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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