ALAS, scientists at the GBF reveal the structure of a life-sustaining enzyme

26-Sep-2005

Scientists of the GBF and the Technical University in Braunschweig have resolved the 3-dimensional structure of the enzyme that catalyses the first step in the synthesis of heme. "ALAS (short for '5-aminolevulinate synthase') was the last remaining enzyme in heme synthesis for which the 3-dimensional structure was not known, " explains Dirk Heinz, head of structural biology at the GBF.

Production of heme in humans and animals works like an assembly line. Ten separate enzymes are involved. Each receives a precursor molecule from the preceding enzyme, modifies it in a predetermined way, and passes it on to the next enzyme in the queue. "ALAS is particularly important," says Dieter Jahn, professor of microbiology at the Technical University, "because it is the first enzyme in the process. If it malfunctions, the entire process of heme synthesis is affected, resulting in severe anaemia".

Dysfunction of ALAS, most often due to genetic defects on the X-chromosome, causes a particularly severe form of anaemia. Overall, a shortage of heme restricts the supply of oxygen to body tissues causing common symptoms including pale skin, tiredness and lack of concentration. In this case, they are, however, combined with the accumulation of toxic levels of iron that cause acute organ damage. "The structure of ALAS will aid our understanding of this form of anaemia, will help to explain the symptoms, and will eventually enable us to improve its treatment," says Wolf-Dieter Schubert, group leader at the GBF.

The structural analysis of ALAS was partly made possible by chance: Nature tends to stick to tried-and-tested biological principles for billions of years. Apart from humans, ALAS is also found in the evolutionary ancient group of proteobacteria. These primitive organisms invented the process of producing heme and related pigments about 3.5 billion years ago, when life itself had barely been established. The scientists could therefore use bacterial ALAS, which is very similar to the human form but much more stable, to analyse the structure.

Original publication: I. Astner, J. O. Schulze, J. van den Heuvel, D. Jahn, W.-D. Schubert, D. W. Heinz; "Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans"; The EMBO Journal 2005, 24, 18, 3166-3177.

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