FabH

FabH, or 3-oxoacyl-ACP synthase III, is a key enzyme of the bacterial type II fatty acid synthase (FAS II) pathway. It catalyzes the first condensation step, joining acetyl-CoA with malonyl-ACP to form acetoacetyl-ACP and initiate fatty acid elongation.

The reaction proceeds via a ping-pong mechanism in which a catalytic cysteine forms an acyl-enzyme intermediate with the acetyl group. A histidine and an asparagine constitute a catalytic triad that facilitates decarboxylation of malonyl-ACP and the Claisen-like condensation.

FabH primarily uses acetyl-CoA as its primer, but some species accommodate other acyl-CoA starters, influencing the initial chain length and branching pattern of the resulting fatty acids. The malonyl-ACP substrate is provided by the FAS II system.

Biologically, FabH is essential for initiating fatty acid biosynthesis in many bacteria. The subsequent steps are carried out by other condensing enzymes, FabB and FabF, which extend the acyl chain. Because of its central role, FabH is considered a potential target for antibiotics.

Structural studies show FabH as a homodimer with a thiolase-like fold and an active-site cysteine near the N-terminus. Activity can be modulated by cellular metabolite levels, and several inhibitors that mimic substrates or disrupt the acyl-enzyme intermediate have been reported as antibiotic leads.

The fabH gene is located within the fatty acid synthesis gene clusters in many bacteria. In some organisms, multiple FabH-like enzymes exist, providing redundancy or altered substrate specificity.