Abstract
Biliverdin reductase catalyses the last step in haem degradation and produces the major lipophilic antioxidant bilirubin via reduction of biliverdin, using NAD(P)H as a cofactor. Despite the importance of biliverdin reductase in maintaining the redox balance, the molecular details of the reaction it catalyses remain unknown. Here we present the crystal structure of biliverdin reductase in complex with biliverdin and NADP+. Unexpectedly, two biliverdin molecules, which we designated the proximal and distal biliverdins, bind with stacked geometry in the active site. The nicotinamide ring of the NADP+ is located close to the reaction site on the proximal biliverdin, supporting that the hydride directly attacks this position of the proximal biliverdin. The results of mutagenesis studies suggest that a conserved Arg185 is essential for the catalysis. The distal biliverdin probably acts as a conduit to deliver the proton from Arg185 to the proximal biliverdin, thus yielding bilirubin.
Highlights
Biliverdin reductase catalyses the last step in haem degradation and produces the major lipophilic antioxidant bilirubin via reduction of biliverdin, using NAD(P)H as a cofactor
Several crystallographic analyses have been performed to date: the structures of rat Biliverdin reductase (BVR) in the apo-form and in complex with NAD þ have been reported by two independent groups[6,7], and the structure of human BVR in complex with NADP þ has been deposited in the RCSB Protein Data Bank (PDB ID: 2H63)
We report the X-ray structures of the apo, NADP þ bound and BV–NADP þ complex forms of BVR. This is the structure of the substrate–cofactor–enzyme ternary complex of BVR, revealing a binding mode in which two biliverdin molecules bind with stacked geometry in the active site
Summary
Biliverdin reductase catalyses the last step in haem degradation and produces the major lipophilic antioxidant bilirubin via reduction of biliverdin, using NAD(P)H as a cofactor. We report the X-ray structures of the apo-, NADP þ bound and BV–NADP þ complex forms of BVR This is the structure of the substrate–cofactor–enzyme ternary complex of BVR, revealing a binding mode in which two biliverdin molecules bind with stacked geometry in the active site. This structure and the results of site-direct mutagenesis can explain how BVR reduces BV to BR, resolving a longstanding mystery regarding the BVR reaction mechanism
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