Which enzyme produced by Mycobacterium tuberculosis catalyzes the synthesis of mycolic acids and is essential for cell wall integrity?

Explanation

## Mycolic Acid Synthesis in M. tuberculosis **Key Point:** Isoniazid-sensitive enoyl-ACP reductase (InhA) is the key enzyme in the mycolic acid biosynthesis pathway and is the primary target of the pro-drug isoniazid (INH). ### Mycolic Acid Biosynthesis Pathway 1. **Fatty acid synthesis** via FAS-I (similar to eukaryotic FAS) 2. **Condensation reactions** via FAS-II (mycobacterial-specific) 3. **InhA-catalyzed reduction** of enoyl intermediates (RATE-LIMITING STEP) 4. **Cyclization and methylation** to form mature mycolic acids 5. **Incorporation** into the cell wall via arabinogalactan **High-Yield:** InhA is the **primary target of isoniazid**. INH is a pro-drug that requires activation by KatG (catalase-peroxidase) to form the INH-NAD adduct, which then inhibits InhA. Mutations in InhA or loss of KatG expression cause INH resistance. ### Mechanism of Isoniazid Action ```mermaid flowchart TD A[Isoniazid INH]:::action --> B[KatG activation]:::action B --> C[INH-NAD adduct formed]:::outcome C --> D[Inhibits InhA enzyme]:::action D --> E[Blocks mycolic acid synthesis]:::action E --> F[Cell wall integrity lost]:::urgent F --> G[Mycobacterial death]:::outcome ``` ### Comparison of M. tuberculosis Drug Targets | Drug | Target Enzyme | Mechanism | Resistance | | --- | --- | --- | --- | | **Isoniazid** | **InhA** | Inhibits mycolic acid synthesis | KatG mutation, InhA overexpression | | Rifampicin | RpoB (RNA polymerase) | Blocks RNA synthesis | RpoB mutations | | Pyrazinamide | PncA → POA | Disrupts membrane potential | pncA mutations | | Ethambutol | EmbC (arabinosyl transferase) | Blocks arabinogalactan synthesis | embCAB mutations | **Clinical Pearl:** Isoniazid is bactericidal for actively dividing M. tuberculosis in the logarithmic growth phase because InhA inhibition directly disrupts cell wall synthesis, which is essential for cell division. **Mnemonic:** **InhA = INH's Arch-nemesis** — InhA is the primary target of isoniazid (INH).