Sandbox Reserved 1073

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.

Image:Mechanism-InhA.png

Structure

Fatty Acyl Binding Crevice

Catalytic Triad

Hydrogen Bonding Interactions

Clinical Applications

Isoniazid

Other Inhibitors

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