Insights into active site cysteine residues in Mycobacterium tuberculosis 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 Mycobacterium tuberculosis (Mtb) and in particular those that relate to its survival, adaptability, and pathogenicity. Mtb 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, as well as in posttranslational modifications of newly synthesized proteins. This review examines five Mtb enzymes that contain an active site cysteine residue and are considered as key targets for anti-tuberculosis drugs, namely the alkyl hydroperoxide reductase (AhpC), the dihydrolipoamide dehydrogenase (Lpd), the aldehyde dehydrogenase (ALDH), the methionine aminopeptidase (MetAP) and the cytochromes P450. AhpC and Lpd protect Mtb against oxidative and nitrosative stress, whereas AhpC neutralizes peroxide/peroxynitrite substrates with two active site cysteine residues. Mtb ALDH detoxifies aldehydes using a nucleophilic active site cysteine to form an oxyanion thiohemiacetal intermediate whereas MtMetAP'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.