(cm) Vitamin B6 plays a central role in the metabolism of all living organisms. Thus it is involved in more physiological functions than any other known vitamin. Just over a year ago ETH researchers working with Teresa Fitzpatrick in Professor Nikolaus Amrhein’s group at the Institute of Plant Science successfully clarified the biosynthesis of vitamin B6 in plants (1)(2). The work also revealed that this production route is much more widespread in living organisms than that of the bacterium Escherichia coli which had served as the model until then. In collaboration with the crystallographer Ivo Tews from the Biochemistry Centre of the University of Heidelberg, the same researchers have now been able to record another success (3): they identified the structure of the synthesis complex of pyridoxal 5´-phosphate (PLP), which represents the biochemically active form of Vitamin B6. The paper was published recently in the scientific journal PNAS (4).

New architecture discovered

The scientists carried out their work with the PLP synthase of the bacterium Bacillus subtilis, which manufactures PLP in the same way as plants. They obtained an atomic model of the PLP synthase complex by using X-ray crystallography. It became apparent that a gigantic multi-enzyme complex is needed to synthesize PLP. This involves the clustering of a total of 24 proteins: twelve Pdx1 proteins form two rings. Twelve additional Pdx2 units bond onto these at their outer surfaces like teeth.

Teresa Fitzpatrick explains an astonishing finding of the new work, namely that the two models hitherto suggested for the PLP production site are incorrect. In fact it was possible to determine a novel protein architecture within the glutamine amidotransferases family. There was also evidence as to how the ammonia, which is important in the synthesis and is liberated from the amino-acid glutamine, is transported inside the complex.

Using the new knowledge in the fight against malaria

Since the central locations in the PLP production site are now known, this also leads to possible ways of interfering with this vital synthesis. According to Fitzpatrick, this could be relevant for example in the fight against malaria. The reason is that the malaria pathogen, Plasmodium falciparum, has a PLP synthesis complex like the one explained above. Because humans do not carry out this synthesis at all, a specific medicinal treatment without any serious side effects in patients is conceivable. The corresponding possibilities are being explored in an EU research project, VitBioMal (5), in which ETH is also participating.