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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 1gcu

E.C. namebiliverdin reductase
SpeciesRattus norvegicus (Rat)
E.C. Number (IntEnz) 1.3.1.24
CSA Homologues of 1gcu1lc0,1lc3,2h63,
CSA Entries With UniProtID P46844
CSA Entries With EC Number 1.3.1.24
PDBe Entry 1gcu
PDBSum Entry 1gcu
MACiE Entry 1gcu

Literature Report

IntroductionBiliverdin reductase is an evolutionarily conserved soluble protein found primarily in mammalian species. The enzyme reduces the gamma-methylene bridge of biliverdin to form bilirubin in the presence of the NAD(P)H cofactor. The reductase is also a serine/threonine kinase which is activated by oxygen radicals and traslocates into the nucleus in response to cGMP and oxidative stress. The substrate and product are immune function modulators and, based on their anti-oxidant properties, it has been suggested, although not universally accepted that biliverdin and bilirubin play a protective role in the cell.
MechansimBiliverdin reductase catalyses the reduction of the biliverdin gamma-methylene bridge with a hydride donated by the NAD(P)H cofactor, initiated by proton transfer from a residue to the pyrrole ring nitrogen. It is unknown whether the protonation and hydride transfer are concerted or sequential.
Mutagenesis has shown catalytic activity to remain at 50% when the putative general acid Tyr 97 is mutated to Ala, indicating that this residue is not essential for catalysis, although no other acid has been identified. Instead of a general acid role, the residue may influence the substrate conformation, and so increasing hydride transfer reactivity. Surrounding Glu residues are thought to stabilise the positively charged NAD(P)+.
Reaction

Catalytic Sites for 1gcu

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrA9797macie:sideChainThe residue is thought to act as a general acid towards the pyrrole ring nitrogen before hydride transfer, although its removal does not knock out reactivity. The residue is then reprotonated by the solvent, with the residue's pKa being influence by interactions with Ser170 and Arg171. While it is the only available general acid, it is thought that the hydride transfer may instead by driven by conformational changes.
SerA170170macie:sideChainThe residue is thought to influence the pKa of Tyr97, facilitating reprotonation from the solvent.
ArgA171171macie:sideChainThe residue is thought to influence the pKa of Tyr97, facilitating reprotonation from the solvent.
GluA9696macie:sideChainThe residue's negatively charged side chain is thought to stabilise the positively charged NAD(P)+ cofactor after hydride transfer to the biliverdin substrate. This electrostatic interaction could play a major role in driving the reaction, since the removal of the putative general acid by mutagenesis does not wipe out reactivity.
GluA123123macie:sideChainThe residue's negatively charged side chain is thought to stabilise the positively charged NAD(P)+ cofactor after hydride transfer to the biliverdin substrate. This electrostatic interaction could play a major role in driving the reaction, since the removal of the putative general acid by mutagenesis does not wipe out reactivity.
GluA126126macie:sideChainThe residue's negatively charged side chain is thought to stabilise the positively charged NAD(P)+ cofactor after hydride transfer to the biliverdin substrate. This electrostatic interaction could play a major role in driving the reaction, since the removal of the putative general acid by mutagenesis does not wipe out reactivity.

Literature References

Notes:
Whitby FG
Crystal structure of a biliverdin IXalpha reductase enzyme-cofactor complex.
J Mol Biol 2002 319 1199-1210
PubMed: 12079357
McDonagh AF.
The biliverdin-bilirubin antioxidant cycle of cellular protection: Missing a wheel?
Free Radic Biol Med 2010 49 814-820
PubMed: 20547221
Lerner-Marmarosh N
Human biliverdin reductase: a member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity.
Proc Natl Acad Sci U S A 2005 102 7109-7114
PubMed: 15870194
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