Zn2+-Induced Conformational Change Affects the SAM Binding in a Mycobacterial SAM-Dependent Methyltransferase

Soneya Majumdar; Umang Gupta; Hariharan V Chinnasamy; Sathishkumar Laxmipathy; Saravanan Matheshwaran

doi:10.1021/acsomega.2c04555

Zn²⁺-Induced Conformational Change Affects the SAM Binding in a Mycobacterial SAM-Dependent Methyltransferase

ACS Omega. 2022 Sep 27;7(40):35901-35910. doi: 10.1021/acsomega.2c04555. eCollection 2022 Oct 11.

Authors

Soneya Majumdar¹, Umang Gupta¹, Hariharan V Chinnasamy¹, Sathishkumar Laxmipathy¹, Saravanan Matheshwaran^{1

2

3}

Affiliations

¹ Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, Uttar Pradesh India.
² Center for Environmental Science and Engineering, Indian Institute of Technology, Kanpur 208016, Uttar Pradesh India.
³ Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology, Kanpur 208016, Uttar Pradesh India.

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.