In biological systems copper plays essential role in redox catalysis. Protein-bound can cycle between the oxidative states I, II and possibly III and thereby facilitate binding and activation of substrates. [1, 2]

The formylglycine generating enzyme (FGE) is a novel copper dependent oxidase, which participates in the activation of sulfatases in bacteria and animals. FGE catalases an O₂-dependent conversion of specific cysteine residue to formylglycine through the abstraction of the peptidyl-cysteine pro-(R)-β-hydrogen [3]. According to the recent structural investigations, FGE in the resting state has a single Cu(I), coordinated only with two cysteines in the linear geometry. The analogous sulfur rich coordination is common for copper trafficking proteins and transcription factors, but unprecedented among copper-dependent oxidases, which predominantly bind the metal in the histidine-rich tetrahedral or square planar coordination geometry. In contrast to the copper trafficking enzymes, FGE active site can bind and activate O₂ to abstract H atom from C-H bond. [4-6]

In this presentation we will describe the crystal structure of FGE from T. curvata in the complex with Cu(I) and a substrate peptide. This high-resolution structure, together with NMR spectroscopy and kinetic data, revealed an acidic O₂ binding pocket, closely located to the copper center. This FGE active site feature plays key role in O₂ activation.

The schematic representation of Cu(I) coordination sphere in the crystal structure of tcFGE in the complex with substrate analog.

[1] E.I. Solomon, et al., Chem Rev, 2014, 114 (7), 3659-853.
[2] W. Keown, J.B. Gary, and T.D. Stack, J Biol Inorg Chem, 2017, 22 (2-3), 289-305.
[3] J. Fey, et al., J Biol Chem, 2001, 276 (50), 47021-8.
[4] A. Messerschmidt, in "Comprehensive Natural Products II: Chemistry and Biology", 2010, 8, 489-545.
[5] M. Meury, M. Knop, and F.P. Seebeck, Angew. Chem. Int. Ed. Engl, 2017, 56 (28), 8115-8119.
[6] M. J. Appel, et al., PNAS, 2019, 16 (12), 5370-5375.