FabI

FabI, or enoyl-acyl carrier protein reductase I, is an enzyme in the bacterial fatty acid biosynthesis II (FAS II) pathway. It catalyzes the NADH-dependent reduction of enoyl-ACP to acyl-ACP, a key step in the elongation of fatty acids used for membrane lipids. The fabI gene encodes the enzyme in many bacteria, and FabI belongs to the short-chain dehydrogenase/reductase (SDR) superfamily.

Mechanism and structure: FabI uses NADH as a cofactor and functions within a catalytic cycle in which the enoyl substrate bound to the acyl carrier protein is reduced to saturated acyl-ACP. The enzyme is typically a dimer or tetramer and features the Rossmann-fold NAD(H) binding domain and active-site residues, including a catalytic tyrosine and lysine that mediate hydride transfer and protonation.

Distribution and functional context: FabI is essential for fatty acid biosynthesis in many bacteria that rely on FAS II. Some bacteria employ alternative enoyl-ACP reductases, such as FabK, FabL, or FabI homologs, reflecting redundancy among ENR enzymes and varying essentiality across species.

Inhibitors and resistance: FabI is a validated drug target. The antimicrobial triclosan inhibits FabI by stabilizing a closed enzyme–NAD+ complex, though resistance can arise through mutations in fabI or increased efflux. Other inhibitors, including pharmaceutical candidates, aim to target FabI to treat bacterial infections, with attention to avoiding cross-resistance related to environmental triclosan exposure.

Clinical relevance and research: In Mycobacterium tuberculosis and related species, the InhA enzyme is a FabI homolog and is targeted by isoniazid after activation. Novel FabI inhibitors, such as afabicin (Debio 1452), are under clinical development for staphylococcal infections. Structural studies of FabI have informed drug design by revealing the NAD(H) binding pocket and the enoyl-ACP substrate site.