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Publication Abstract from PubMed

Pathogenic Staphylococcus aureus endures bursts of host-derived reactive nitrogen species, yet the molecular defenses that enable this resilience have remained unclear. We now show that the previously enigmatic di-iron enzyme ScdA functions as a nitrite reductase, converting nitrite to nitric oxide (NO), and we elucidate the structural elements that support this activity. Using an integrative toolkit horizontal line X-ray crystallography, solution NMR, AlphaFold modeling, and pulsed EPR/DEER horizontal line we solved the full-length homodimeric structure of ScdA and identified a robust di-iron center that forms stable iron-nitrosyl intermediates. Targeted mutagenesis reveals that redox-active cysteines and dimerization state tune catalytic output, whereas steady-state kinetics confirm efficient nitrite-to-NO turnover. In vivo, ScdA overexpression in Escherichia coli suppresses growth under nitrite-rich conditions, highlighting the cytotoxic potency of the NO it generates. By coupling structure to function, our work clarifies S. aureus strategies for managing nitrosylative stress and points to ScdA as a potential vulnerability in antibiotic-resistant pathogens.

Structure and Nitrite Reductase Activity of the Di-iron Protein ScdA in Staphylococcus aureus.,Chen HY, Tsai RF, Lu YS, Cheng YC, Fan-Chiang HY, Wu CY, Lo FC, Kuo HW, Yang WK, Liao WY, Hu NJ, Sue SC, Chiang YW J Am Chem Soc. 2025 Sep 3;147(35):31558-31569. doi: 10.1021/jacs.5c05573. Epub , 2025 Aug 22. PMID:40846682^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.