Prostaglandin F2 Formation from Prostaglandin H2 by Prostaglandin F Synthase (PGFS): Crystal Struct
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- 作者：Junichi Komoto ; Taro Yamada ; Kikuko Watanabe ; David F. Woodward ; and Fusao Takusagawa
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：February 21, 2006
- 年：2006
- 卷：45
- 期：7
- 页码：1987 - 1996
- 全文大小：474K
- 年卷期：v.45,no.7(February 21, 2006)
- ISSN：1520-4995
文摘
Prostaglandin H2 (PGH2) formed from arachidonic acid is an unstable intermediate and isefficiently converted into more stable arachidonate metabolites by the action of enzymes. ProstaglandinF synthase (PGFS) has dual catalytic activities: formation of PGF2
from PGH2 by the PGH2 9,11-endoperoxide reductase activity and 9,11
-PGF2 (PGF2) from PGD2 by the PGD2 11-ketoreductaseactivity in the presence of NADPH. Bimatoprost (BMP), which is a highly effective ocular hypotensiveagent, is a PGF2 analogue that inhibits both the PGD2 11-ketoreductase and PGH2 9,11-endoperoxidereductase activities of PGFS. To examine the catalytic mechanism of PGH2 9,11-endoperoxide reductase,a crystal structure of PGFS[NADPH + BMP] has been determined at 2.0 Å resolution. BMP binds nearthe PGD2 binding site, but the - and 
-chains of BMP are locate on the - and -chains of PGD2,respectively. Consequently, the bound BMP and PGD2 direct their opposite faces of the cyclopentanemoieties toward the nicotinamide ring of the bound NADP. The - and -chains of BMP are involvedin H-bonding with protein residues, while the cyclopentane moiety is surrounded by water molecules andis not directly attached to either the protein or the bound NADPH, indicating that the cyclopentane moietyis movable in the active site. From the complex structure, two model structures of PGFS containing PGF2and PGH2 were built. On the basis of the model structures and inhibition data, a putative catalytic mechanismof PGH2 9,11-endoperoxide reductase of PGFS is proposed. Formation of PGF2 from PGH2 most likelyinvolves a direct hydride transfer from the bound NADPH to the endoperoxide of PGH2 without theparticipation of specific amino acid residues.
from PGH2 by the PGH2 9,11-endoperoxide reductase activity and 9,11-PGF2 (PGF2) from PGD2 by the PGD2 11-ketoreductaseactivity in the presence of NADPH. Bimatoprost (BMP), which is a highly effective ocular hypotensiveagent, is a PGF2 analogue that inhibits both the PGD2 11-ketoreductase and PGH2 9,11-endoperoxidereductase activities of PGFS. To examine the catalytic mechanism of PGH2 9,11-endoperoxide reductase,a crystal structure of PGFS[NADPH + BMP] has been determined at 2.0 Å resolution. BMP binds nearthe PGD2 binding site, but the - and -chains of BMP are locate on the - and -chains of PGD2,respectively. Consequently, the bound BMP and PGD2 direct their opposite faces of the cyclopentanemoieties toward the nicotinamide ring of the bound NADP. The - and -chains of BMP are involvedin H-bonding with protein residues, while the cyclopentane moiety is surrounded by water molecules andis not directly attached to either the protein or the bound NADPH, indicating that the cyclopentane moietyis movable in the active site. From the complex structure, two model structures of PGFS containing PGF2and PGH2 were built. On the basis of the model structures and inhibition data, a putative catalytic mechanismof PGH2 9,11-endoperoxide reductase of PGFS is proposed. Formation of PGF2 from PGH2 most likelyinvolves a direct hydride transfer from the bound NADPH to the endoperoxide of PGH2 without theparticipation of specific amino acid residues.