Chemoproteomics Reveals Disruption of Metal Homeostasis and Metalloproteins by the Antibiotic Holomycin.

Autor:	Chan AN; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Chen X; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Falco JA; Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02467, United States., Bak DW; Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02467, United States., Weerapana E; Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02467, United States., Li B; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2023 Sep 15; Vol. 18 (9), pp. 1909-1914. Date of Electronic Publication: 2023 Aug 10.
DOI:	10.1021/acschembio.3c00360
Abstrakt:	The natural product holomycin contains a unique cyclic ene-disulfide and exhibits broad-spectrum antimicrobial activities. Reduced holomycin chelates metal ions with a high affinity and disrupts metal homeostasis in the cell. To identify cellular metalloproteins inhibited by holomycin, reactive-cysteine profiling was performed using isotopic tandem orthogonal proteolysis-activity-based protein profiling (isoTOP-ABPP). This chemoproteomic analysis demonstrated that holomycin treatment increases the reactivity of metal-coordinating cysteine residues in several zinc-dependent and iron-sulfur cluster-dependent enzymes, including carbonic anhydrase II and fumarase A. We validated that holomycin inhibits fumarase A activity in bacterial cells and diminishes the presence of iron-sulfur clusters in fumarase A. Whole-proteome abundance analysis revealed that holomycin treatment induces zinc and iron starvation and cellular stress. This study suggests that holomycin inhibits bacterial growth by impairing the functions of multiple metalloenzymes and sets the stage for investigating the impact of metal-binding molecules on metalloproteomes by using chemoproteomics.
Databáze:	MEDLINE
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