Structural Basis for Copper–Oxygen Mediated C−H Bond Activation by the Formylglycine‐Generating Enzyme

Abstract

The formylglycine-generating enzyme (FGE) is aunique copper protein that catalyzes oxygen-dependent C À H activation. We describe 1.66 -a nd 1.28 -resolution crystal structures of FGE from Thermomonospora curvata in complex with either Ag I or Cd II providing definitive evidence for ahigh-affinity metal-binding site in this enzyme.The structures reveal ab is-cysteine linear coordination of the monovalent metal, and tetrahedral coordination of the bivalent metal. Similar coordination changes may occur in the active enzyme as ar esult of Cu I/II redoxc ycling. Complexation of copper atoms by two cysteine residues is common among coppertrafficking proteins,b ut is unprecedented for redox-active copper enzymes or synthetic copper catalysts. Figure 3. Left:Model of FGE curvata as the Cu II superoxo-complex in complex with the peptidyl-cysteine substrate. Right:Proposed catalytic mechanism of FGE (see text for details).T he Cu II superoxo-complex is highlighted in yellow. Angewandte Chemie Communications 8117

Formylglycine-generating enzyme-like proteins constitute a novel family of widespread type VI secretion system immunity proteins

“…Specifically, FGE converts sulfatase cysteines or serines within a conserved [C/S]-X-P-X-R motif to formylglycine (48)(49)(50). This oxygen-dependent reaction relies on two active site cysteines to coordinate a copper ion, which in turn binds the FGE substrate and primes it for reaction with oxygen (51)(52)(53). Notably, we found that Tsi3 homologs lack the catalytic cysteines essential to FGE function (Fig.…”

“…The striking relatedness of Tsi3 homologs to FGE domain-containing proteins suggests that these proteins likely share a common ancestor. Crystal structures from several FGE homologs indicate that the FGE domain adopts a unique “FGE fold” with low secondary structure (<20% of each β-sheets and α-helices) (49, 50, 52, 53, 63, 64). The FGE fold is also found in the X-ray crystal structures of non-FGE enzymes, including the putative oxidoreductase PvdO and the sulfoxide synthase EgtB.…”

Inhibition of direct-electron-transfer-type bioelectrocatalysis of bilirubin oxidase by silver ions

“…The absorption band at 600 nm from the coordination of cysteine to T1 Cu disappeared at high Ag + concentrations. Additionally, the inhibition of copper enzymes often involves the substitution of Cu + in the catalytic site by Ag + because of the analogous behavior of these two ions [24][25][26]. Table 2 lists the BOD activity with the addition of various Ag + solutions, demonstrating that the inhibition of T1 Cu decreased the enzymatic activity.…”

Crystal Structure of the Ergothioneine Sulfoxide Synthase from Candidatus Chloracidobacterium thermophilum and Structure-Guided Engineering To Modulate Its Substrate Selectivity

“…A Dali search revealed that the N -terminal domain most closely resembles the damage-inducible protein Din-B (PDB ID: 5WK0 ) and the C -terminal domain is structurally similar to the formylglycine generating enzyme (PDB ID: 5NXL). The C -terminal domain shares a high structural similarity with the catalytic domain of EgtB Mth …”