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

Biliverdin IX beta reductase (BVR-B) catalyzes the pyridine nucleotide-depe ndent production of bilirubin-IX beta, the major heme catabolite during ear ly fetal development, BVR-B displays a preference for biliverdin isomers wi thout propionates straddling the C10 position, in contrast to biliverdin IX alpha reductase (BVR-A), the major form of BVR in adult human liver, In ad dition to its tetrapyrrole clearance role in the fetus, BVR-B has flavin an d 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 str uctures of ternary complexes with mesobiliverdin IV alpha, biliverdin IX al pha, FMN and lumichrome show that human BVR-B has a single substrate bindin g site, to which substrates and inhibitors bind primarily through hydrophob ic interactions, explaining its broad specificity. The reducible atom of bo th biliverdin and flavin substrates lies above the reactive C4 of the cofac tor, an appropriate position for direct hydride transfer, BVR-B discriminat es against the biliverdin IX alpha isomer through steric hindrance at the b ilatriene side chain binding pockets. The structure also explains the enzym e's preference for NADP(H) and its B-face stereospecificity.