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- Title
Structure of human biliverdin IXβ reductase, an early fetal bilirubin IXβ producing enzyme.
- Authors
Pereira, Pedro José Barbosa; Macedo-Ribeiro, Sandra; Párraga, Antonio; Pérez-Luque, Rosa; Cunningham, Orla; Darcy, Kevin; Mantle, Timothy J.; Coll, Miquel
- Abstract
Biliverdin IXβ reductase (BVR-B) catalyzes the pyridine nucleotide-dependent production of bilirubin-IXβ, the major heme catabolite during early fetal development. BVR-B displays a preference for biliverdin isomers without propionates straddling the C10 position, in contrast to biliverdin IXα reductase (BVR-A), the major form of BVR in adult human liver. In addition to its tetrapyrrole clearance role in the fetus, BVR-B has flavin and ferric reductase activities in the adult. We have solved the structure of human BVR-B in complex with NADP+ at 1.15 Å resolution. Human BVR-B is a monomer displaying an α/β dinucleotide binding fold. The structures of ternary complexes with mesobiliverdin IVα, biliverdin IXα, FMN and lumichrome show that human BVR-B has a single substrate binding site, to which substrates and inhibitors bind primarily through hydrophobic interactions, explaining its broad specificity. The reducible atom of both biliverdin and flavin substrates lies above the reactive C4 of the cofactor, an appropriate position for direct hydride transfer. BVR-B discriminates against the biliverdin IXα isomer through steric hindrance at the bilatriene side chain binding pockets. The structure also explains the enzyme's preference for NADP(H) and its B-face stereospecificity.
- Subjects
PROTEINS; BILIRUBIN
- Publication
Nature Structural Biology, 2001, Vol 8, Issue 3, p215
- ISSN
1072-8368
- Publication type
Article
- DOI
10.1038/84948