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Re-designing hydrogenases

Crystal structure of [NiFe] hydrogenase (Wiki Commons)

Crystal structure of [NiFe] hydrogenase (Wiki Commons)

EPFL chemists have synthesized the first ever functional non-native metal hydrogenase.

Hydrogenases are enzymes that catalyze hydrogen activation. There are three types of hydrogenases in nature, all containing iron and some of them nickel. But in synthetic chemistry there is a whole host of metals that can activate molecular hydrogen and catalyze hydrogenation reactions.

“Why doesn’t nature use other metals in hydrogenases? Is it purely due to bioavailability?” asks Xile Hu, head of the Laboratory of Inorganic Synthesis and Catalysis at EPFL. The answer is probably not simple, since metalloenzymes containing molybdenum, manganese, cobalt, and copper are pretty common.

Working with the lab of Seigo Shima at the Max Planck Institute for Terrestrial Microbiology, Hu’s lab has now synthesized a manganese-hydrogenase by incorporating a manganese complex into the apoenzyme (the active-site free part) of iron-hydrogenase.

“What is exciting is that this semi-synthetic manganese-hydrogenase is active for the native reaction of iron-hydrogenase,” says Hu. This is important because, generally speaking, replacing native metals while maintaining the enzyme’s activity is rare. “To our knowledge, this is the first functional non-native metal hydrogenase.”

Other contributors

  • Max Planck Institute for Terrestrial Microbiology
  • EPFL Laboratory for Computational Molecular Design
  • Freie Universität Berlin

Swiss National Science Foundation, European Union Marie Sklodowska-Curie Individual Fellowships, Max Planck Society, Deutsche Forschungsgemeinschaft (German Research foundation), EPFL, China Scholarship Council


Hui-Jie Pan, Gangfeng Huang, Matthew D. Wodrich, Farzaneh Fadaei Tirani, Kenichi Ataka, Seigo Shima, Xile Hu. A catalytically active [Mn]-hydrogenase incorporating a non-native metal cofactor. Nature Chemistry 20 May 2019. DOI: 10.1038/s41557-019-0266-1