TY - JOUR
T1 - Is it worth expending energy to convert biliverdin into bilirubin?
AU - Nam, Joon
AU - Lee, Yonghyun
AU - Yang, Yejin
AU - Jeong, Seongkeun
AU - Kim, Wooseong
AU - Yoo, Jin Wook
AU - Moon, Jeon Ok
AU - Lee, Changyong
AU - Chung, Hae Young
AU - Kim, Min Soo
AU - Jon, Sangyong
AU - Jung, Yunjin
N1 - Publisher Copyright:
© 2018
PY - 2018/8/20
Y1 - 2018/8/20
N2 - 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.
AB - 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.
KW - Bilirubin
KW - Biliverdin
KW - Biliverdin reductase
KW - Electrophile
KW - Kelch-like ECH-associated protein 1
KW - Michael reaction acceptor
KW - Nuclear factor-erythroid 2 (NF-E2) p45-related factor 2
UR - http://www.scopus.com/inward/record.url?scp=85048841839&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2018.06.010
DO - 10.1016/j.freeradbiomed.2018.06.010
M3 - Article
C2 - 29898414
AN - SCOPUS:85048841839
SN - 0891-5849
VL - 124
SP - 232
EP - 240
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -