Crystal Structure of Human Prostaglandin F Synthase (AKR1C3)
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- 作者：Junichi Komoto ; Taro Yamada ; Kikuko Watanabe ; and Fusao Takusagawa
- 刊名：Biochemistry
- 出版年：2004
- 出版时间：March 2, 2004
- 年：2004
- 卷：43
- 期：8
- 页码：2188 - 2198
- 全文大小：965K
- 年卷期：v.43,no.8(March 2, 2004)
- ISSN：1520-4995
文摘
Prostaglandin H2 (PGH2) formed from arachidonic acid is an unstable intermediate and isefficiently converted into more stable arachidonate metabolites (PGD2, PGE2, and PGF2) by the action ofthree groups of enzymes. Prostaglandin F synthase (PGFS) was first purified from bovine lung and catalyzesthe formation of 9
,11
-PGF2 from PGD2 and PGF2 from PGH2 in the presence of NADPH. HumanPGFS is 3-hydroxysteroid dehydrogenase (3-HSD) type II and has PGFS activity and 3-HSD activity.Human lung PGFS has been crystallized with the cofactor NADP+ and the substrate PGD2, and with thecofactor NADPH and the inhibitor rutin. These complex structures have been determined at 1.69 Åresolution. PGFS has an (/)8 barrel structure. The cofactor and substrate or inhibitor bind in a cavityat the C-terminal end of the barrel. The cofactor binds deeply in the cavity and has extensive interactionswith PGFS through hydrogen bonds, whereas the substrate (PGD2) is located above the bound cofactorand has little interaction with PGFS. Despite being largely structurally different from PGD2, rutin is locatedat the same site of PGD2, and its catechol and rhamnose moieties are involved in hydrogen bonds withPGFS. The catalytic site of PGFS contains the conserved Y55 and H117 residues. The carbonyl O11 ofPGD2 and the hydroxyl O13 of rutin are involved in hydrogen bonds with Y55 and H117. The cyclopentanering of PGD2 and the phenyl ring of rutin face the re-side of the nicotinamide ring of the cofactor. On thebasis of the catalytic geometry, a direct hydride transfer from NADPH to PGD2 would be a reasonablecatalytic mechanism. The hydride transfer is facilitated by protonation of carbonyl O11 of PGD2 fromeither H117 (at low pH) or Y55 (at high pH). Since the substrate binding cavity of PGFS is relativelylarge in comparison with those of AKR1C1 and AKR1C2, PGFS (AKR1C3) could catalyze the reductionand/or oxidation reactions of various compounds over a relatively wide pH range.
,11-PGF2 from PGD2 and PGF2 from PGH2 in the presence of NADPH. HumanPGFS is 3-hydroxysteroid dehydrogenase (3-HSD) type II and has PGFS activity and 3-HSD activity.Human lung PGFS has been crystallized with the cofactor NADP+ and the substrate PGD2, and with thecofactor NADPH and the inhibitor rutin. These complex structures have been determined at 1.69 Åresolution. PGFS has an (/)8 barrel structure. The cofactor and substrate or inhibitor bind in a cavityat the C-terminal end of the barrel. The cofactor binds deeply in the cavity and has extensive interactionswith PGFS through hydrogen bonds, whereas the substrate (PGD2) is located above the bound cofactorand has little interaction with PGFS. Despite being largely structurally different from PGD2, rutin is locatedat the same site of PGD2, and its catechol and rhamnose moieties are involved in hydrogen bonds withPGFS. The catalytic site of PGFS contains the conserved Y55 and H117 residues. The carbonyl O11 ofPGD2 and the hydroxyl O13 of rutin are involved in hydrogen bonds with Y55 and H117. The cyclopentanering of PGD2 and the phenyl ring of rutin face the re-side of the nicotinamide ring of the cofactor. On thebasis of the catalytic geometry, a direct hydride transfer from NADPH to PGD2 would be a reasonablecatalytic mechanism. The hydride transfer is facilitated by protonation of carbonyl O11 of PGD2 fromeither H117 (at low pH) or Y55 (at high pH). Since the substrate binding cavity of PGFS is relativelylarge in comparison with those of AKR1C1 and AKR1C2, PGFS (AKR1C3) could catalyze the reductionand/or oxidation reactions of various compounds over a relatively wide pH range.