The role of CopA in Streptococcus pyogenes copper homeostasis and virulence

Resisting death by metal: metabolism and Cu/Zn homeostasis in bacteria

“…The authors attributed this observation to nutritional deficiency since supplementation with a mixture of exogenous amino acids rescued this defect in survival at stationary phase. Supplementation with cysteine ( Figure 1A ), which forms Cu-binding ligands in proteins [ 37 ], enhanced survival in conditions of high Cu stress in S. pyogenes [ 38 ], consistent with prior studies of Cu intoxication in Escherichia coli [ 31 ]. Dao et al [ 38 ] suggest that cysteine may rescue S. pyogenes from Cu toxicity due to this thiol-containing amino acid acting as a low-affinity pool for buffering free Cu.…”

“…Supplementation with cysteine ( Figure 1A ), which forms Cu-binding ligands in proteins [ 37 ], enhanced survival in conditions of high Cu stress in S. pyogenes [ 38 ], consistent with prior studies of Cu intoxication in Escherichia coli [ 31 ]. Dao et al [ 38 ] suggest that cysteine may rescue S. pyogenes from Cu toxicity due to this thiol-containing amino acid acting as a low-affinity pool for buffering free Cu. In comparing the work of Stewart et al [ 35 ] and Dao et al [ 38 ], which both analysed Δ copA mutants to study Cu intoxication in S. pyogenes , it is noteworthy that the two studies used distinctly different growth media.…”

“… ( A ) Cu intoxication causes a reduction (red arrows) in cellular glutathione, metal management [ 35 ] and reduction in viability at late stationary phase [ 38 ] in S. pyogenes . Cu-binding to histidine and cysteine residues in the catalytic site of GapA likely leads to a reduction in activity and subsequent flux through the fermentative pathway [ 35 ].…”

“…Cu-binding to histidine and cysteine residues in the catalytic site of GapA likely leads to a reduction in activity and subsequent flux through the fermentative pathway [ 35 ]. Growth inhibition in S. pyogenes undergoing Cu intoxication can be rescued by supplementation with the small molecules glutathione [ 35 ] or cysteine [ 38 ], likely due to chelation of excess Cu. ( B ) Cu binds to and destroys solvent-accessible Fe–S clusters in enzymes such as in IPMI and fumarase.…”

Expanding the genetic toolbox for the obligate human pathogenStreptococcus pyogenes

“…P Zn therefore showed a higher maximum fold change than the previously used inducible promoters P tet and P nisA (Figure 4B). We also tested other metal-inducible promoters, such as the promoter of the copper-specific exporter CopA (59,60) and the cation-diffusion facilitator (CDF) family transporter MntE, a paralog of the zinc exporter CzcD reported to transport manganese (61,62). We noticed only a modest induction of P copA after the addition of 80 µM CuSO 4 and no induction of P mntE , when 80 µM MnSO 4 were added (Supplementary Figure 8).…”