Emerging structural and functional diversity in proteins with dioxygen-reactive dinuclear transition metal cofactors

Lauren J. Rajakovich, Bo Zhang, Molly J. McBride, Amie K. Boal, Carsten Krebs, J. Martin Bollinger

Research output: Chapter in Book/Report/Conference proceedingChapter

18 Scopus citations


Molecular oxygen is a powerful oxidant thermodynamically, but its triplet (S ¼ 1) electron-spin ground state imposes a high kinetic barrier for direct reaction with singlet (S ¼ 0) organic matter.1 Upon partial reduction, however, more reactive species—superoxide, peroxide, and hydroxyl radical—are produced. In biology, the controlled, partial reduction of O2 by an organic or transition metal enzyme cofactor is a versatile strategy to harness the potency of reduced oxygen species for useful chemical transformations. For metalloenzymes, the metal-oxygen adducts produced can be potent nucleophiles, electrophiles, or hydrogen-atom (H%) abstractors. Collectively, these intermediates allow for transformation of even chemically inert centers of organic compounds present in the biosphere. In reductive activation of O2, the first step, reduction to superoxide, is by far the least thermochemically favorable.1 Enzymes with organic cofactors (e.g., flavins) can kinetically couple the initial uphill step with a second, favorable electron-transfer or radical-coupling step that generates a more stable (yet still potent) peroxide-level intermediate.2 In enzymes that activate O2 with transition metals, the appropriate combination of a metal ion (Mn+) and ligands can make addition of O2 more favorable, so that subsequent steps can then proceed efficiently from an accumulating (formally) M(n+1)+–superoxide complex.1 Heme-dependent oxygenases exemplify this strategy, forming a common, stable FeIII-O2% adduct known as “compound 0” that undergoes rapid reduction by outer-sphere electron transfer.3 An alternative strategy for overcoming the unfavorable initial reduction step is approximation of two redox centers to enable concerted or coupled two-electron reduction of O2 to peroxide-level complexes.

Original languageEnglish (US)
Title of host publicationComprehensive Natural Products III
Number of pages36
ISBN (Electronic)9780081026908
ISBN (Print)9780081026915
StatePublished - Jul 22 2020

All Science Journal Classification (ASJC) codes

  • General Chemistry

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