March 6, 2006 | David F. Coppedge

In Praise of Fat

Well, great balls of fat.  Cells have spherical globs of lipid (fat) molecules that never had gotten much attention nor respect.  They have been called lipid droplets, oil bodies, fat globules and other names suggesting they were just the beer bellies of the cell.  Not any more.  Scientists have been taking a closer look at these globs and are finding them to be dynamic, functional sites of critical metabolic activity.  No longer are they bags of superfluous undesirable molecules: they have been promoted to essential organelles, named adiposomes.
    Mary Beckman introduced two papers in Science with a summary of the new discoveries.1 

Whatever their name, these intracellular blobs of triglycerides or cholesterol esters, encased in a thin phospholipid membrane, are catching the attention of more and more biologists.  It turns out these lively balls of fat have as many potential roles within cells and tissues as they have names.  Pockmarked with proteins with wide-ranging biochemical activities, they shuffle components around the cell, store energy in the form of neutral lipids, and possibly maintain the many membranes of the cell.  The particles could also be involved in lipid diseases, diabetes, cardiovascular trouble, and liver problems.   (Emphasis added in all quotes.)

Beckman discussed several recent findings demonstrating what happens when fat regulation by adiposomes is disrupted.  Since there is still much to be learned about adiposomes, Beckman mainly teased the readers with the possibilities that lie ahead.  She quoted one biologist who called the biology of lipid droplets “immense and untapped.”
    A Perspectives paper in the same issue by Stuart Smith introduced new findings about the machines that make fat.2  He summarized a paper by Maier, Jenni and Ban revealing, in unprecedented detail, the structure of mammalian Fatty Acid Synthase (FAS),3 and another by the same authors plus Leibundgut about the comparable FAS machine in fungi.4  The former looks somewhat like a flying saucer; the latter, like a wheel with spokes from the top, or a complex cage from the side.  The diagrams of these machines point out “active sites” and “reaction chambers” where complex molecules are assembled in a specific sequence.  The machines apparently have moving parts.  The conclusion of the mammalian FAS paper hints how everything must be done in order and with the right specifications:

The overall architecture of mammalian FAS has been revealed by x-ray crystallography at intermediate resolution.  The dimeric [two-part] synthase adopts an asymmetric X-shaped conformation with two reaction chambers on each side formed by a full set of enzymatic domains required for fatty acid elongation, which are separated by considerable distances.  Substantial flexibility of the reaction chamber must accompany the handover of reaction intermediates during the FAS cycle, and further conformational transitions are required to explain the presence of alternative inter- and intrasubunit synthetic routes in FAS.  The results presented here provide a new structural basis to further experiments required for a detailed understanding of the complex mechanism of mammalian FAS.

Even for the fungal machine, the authors spoke of the “remarkable architectural principles” it exemplifies.  It’s a whole new world of fat.  Let that go to your understanding, not to your waist.

1Mary Beckman, “Great Balls of Fat,” Science, 3 March 2006: Vol. 311. no. 5765, pp. 1232 – 1234, DOI: 10.1126/science.311.5765.1232.
2Stuart Smith, “Architectural Options for a Fatty Acid Synthase,” Science, 3 March 2006: Vol. 311. no. 5765, pp. 1251 – 1252, DOI: 10.1126/science.1125411.
3Timm Maier, Simon Jenni, Nenad Ban, “Architecture of Mammalian Fatty Acid Synthase at 4.5 � Resolution,” Science, 3 March 2006: Vol. 311. no. 5765, pp. 1258 – 1262, DOI: 10.1126/science.1123248.
4Simon Jenni, Marc Leibundgut, Timm Maier, Nenad Ban, “Architecture of a Fungal Fatty Acid Synthase at 5 � Resolution,” Science, 3 March 2006: Vol. 311. no. 5765, pp. 1263 – 1267, DOI: 10.1126/science.1123251.

The closer they look, the more wondrous the cell gets.  Who would have thought that blobs of fat would contain machinery with moving parts and reaction chambers?  Who would have imagined their surfaces would be covered with complex proteins that regulate the production inside?  Who would have realized that fat was so important, the cell had complex assembly plants to build it?  Fat is almost a mild cussword in our vocabulary, but it is another class of molecular building blocks we couldn’t live without.  Fats, sugars, proteins and nucleic acids all work together in life, from humans to lowly fungi.  Each class of molecules has immense variety, each is essential, and each is manufactured to spec by precision machinery.  What a wonderful post-Darwinian world.

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