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Structure of human biliverdin IXβ reductase, an early fetal bilirubin IXβ producing enzyme

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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.

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Figure 1: BVR-B displays an α/β dinucleotide binding fold.
Figure 2: Human BVR-B binds specifically to NADP.
Figure 3: Structural formulas of some human BVR-B substrates and inhibitors.
Figure 4: Binding mode of substrates and inhibitors to human BVR-B.

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Acknowledgements

This work was supported by grants from the Ministerio de Educación y Cultura and the Generalitat de Catalunya to M.C. P.J.B.P. was supported in part by a FEBS Long Term fellowship. P.J.B.P. and S.M.R. acknowledge postdoctoral fellowships from Programa Praxis XXI (FCT, Portugal). O.C. was supported by the Health Research Board, Ireland. We thank D.A. Lightner for supplying the various verdins used in this work. Synchrotron data collection was supported by EU grants and the ESRF.

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Author notes

  1. Pedro José Barbosa Pereira, Sandra Macedo-Ribeiro, Orla Cunningham, Kevin Darcy and Timothy J. Mantle: These authors contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Instituto de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Jordi Girona, 18-26, Barcelona, 08034, Spain

    Pedro José Barbosa Pereira, Sandra Macedo-Ribeiro, Antonio Párraga, Rosa Pérez-Luque & Miquel Coll

  2. Department of Biochemistry, Trinity College, Dublin, 2, Ireland

    Orla Cunningham, Kevin Darcy & Timothy J. Mantle

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  1. Pedro José Barbosa Pereira
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  2. Sandra Macedo-Ribeiro
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  4. Rosa Pérez-Luque
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  5. Orla Cunningham
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  6. Kevin Darcy
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  7. Timothy J. Mantle
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  8. Miquel Coll
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Correspondence to Miquel Coll.

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Pereira, P., Macedo-Ribeiro, S., Párraga, A. et al. Structure of human biliverdin IXβ reductase, an early fetal bilirubin IXβ producing enzyme. Nat Struct Mol Biol 8, 215–220 (2001). https://doi.org/10.1038/84948

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