
Kai, Y
Urade, Y [1 ]
机构
[1] Japan Sci & Technol Corp, CREST, Osaka Biosci Inst, Osaka 5650874, Japan
[2] Osaka Univ, Grad Sch Engn, Dept Chem Mat, Suita, Osaka 5650871, Japan
[3] Japan Sci & Technol Corp, PRESTO, Struct & Funct Biomol Grp, Kyoto 6040847, Japan
[4] RIKEN, Inst Phys & Chem Res, Harima Inst, Hyogo 6795143, Japan
[5] Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Life Sci, Kanagawa 2268501, Japan
关键词
D O I
10.1038/nsb907
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Here 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 PGH(2) to PGD(2), a mediator for allergy response. The enzyme is a homodimer, and Ca2+ or Mg2+ increases its activity to similar to150% of the basal level, with half maximum effective concentrations of 400 muM for Ca2+ and 50 M 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 Arg14 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 Arg14 and GSH. This effect explains a four-fold reduction in the K-m of the enzyme for GSH. The structure provides insights into how Ca2+ or Mg2+ binding activates human hematopoietic PGD synthase.
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页码:291 / 296
页数:6
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