Serine palmitoyltransferase / structure and function of the first enzyme in sphingolipid biosynthesis.

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All cell walls have to be tough and durable and provide a physical barrier to protect the cell from external factors. They have to keep the cell contents inside but also allow molecules (e.g. nutrients) to pass into the cell and waste to leave. Humans, plants and bacteria have different cell wall components and they are made up of numerous complex building blocks called sphingolipids. It was recently discovered that the chemical reaction at the start of the sphingolipid synthetic pathway in all species is the same and begins by connecting an amino acid to a fatty acid. This reaction is catalysed by an enzyme called serine palmitoyltransferase (SPT) and is dependent on a B vitamin cofactor. We'd like to understand in molecular detail how sphingolipid membranes are made. Studying sphingolipid chemistry and the enzymes that make them in humans and plants is difficult because the building blocks and enzymes are embedded in membranes. To make it easier to study them, it helps to extract them into water and to do this we have to use detergents. Unfortunately, the enzymes often stop working in water. However, a bacterium (called Sphingomonas) was discovered that makes only one type of sphingolipid and its SPT enzyme is soluble in water. We can purify milligram amounts of this SPT and we have recently determined its 3D molecular structure to atomic resolution. We'd now like to understand how it catalyses the chemical reaction and how it can be inhibited. It turns out that sphingolipids not only play structural roles in cells, but also regulate and control the way the cell works. Inhibitors of sphingolipid production might turn out to be new anti-cancer or anti-inflammatory drugs. We can use our bacterial water-soluble SPT structure as a model for the human membrane-bound enzyme. Also, it has been discovered that some people have a neurological disease where their SPT enzyme is mutated so we can also use our model to understand how these mutations can cause problems with spingolipid chemistry in the brain.