[FeFe]- and [NiFe]-Hydrogenase Diversity, Mechanism, and Maturation

Paul King, David Mulder, John Peters, Gerritt Schut, Eric Boyd, Eric Shepard, Joan Broderick, Michael Adams

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360 Scopus Citations


The [FeFe]- and [NiFe]-hydrogenases catalyze the formal interconversion between hydrogen and protons and electrons, possess characteristic non-protein ligands at their catalytic sites and thus share common mechanistic features. Despite the similarities between these two types of hydrogenases, they clearly have distinct evolutionary origins and likely emerged from different selective pressures. [FeFe]-hydrogenases are widely distributed in fermentative anaerobic microorganisms and likely evolved under selective pressure to couple hydrogen production to the recycling of electron carriers that accumulate during anaerobic metabolism. In contrast, many [NiFe]-hydrogenases catalyze hydrogen oxidation as part of energy metabolism and were likely key enzymes in early life and arguably represent the predecessors of modern respiratory metabolism. Although the reversible combination of protons and electrons to generate hydrogen gas is the simplest of chemical reactions, the [FeFe]- and [NiFe]-hydrogenases have distinct mechanisms and differ in the fundamental chemistry associated with proton transfer and control of electron flow that also help to define catalytic bias. A unifying feature of these enzymes is that hydrogen activation itself has been restricted to one solution involving diatomic ligands (carbon monoxide and cyanide) bound to an Fe ion. On the other hand, and quite remarkably, the biosynthetic mechanisms to produce these ligands are exclusive to each type of enzyme. Furthermore, these mechanisms represent two independent solutions to the formation of complex bioinorganic active sites for catalyzing the simplest of chemical reactions, reversible hydrogen oxidation. As such, the [FeFe]- and [NiFe]-hydrogenases are arguably the most profound case of convergent evolution. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases.

Original languageAmerican English
Pages (from-to)1350-1369
Number of pages20
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Issue number6
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© 2014 Elsevier B.V.

NREL Publication Number

  • NREL/JA-2700-62633


  • Bifurcation
  • Carbon monoxide
  • Cyanide
  • Hydrogen oxidation
  • Iron-sulfur
  • Proton reduction


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