Enzymes could be new target for anti-malarial drugs

A recent study of enzyme inhibitors revealed potential new routes to anti-malarial drugs.

The study, carried out in collaboration by the researchers at the University of Leeds and University of Helsinki,  looked at enzymes that are important in plants in cold, drought and salt stress.

These enzymes are also important in the life cycle of protozoan parasites – such as the ones that cause Malaria, African sleeping sickness and Toxoplasma – the reason that pregnant woman shouldn’t touch cats. Toxoplasma infects about 30% of the world’s population, including up to 90% in some European countries, and has been connected to schizophrenia and other mental illnesses. Malaria, on the other hand, infects about 250 million people in developing countries, causing about 500,000 deaths each year. Global warming will lead to the malaria mosquito vector re-emerging as far North as England by 2050 – and resistance to the front-line drug, artemisinin, is emerging.

International collaboration

Professor Adrian Goldman from the School of Biomedical Sciences at the University of Leeds led the research in collaboration with Professor Jari Yli-Kauhaluoma, Dr. Henri Xhaard and Professor Seppo Meri at the University of Helsinki.

The paper was published in the AAAS journal Science Advances.

Using a large inhibitor screen, scientists were also able to show that the enzyme mechanism is more complicated than previously thought. The enzyme is a dimer, and the team of scientists were able to discover that both sides of the dimer work in concert in a push-me-pull-you mechanism. By preventing this happening, they uncovered new inhibitors and a new way of obstructing these enzymes.

We designed ATC to sit in the active site - but it does something completely different and much more interesting. We think it shows just how important collaboration is - this was a team of molecular modellers, synthetic organic chemists, specialists in malarial diseases, and membrane biologists all working together. We needed all of us to make this happen.

Professor Adrian Goldman, senior author

While it is known that other enzymes in this family pump both protons and sodium ions, it has always been unclear how. However, thanks to this research we think we now understand.

A “push-me-pull-you” mechanism explains all.  The pull side would pump a proton, so that the push side can pump a sodium, and so on.

The new inhibitors do not work against protozoan parasites yet, but these scientists did discover compounds that could be potential inhibitors to help fight against diseases.

This image shows a colourful graphic in green, grey, blue, red, yellow and pink on a white background. The colours represent 46 atoms.The new inhibitor, ATC, named after the pop group ‘A Touch of Class’. Just 46 atoms by the exit channel can gum up a protein of more than 10000 atoms.


Further information

Access the recent publication "Asymmetry in catalysis by Thermotoga maritima membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor" at: https://advances.sciencemag.org/content/5/5/eaav7574

Access the press release from the University of Helsinki at: https://www.helsinki.fi/en/news/life-science-news/enzymes-could-be-new-target-for-anti-malarial-drugs

Access the Indonesian language version of this article at: https://sainspop.com/potensi-target-baru-untuk-obat-anti-malaria/

For related work, see: biologicalsciences.leeds.ac.uk/biological-sciences/news/article/190/manipulation-of-the-brain-by-microscopic-parasite-may-provide-insight-to-schizophrenia

For further information, please contact University of Leeds press officer Simon Moore on +44(0)113 34 38059 and s.i.moore@leeds.ac.uk