A three-dimensional study of how enzymes in the malaria parasite Plasmodium synthesize essential vitamins, could help develop new drugs to combat the disease. Using electron microscopy, a team of scientists from Germany and the UK studied how the enzymes synthesize Vitamin B6, which has already been proposed as a target for new drugs.
Dr Ivo Tews, a Lecturer in Structural Biology at the University of Southampton, and colleagues, write about their findings in a paper published online in the journal Structure on 11 January.
Malaria is one of the most devastating infectious diseases in the world. Every year, nearly 250 million people are newly infected and about 1 million die from it. People become infected when they are bitten by mosquitoes carrying the Plasmodium parasite.
There is an urgent need to identify new drugs and targets because Plasmodium species are becoming highly resistant to current drugs.
The biochemical process of making Vitamin B6 is highly organized and involves an enzyme complex of 24 protein subunits. The malarial enzymes make an active form of Vitamin B6 known as “pyridoxal 5′-phosphate”, or PLP.
Tews and colleagues used electron microscopy to study the 3D crystal structure of the assembly from individual proteins.
Tews told the press:
“The structural studies explain how these vital enzymes are activated and show the substrate of vitamin B6 biosynthesis bound to give insights into the chemistry of PLP biosynthesis.”
One of the key features they uncovered was that the “enzyme complex has a fascinating internal tunnel for the transfer of reactive reaction intermediates”, said Tews.
The team also discovered an unexpected organization of enzyme complexes into fibres.
Tews said their data serves as a good starting point for developing specific inhibitors that could either target active enzyme sites, or the assembly of proteins.
Funds from the EU helped pay for the research.
Written by Catharine Paddock PhD