Introduction
The Enoyl-ACP Reductase InhA, from Mycobacterium tuberculosis, catalyzes the NADH-dependent reduction of long-chain trans-2-enoyl-ACP fatty acids in the type II fatty acid biosynthesis pathway of M. tuberculosis. InhA is a member of the short chain dehydrogenase/reductase (SDR) family of enzymes. InhA is the only enoyl-ACP reductase found in tuberculosis, making the enzyme a potential drug target.
FAS-II System
Mycolic acids are very long-chain fatty acids (C60 -C90) that are essential components of the mycobacterial cell wall. Mycolic acids are synthesized by at least two known elongation systems, type I and type II fatty acid synthases (FAS-I and FAS-II). The FAS-II system prefers C16 as a starting substrate and can extend up to C56. The FAS-II system utilizes the products from the FAS-I system as primers to extend the chain lengths further. The products of the FAS-II system are the precursors of mycolic acids. Elongation by the FAS-II system occurs by a condensation reactionof acetyl and malonyl substrates, which is achieved in three steps. Step 1 involves transfer of the acyl primer, step 2 involves decarboxylation of the substrate to yield a carbanion, and step 3 involves nucleophilic attack of the carbanion to yield the elongated product.
Mechanism of Action
The InhA gene encodes for the InhA protein. InhA catalyzes the NADH-dependent reduction of the trans double bond between positions C2-C3 of fatty acyl substrates. InhA prefers fatty acyl substrates of C16 or longer, which is consistent of the protein being a member of the FAS-II system. The longer chain length specificity of InhA distinguishes the enzyme from other enoyl-ACP reductase analogues.
Structure
Fatty Acyl Binding Crevice
Catalytic Triad
Hydrogen Bonding Interactions
Clinical Applications
Isoniazid
Other Inhibitors
This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
