15 July 2016

Publication in Journal of Biological Chemistry

Unravelling the mechanism behind bacterial protein MraY opens new opportunities for development of antibiotics

A team of 10 researchers, including seven from Utrecht University, have unravelled the mechanism behind the protein MraY. This protein, called phospho-MurNAC-pentapeptide translocase, plays an essential role in bacterial cell wall synthesis. According to the researchers’ publication in the 15 July issue of The Journal of Biological Chemistry (JBC), knowledge of how MraY works provides new insights that could be used to develop antibiotics.

Cell wall synthesis

MraY is an enzyme that occurs in the cell membranes of bacteria. This means that it functions as a catalyst in a specific chemical reaction, and in this case provides an important step in cell wall synthesis. The cell wall is a layer formed around a cell’s outer membrane. If MraY does not function correctly, then the bacteria cannot create a cell wall. This will eventually cause the bacteria to burst, as the weakened cell wall cannot hold against the difference in pressure inside the cell and outside. Human cells do not have cell walls, so MraY may be a good target for antibiotics.

Target for antibiotics

MraY is responsible for the first membrane-related step in cell wall synthesis. It binds a sugar molecule attached to a chain of five amino acids, which are the building blocks of proteins, to a special lipid anchor located on the surface of the cell membrane. The researchers studied this process in detail and found that one of the amino acids in MraY, histidine 289, plays an important role. This is a location in the protein that has not yet been used as a target for designing antibiotics.

The right half shows that 289 Histidine (bright purple colored in the middle) comes closer to the phosphate groups (the three dots on the orange red spheres) of the substrate. Binding of MraY with the substrate is important for the activity of MraY.

Research in Utrecht

A number of research groups at Utrecht University contributed to this study. Dr. Yao Liu (Membrane Biochemistry and Biophysics) recently earned her PhD on new approaches to antibiotics resistance. She developed the experiments together with Dr. Eefjan Breukink and Prof. Maarten Egmond. Dr. Joao Rodrigues and Prof. Alexandre Bonvin (Computational Structural Biology) performed the modelling work. PhD candidate Esther Zaal and Dr. Celia Berkers (Biomolecular Mass Spectrometry and Proteomics) conducted the mass spectrometry and data analysis.

Our research has exposed new opportunities for the development of antibiotics. That’s going to be extremely welcome in light of the current rise of resistant bacteria.

Publication Y. Liu et al. ‘’New Insight into the Catalytic Mechanism of Bacterial MraY from Enzyme Kinetics and Docking Studies’’, The Journal of Biological Chemistry (2016); dio: 10.1074/jbc.M116.717884