Megaenzyme Revealed

Fatty acids are the foundation of mammalian biological membranes. They also store energy and act as cellular messengers. Timm Maier, Marc Leibundgut, and Nenad Ban at the Swiss Federal Institute of Technology, Zurich, now report a sharp 3.2-Å-resolution crystal structure of the colossal 540-kilodalton fatty acid synthase that catalyzes 42 reaction steps to build 18-carbon fatty acid chains (Science 2008, 321, 1315). The new structure is focused enough to permit careful examination of five of the megaenzyme's six catalytic sites, including "all active sites of the fatty acid elongation cycle," Maier says. The team reports that the enzyme is divided into two main wings, one for selecting and adding building blocks to the growing chain and another for chemically processing chain intermediates. Because the synthase is overproduced in many cancer cells and inhibitors have been shown to block tumor activity in vivo, the team hopes the structure will spark development of potent and specific inhibitors of the megaenzyme.