Fatty acids are central building block of all forms of life. They are components of biological membranes, important for storing energy, and they also act as messenger molecules. Owing to this central role the route for biochemical synthesis is conserved. This does not mean, however, that the spatial organisation of the whole production is the same in all organisms. Researchers around Professor Nenad Ban (1)(2) at the ETH Institute of Molecular Biology and Biophysics have now succeeded in determining the structure of fatty acid production plants in the cells of mammals and fungi so that it is clear now how the individual reactions of the synthesis are spatially co-ordinated. The work, on animal tissue material on the one hand, and from thermophile fungi on the other, has led to a publication on each in last week's issue of "Science“ (3)(4).

Protected molecular production

The structural analyses, which were carried out with highly brilliant x-ray beams at the Swiss Light Source of the Paul Scherrer Institute in Würenlingen(5). Results of this examination show that the spatial organisation of the fatty acid synthesis is totally different for mammals and fungi. In the latter, the entire production is situated in a barrel-shaped structure that is divided in the middle into two distinctive production sites by a wheel. The individual production locations, i.e. the enzymatic active centres, are all oriented towards the interior. This affords better protection to the processes and is also more efficient, explains Nenad Ban the result.

ETH Professor Nenad Ban, Timm Maier, Marc Leibundgut and Simon Jenni (left to right) were so successful with their work on the structural analyses of fatty acid synthases in mammals and fungi that they had two publications in the same issue of "Science" (Picture: Nenad Ban). large

A protected production plant also exists for the fatty acid synthesis of mammals. Instead of a barrel-shaped molecule, however, this takes place in one that is X-shaped. In this, the side arms of the mammalian fatty acid synthase build a flexible reaction chamber around which the enzymatic active centres arrange themselves. It had surprised the scientists, according to Ban, that the individual active centres lay relatively far apart. This disproved the widespread assumption that a cofactor serves as a swinging arm that passes the growing fatty acid on from one centre to the next. It now had to be assumed that it was more like a mobile transport system that was supported by the flexibility of the whole structure.

The structure of fatty acid synthase of fungi resembles a barrel. Individual enzymes are coloured, the matrix structure is grey. (Picture: Simon Jenni and Marc Leibundgut) large

Further analyses promises therapies

The structures of the individual enzymes involved in fatty acid synthesis in bacteria was known. In sum, the scientists have now succeeded in locating these structures also in the big production complexes of mammals and fungi. Thereby it appeared that the individual enzymes make up around a third of the total structure and the rest serve as the matrix that syntonises the unfolding of the entire synthesis. The new work also provides insights into the fine structure of the matrix itself, in which, as it is now known, the so-called alpha helices or beta folds occur. In a next step Ban and his team want to turn their attention to the construction of an atomic model of both synthesis complexes. In addition to an understanding of the interaction of individual production locations, the results of this work, which according to Nenad Ban will take up to two years, will be a detailed picture of the atomic structure of the individual reaction centres.

This information can then be used to develop specifically targeted drugs to treat conditions connected to the function and regulation of fatty acid synthases. Examples of such conditions are obesity, and secondary conditions arising from this–like diabetes or cardiovascular disorders, as well as numerous types of cancer. The structural difference between fungi and human synthase promises to uncover specific fungi inhibiting substances, too. The scientists will not therefore, be lying back and basking, like Diogenes, in their results in front of their barrel but want to push on as quickly as possible with the structural analysis of the molecular–barrel or X-shaped–fatty acid production factories.

Not an X-chromosome, but the structure of the fatty acid synthase complex of mammals. Individual enzymes are coloured, the matrix structure is grey. (Picture: Timm Maier): large