Regulation of antigen 85C activity by reversible S-glutathionylation

• Published in: IUBMB life Vol. 70; no. 11; p. 1111
• Main Authors: Mandato, Alysia, Chai, Yuh-Cherng
• Format: Journal Article
• Language: English
• Published: England 01.11.2018
• Subjects: Acyltransferases - metabolism; Antigens, Bacterial - metabolism; Bacterial Proteins - metabolism; Gene Expression Regulation, Enzymologic; Glutathione - chemistry; Oxidation-Reduction; Protein Processing, Post-Translational; Sulfhydryl Compounds - chemistry; antigen 85 protein C (Ag85C); Mycobacterium tuberculosis; glutathione; cysteine; post-translational modification; S-glutathionylation; oxidative stress
• ISSN: 1521-6551
• DOI: 10.1002/iub.1923

Mycobacterium tuberculosis is the causative agent of many strains of tuberculosis, as it is composed of an impenetrable, complex cell wall. The proteins active in the synthesis of the cell wall are mycolyl transferase antigens 85A, 85B, and 85C, encoded by genes fbpA, fbpB, and fbpC. Antigen 85C contains one cysteine residue. S-Glutathionylation is the formation of a mixed disulfide between a protein cysteine residue and glutathione (GSH), 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 diseases. By S-glutathionylation, the lone cysteine residue in antigen 85C is modified by biotinylated GSH 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 promoting oxidation of the lone cysteine residue. To our knowledge, this is a novel finding to demonstrate the modification of antigen 85C and the regulation of its activity by a physiological molecule. © 2018 IUBMB Life, 70(11):1111-1114, 2018.