Title:Recent Advances in the Understanding of the Reaction Chemistries of the Heme Catabolizing Enzymes HO and BVR Based on High Resolution Protein Structures
VOLUME: 27 ISSUE: 21
Author(s):Masakazu Sugishima*, Kei Wada and Keiichi Fukuyama*
Affiliation:Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Department of Medical Sciences, University of Miyazaki, Miyazaki, Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka
Keywords:X-ray crystallography, Protein structure, Redox complex, Heme metabolism, Enzymatic reaction,
Ligand discrimination, Stacked substrate-binding mode.
Abstract:In mammals, catabolism of the heme group is indispensable for life. Heme is first cleaved
by the enzyme Heme Oxygenase (HO) to the linear tetrapyrrole Biliverdin IXα (BV), and BV is
then converted into bilirubin by Biliverdin Reductase (BVR). HO utilizes three Oxygen molecules
(O2) and seven electrons supplied by NADPH-cytochrome P450 oxidoreductase (CPR) to open the
heme ring and BVR reduces BV through the use of NAD(P)H. Structural studies of HOs, including
substrate-bound, reaction intermediate-bound, and several specific inhibitor-bound forms, reveal
details explaining substrate binding to HO and mechanisms underlying-specific HO reaction progression.
Cryo-trapped structures and a time-resolved spectroscopic study examining photolysis of
the bond between the distal ligand and heme iron demonstrate how CO, produced during the HO
reaction, dissociates from the reaction site with a corresponding conformational change in HO. The
complex structure containing HO and CPR provides details of how electrons are transferred to the
heme-HO complex. Although the tertiary structure of BVR and its complex with NAD+ was determined
more than 10 years ago, the catalytic residues and the reaction mechanism of BVR remain
unknown. A recent crystallographic study examining cyanobacterial BVR in complex with NADP+
and substrate BV provided some clarification regarding these issues. Two BV molecules are bound
to BVR in a stacked manner, and one BV may assist in the reductive catalysis of the other BV. In
this review, recent advances illustrated by biochemical, spectroscopic, and crystallographic studies
detailing the chemistry underlying the molecular mechanism of HO and BVR reactions are presented.