Bruska MK Stiebritz MT Reiher M 2011 The H(2)-evolving potential of [FeFe] hydrogenases is severely limited by the oxygen sensitivity of this class of enzymes. Recent experimental studies on hydrogenase from C. reinhardtii point to O(2)-induced structural changes in the [Fe(4)S(4)] subsite of the H cluster. Here, we investigate the mechanistic basis of this observation by means of density functional theory. Unexpectedly, we find that the isolated H cluster shows a pathological catalytic activity for the formation of reactive oxygen species such as O(2)(-) and HO(2)(-). After protonation of O(2)(-), an OOH radical may coordinate to the Fe atoms of the cubane, whereas H(2)O(2) specifically reacts with the S atoms of the cubane-coordinating cysteine residues. Both pathways are accompanied by significant structural distortions that compromise cluster integrity and thus catalytic activity. These results explain the experimental observation that O(2)-induced inhibition is accompanied by distortions of the [Fe(4)S(4)] moiety and account for the irreversibility of this process. https://sonar.ch/global/documents/143325 eng info:eu-repo/semantics/altIdentifier/doi/10.1021/ja209165r info:eu-repo/semantics/altIdentifier/pmid/22106822 Journal of the American Chemical Society. - 2011 Catalysis Hydrogen Models, Molecular Oxidation-Reduction Regioselectivity of H cluster oxidation. http://purl.org/coar/resource_type/c_6501