Is it worth expending energy to convert biliverdin into bilirubin?

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>Bilirubin (BR) is generated by the reduction of biliverdin (BV), a metabolite that results from the catalytic degradation of heme by the isoforms of heme oxygenase (HO). BV is nontoxic and water-soluble but BR is potentially toxic and lipophilic. Therefore, a further metabolic step is required for BR before excretion is possible. The reductive conversion of BV to BR costs energy and is evolutionarily conserved in human physiology. There must be a compelling reason for this apparently nonsensical evolutionary conservation. In addition to the differences between BR and BV—such as water solubility, antioxidant activity, and participation as a receptor ligand—in the present study, we focused on the chemistry of the two metabolites with regard to an electrophilic functional group called a Michael reaction acceptor (MRA). Our data reveal that the BR reacts with thiol compounds forming adducts, whereas no reaction occurs with BV. Furthermore, the binding of biotin-tagged BR to Kelch-like ECH-associated protein 1 (KEAP1)—a biological electrophile sensor—was prevented by pretreatment with BR or a thiol compound, but was not by pretreatment with BV. In cells, BR could bind to KEAP1 to release and activate nuclear factor-erythroid 2 (NF-E2) p45-related factor 2, a cytoprotective transcription factor, leading to the induction of HO-1. These findings may provide a physiological rationale for the energy-consuming conversion of BV to BR.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Bilirubin (BR) but not biliverdin (BV) is sufficiently electrophilic to react with thiol compounds. </LI> <LI> BR but not BV covalently binds to KEAP1 and releases Nrf2. </LI> <LI> BR activates Nrf2 pathway in cells. </LI> <LI> BV activation of Nrf2 is blunted by siRNA knockdown of BV reductase converting BV to BR. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>