Insights into Active Site Cysteine Residues in Enzymes: Potential Targets for Anti-Tuberculosis Intervention.

Cysteine, a semi-essential amino acid, is found in the active site of a number of vital enzymes of the bacterium () and in particular those that relate to its survival, adaptability and pathogenicity. is the causative agent of tuberculosis, an infectious disease that affects millions of people globally. Common anti-tuberculosis targets are focused on immobilizing a vital cysteine amino acid residue in enzymes that plays critical roles in redox and non-redox catalysis, the modulation of the protein, enzyme activity, protein structure and folding, metal coordination, and posttranslational modifications of newly synthesized proteins. This review examines five enzymes that contain an active site cysteine residue and are considered as key targets for anti-tuberculosis drugs, namely alkyl hydroperoxide reductase (AhpC), dihydrolipoamide dehydrogenase (Lpd), aldehyde dehydrogenase (ALDH), methionine aminopeptidase (MetAP) and cytochromes P450. AhpC and Lpd protect against oxidative and nitrosative stress, whereas AhpC neutralizes peroxide/peroxynitrite substrates with two active site cysteine residues. ALDH detoxifies aldehydes, using a nucleophilic active site cysteine to form an oxyanion thiohemiacetal intermediate, whereas MetAP's active site cysteine is essential for substrate recognition. The P450s metabolize various endogenous and exogenous compounds. Targeting these critical active site cysteine residues could disrupt enzyme functions, presenting a promising avenue for developing anti-mycobacterial agents.