Zinc is a cofactor for enzymes involved in DNA replication, peptidoglycan hydrolysis, and pH maintenance, in addition to the transfer of the methyl group to thiols. Here, we discovered a… Click to show full abstract
Zinc is a cofactor for enzymes involved in DNA replication, peptidoglycan hydrolysis, and pH maintenance, in addition to the transfer of the methyl group to thiols. Here, we discovered a new role of Zn2+ as an inhibitor for S-adenosyl methionine (SAM) binding in a mycobacterial methyltransferase. Rv1377c is annotated as a putative methyltransferase that is upregulated upon the mitomycin C treatment of Mycobacterium tuberculosis. Sequence analysis and experimental validation allowed the identification of distinct motifs responsible for SAM binding. A detailed analysis of the AlphaFold-predicted structure of Rv1377c revealed four cysteine residues capable of coordinating a Zn2+ ion located in proximity to the SAM-binding site. Further, experimental studies showed distinct conformational changes upon Zn2+ binding to the protein, which compromised its ability to bind SAM. This is the first report wherein Zn2+-driven conformational changes in a methyltransferase undermines its ability to bind SAM.
               
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