1ry8: Difference between revisions

Revision as of 15:55, 21 February 2008

Prostaglandin F synthase complexed with NADPH and rutin

OverviewOverview

Prostaglandin H(2) (PGH(2)) formed from arachidonic acid is an unstable intermediate and is efficiently converted into more stable arachidonate metabolites (PGD(2), PGE(2), and PGF(2)) by the action of three groups of enzymes. Prostaglandin F synthase (PGFS) was first purified from bovine lung and catalyzes the formation of 9 alpha,11 beta-PGF(2) from PGD(2) and PGF(2)(alpha) from PGH(2) in the presence of NADPH. Human PGFS is 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) type II and has PGFS activity and 3 alpha-HSD activity. Human lung PGFS has been crystallized with the cofactor NADP(+) and the substrate PGD(2), and with the cofactor NADPH and the inhibitor rutin. These complex structures have been determined at 1.69 A resolution. PGFS has an (alpha/beta)(8) barrel structure. The cofactor and substrate or inhibitor bind in a cavity at the C-terminal end of the barrel. The cofactor binds deeply in the cavity and has extensive interactions with PGFS through hydrogen bonds, whereas the substrate (PGD(2)) is located above the bound cofactor and has little interaction with PGFS. Despite being largely structurally different from PGD(2), rutin is located at the same site of PGD(2), and its catechol and rhamnose moieties are involved in hydrogen bonds with PGFS. The catalytic site of PGFS contains the conserved Y55 and H117 residues. The carbonyl O(11) of PGD(2) and the hydroxyl O(13) of rutin are involved in hydrogen bonds with Y55 and H117. The cyclopentane ring of PGD(2) and the phenyl ring of rutin face the re-side of the nicotinamide ring of the cofactor. On the basis of the catalytic geometry, a direct hydride transfer from NADPH to PGD(2) would be a reasonable catalytic mechanism. The hydride transfer is facilitated by protonation of carbonyl O(11) of PGD(2) from either H117 (at low pH) or Y55 (at high pH). Since the substrate binding cavity of PGFS is relatively large in comparison with those of AKR1C1 and AKR1C2, PGFS (AKR1C3) could catalyze the reduction and/or oxidation reactions of various compounds over a relatively wide pH range.

About this StructureAbout this Structure

1RY8 is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Crystal structure of human prostaglandin F synthase (AKR1C3)., Komoto J, Yamada T, Watanabe K, Takusagawa F, Biochemistry. 2004 Mar 2;43(8):2188-98. PMID:14979715

Page seeded by OCA on Thu Feb 21 14:55:48 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 4: / Line 4: @@
 ==Overview==
-Prostaglandin H(2) (PGH(2)) formed from arachidonic acid is an unstable, intermediate and is efficiently converted into more stable arachidonate, metabolites (PGD(2), PGE(2), and PGF(2)) by the action of three groups of, enzymes. Prostaglandin F synthase (PGFS) was first purified from bovine, lung and catalyzes the formation of 9 alpha,11 beta-PGF(2) from PGD(2) and, PGF(2)(alpha) from PGH(2) in the presence of NADPH. Human PGFS is 3, alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) type II and has PGFS, activity and 3 alpha-HSD activity. Human lung PGFS has been crystallized, with the cofactor NADP(+) and the substrate PGD(2), and with the cofactor, NADPH and the inhibitor rutin. These complex structures have been, determined at 1.69 A resolution. PGFS has an (alpha/beta)(8) barrel, structure. The cofactor and substrate or inhibitor bind in a cavity at the, C-terminal end of the barrel. The cofactor binds deeply in the cavity and, has extensive interactions with PGFS through hydrogen bonds, whereas the, substrate (PGD(2)) is located above the bound cofactor and has little, interaction with PGFS. Despite being largely structurally different from, PGD(2), rutin is located at the same site of PGD(2), and its catechol and, rhamnose moieties are involved in hydrogen bonds with PGFS. The catalytic, site of PGFS contains the conserved Y55 and H117 residues. The carbonyl, O(11) of PGD(2) and the hydroxyl O(13) of rutin are involved in hydrogen, bonds with Y55 and H117. The cyclopentane ring of PGD(2) and the phenyl, ring of rutin face the re-side of the nicotinamide ring of the cofactor., On the basis of the catalytic geometry, a direct hydride transfer from, NADPH to PGD(2) would be a reasonable catalytic mechanism. The hydride, transfer is facilitated by protonation of carbonyl O(11) of PGD(2) from, either H117 (at low pH) or Y55 (at high pH). Since the substrate binding, cavity of PGFS is relatively large in comparison with those of AKR1C1 and, AKR1C2, PGFS (AKR1C3) could catalyze the reduction and/or oxidation, reactions of various compounds over a relatively wide pH range.
+Prostaglandin H(2) (PGH(2)) formed from arachidonic acid is an unstable intermediate and is efficiently converted into more stable arachidonate metabolites (PGD(2), PGE(2), and PGF(2)) by the action of three groups of enzymes. Prostaglandin F synthase (PGFS) was first purified from bovine lung and catalyzes the formation of 9 alpha,11 beta-PGF(2) from PGD(2) and PGF(2)(alpha) from PGH(2) in the presence of NADPH. Human PGFS is 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) type II and has PGFS activity and 3 alpha-HSD activity. Human lung PGFS has been crystallized with the cofactor NADP(+) and the substrate PGD(2), and with the cofactor NADPH and the inhibitor rutin. These complex structures have been determined at 1.69 A resolution. PGFS has an (alpha/beta)(8) barrel structure. The cofactor and substrate or inhibitor bind in a cavity at the C-terminal end of the barrel. The cofactor binds deeply in the cavity and has extensive interactions with PGFS through hydrogen bonds, whereas the substrate (PGD(2)) is located above the bound cofactor and has little interaction with PGFS. Despite being largely structurally different from PGD(2), rutin is located at the same site of PGD(2), and its catechol and rhamnose moieties are involved in hydrogen bonds with PGFS. The catalytic site of PGFS contains the conserved Y55 and H117 residues. The carbonyl O(11) of PGD(2) and the hydroxyl O(13) of rutin are involved in hydrogen bonds with Y55 and H117. The cyclopentane ring of PGD(2) and the phenyl ring of rutin face the re-side of the nicotinamide ring of the cofactor. On the basis of the catalytic geometry, a direct hydride transfer from NADPH to PGD(2) would be a reasonable catalytic mechanism. The hydride transfer is facilitated by protonation of carbonyl O(11) of PGD(2) from either H117 (at low pH) or Y55 (at high pH). Since the substrate binding cavity of PGFS is relatively large in comparison with those of AKR1C1 and AKR1C2, PGFS (AKR1C3) could catalyze the reduction and/or oxidation reactions of various compounds over a relatively wide pH range.
 ==About this Structure==
@@ Line 23: / Line 23: @@
 [[Category: rutin]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:50:51 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:55:48 2008''