Structure of human biliverdin IXbeta reductase, an early fetal bilirubin IXbeta producing enzyme.
Biliverdin IXbeta reductase (BVR-B) catalyzes the pyridine nucleotide-dependent production of bilirubin-IXbeta, 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 IXalpha 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 A resolution. Human BVR-B is a monomer displaying an alpha/beta dinucleotide binding fold. The structures of ternary complexes with mesobiliverdin IValpha, biliverdin IXalpha, 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 IXalpha 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.
Instituto de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Jordi Girona, 18-26, 08034 Barcelona, Spain.
P J
PJ
Pereira
S
S
Macedo-Ribeiro
A
A
Párraga
R
R
Pérez-Luque
O
O
Cunningham
K
K
Darcy
T J
TJ
Mantle
M
M
Coll
D000595:Amino Acid Sequence; D001663:Bilirubin / Q000096:biosynthesis / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005333:Fetus / Q000201:enzymology* / Q000378:metabolism; D005486:Flavin Mononucleotide / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D017433:Protein Structure, Secondary; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013237:Stereoisomerism; D013379:Substrate Specificity; D045725:Tetrapyrroles
D011758:Pyrroles; D045725:Tetrapyrroles; D009249:NADP; D005486:Flavin Mononucleotide; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D001663:Bilirubin