A Reaction Chamber for Fatty Acid Synthesis

Fatty acid synthesis consists of tethering an an acetyl group (2 carbons) to ACP (Acyl Carrier protein) that then bounces around to 5 different enzymes to add 2 carbons to the end of the acetyl group. This process is repeated, each cycle resulting in the addition of two extra carbons. Eventually the long lipid chain is released from ACP resulting in a free fatty acid that is 16 (palmate), 18 (Stearate) or some other number of carbons long. To learn more on fatty acid synthesis, follow this link to a great summary from the Chemistry department at the University of Arkon.

In fungi these 6 enzymes (ACP + the 5 synthesis enzymes) are encoded on two polypeptide chains and the structure of the complex of the six proteins was described in the March 3rd issue of Science. The final super-structure is composed of 6 copies of each chain (thus 36 total enzymes) that coalesce into a large soccer-ball-like structure with 6 cages that act as reaction chambers. Each cage has a chamber of about 130 angstroms in diameter, and three of these cages form a hemi-sphere of the soccer-ball. ACP could not be seen in the crystal structure but is thought to sit in the center of each cage allowing it to shuttle from enzyme to enzyme to complete each cycle of fatty acid chain elongation.

There are two side points from this paper. First, by forming a cage, the enzymes can isolate the reaction from the rest of the cells workings. The proximity of the 6 enzymes allows the reaction to be much more efficient. Second, the Fatty Acid Synthase (the name of this big complex) was isolated from Thermomyces lanuginosa ... a thermophilic fungi! Themophiles (lovers of heat) are organisms that grow at elevated temperatures and thus have sturdy, densely packed proteins that are resistant to denaturation at high temperatures. The fact that the proteins are dense allows them to be packed easily in crystal arrays (if they can be pack at all!) and facilitates x-ray crystallography. This is the first time that I've encountered a thermophilic eukaryote, (most termophiles are archaebacteria) ... if I were an X-ray crystallographer (LOL), trying to crystallize and solve the structure of various enzymes, I'd get these critters. They grow at 50'C (modest in comparison to most bacterial thermophiles that can grow at > 70'C) and you can grow them in huge quantities (for this paper they grew half a kilo of the critters).

I should also mention that the same group solved the structure for the mammalian version of this complex - the article is in the same issue of Science. In mammalian cells the shape of the fatty acid synthase complex is very different from fungi, yet the enzymes are conserved (at the level of amino acid sequence). The possible implications could be discussed in the comments. (Bil?)

Refs: Simon Jenni, Marc Leibundgut, Timm Maier, Nenad Ban. Architecture of a Fungal Fatty Acid Synthase at 5 Ã Resolution. Science (2006) 311:1263 - 1267

Timm Maier, Simon Jenni, Nenad Ban. Architecture of Mammalian Fatty Acid Synthase at 4.5 Ã Resolution. Science (2006) 311:1258 - 1262