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

Biliverdin IX beta reductase (BVR-B) catalyzes the pyridine nucleotide-dependent production of bilirubin-IX beta, 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 IX alpha 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 Angstrom resolution. Human BVR-B is a monomer displaying an alpha/beta dinucleotide binding fold, The structures of ternary complexes with mesobiliverdin IV alpha, biliverdin IX alpha, 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 IX alpha 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.