Mycobacterium tuberculosis is the causative agent of many strains of tuberculosis, as it has an impenetrable, complex cell well. One gene in the bacterium codes for the mycolyl transferase antigens 85A, 85B, and 85C, which are active in the synthesis of the cell wall. The structure of antigen 85C contains one cysteine residue. S-glutathionylation is the formation of a mixed disulfide between a protein cysteine residue and glutathione, an abundant antioxidant molecule. It is a post-translational modification of cysteine residues which can occur under oxidative stress or physiological conditions. It is a known mechanism to regulate enzyme activity, signaling pathways, and the progression of disease. Through S-glutathionylation, the lone cysteine residue in antigen 85C is modified by biotinylated glutathione ethyl ester to form a mixed disulfide. This modification results in a decrease in enzyme activity by 90%, representing a decrease in ability of the protein to synthesize the bacterial cell wall. Both the modification and the enzymatic activity of the protein are concentration dependent and can be reversed upon addition of a thiol reducing agent. The results provide a potential strategy for inhibiting the synthesis of the cell wall of M. tuberculosis by introducing an oxidative environment. To our knowledge, this is a novel finding to demonstrate the modification of antigen 85C and its activity by a physiological molecule.

Functional cysteine residues for antigen 85C activity

255th National Meeting (2018)

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