A substrate-bound structure of cyanobacterial biliverdin reductase identifies stacked substrates as critical for activity

Haruna Takao, Kei Hirabayashi, Yuki Nishigaya, Haruna Kouriki, Tetsuko Nakaniwa, Yoshinori Hagiwara, Jiro Harada, Hideaki Sato, Toshimasa Yamazaki, Yoichi Sakakibara, Masahito Suiko, Yujiro Asada, Yasuhiro Takahashi, Ken Yamamoto, Keiichi Fukuyama, Masakazu Sugishima () and Kei Wada ()
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Haruna Takao: Organization for Promotion of Tenure Track, University of Miyazaki
Kei Hirabayashi: Organization for Promotion of Tenure Track, University of Miyazaki
Yuki Nishigaya: Advanced Analysis Center, National Agriculture and Food Research Organization
Haruna Kouriki: Organization for Promotion of Tenure Track, University of Miyazaki
Tetsuko Nakaniwa: Graduate School of Science, Osaka University
Yoshinori Hagiwara: National Institute of Technology, Kurume College
Jiro Harada: Kurume University School of Medicine
Hideaki Sato: Kurume University School of Medicine
Toshimasa Yamazaki: Advanced Analysis Center, National Agriculture and Food Research Organization
Yoichi Sakakibara: Faculty of Agriculture, University of Miyazaki
Masahito Suiko: Faculty of Agriculture, University of Miyazaki
Yujiro Asada: Faculty of Medicine, University of Miyazaki
Yasuhiro Takahashi: Graduate School of Science and Engineering, Saitama University
Ken Yamamoto: Kurume University School of Medicine
Keiichi Fukuyama: Graduate School of Science, Osaka University
Masakazu Sugishima: Kurume University School of Medicine
Kei Wada: Organization for Promotion of Tenure Track, University of Miyazaki

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Biliverdin reductase catalyses the last step in haem degradation and produces the major lipophilic antioxidant bilirubin via reduction of biliverdin, using NAD(P)H as a cofactor. Despite the importance of biliverdin reductase in maintaining the redox balance, the molecular details of the reaction it catalyses remain unknown. Here we present the crystal structure of biliverdin reductase in complex with biliverdin and NADP+. Unexpectedly, two biliverdin molecules, which we designated the proximal and distal biliverdins, bind with stacked geometry in the active site. The nicotinamide ring of the NADP+ is located close to the reaction site on the proximal biliverdin, supporting that the hydride directly attacks this position of the proximal biliverdin. The results of mutagenesis studies suggest that a conserved Arg185 is essential for the catalysis. The distal biliverdin probably acts as a conduit to deliver the proton from Arg185 to the proximal biliverdin, thus yielding bilirubin.

Date: 2017
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DOI: 10.1038/ncomms14397

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