Is it worth expending energy to convert biliverdin into bilirubin?

Joon Nam, Yonghyun Lee, Yejin Yang, Seongkeun Jeong, Wooseong Kim, Jin Wook Yoo, Jeon Ok Moon, Changyong Lee, Hae Young Chung, Min Soo Kim, Sangyong Jon, Yunjin Jung

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish
Pages (from-to)232-240
Number of pages9
JournalFree Radical Biology and Medicine
StatePublished - 20 Aug 2018

Bibliographical note

Funding Information:
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (grant number 2009-0083538 ).

Publisher Copyright:
© 2018


  • Bilirubin
  • Biliverdin
  • Biliverdin reductase
  • Electrophile
  • Kelch-like ECH-associated protein 1
  • Michael reaction acceptor
  • Nuclear factor-erythroid 2 (NF-E2) p45-related factor 2


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