Targeting Uptake Source could fight TB longer supply itself with trehalose and becomes less pathogenic.
The researchers from Warwick’s School of Life Sciences used X-ray crystallography to determine the 3-dimensional structure of LpqY and analysed how this important transport protein is able to bind and recognise trehalose. They then went on to use a number of experimental techniques which showed that while LpqY is highly specific for trehalose, it is also able to recognise sugars that are similar to trehalose with small modifications and map key recognition features.
Dr Elizabeth Fullam, who is a Sir Henry Dale Fellow from the School of Life Sciences at the University of Warwick commented:
Molecular-level detail of the interaction of trehalose bound to the mycobacterial LpqY transporter. (Credit: University of Warwick)
Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb) is the leading cause of death from a single infectious agent world-wide claiming over 1.5 million lives each year. With an increase in resistance to current antibiotics means that novel drugs to kill Mtb are urgently needed. Researchers from the University of Warwick have successfully discovered how Mycobacterium tuberculosis uses an essential sugar to survive in the human body for long time periods; this provides a platform to design new and improved TB drugs and diagnostic agents.
Trehalose is one source of energy found in the pathogen’s own cell wall and it appears that Mtb has evolved a strategy to recycle and reuse this sugar as a valuable food source.
The transport protein LpqY, which is responsible for the uptake of trehalose, is essential for Mtb to establish infection. If the LpqY protein is deleted and no longer able to function then Mtb can no
“It is vital that we find new innovative strategies to combat TB. The LpqY trehalose transporter is a potential drug target because when it is not functioning it results in Mtb becoming less virulent. Now that we understand exactly how trehalose is recognised we will be able to design specific molecules that will enable us to kill TB. Alternatively, another possibility is that we can use the LpqY transporter to our advantage and find ways to deliver compounds for TB diagnosis.”
The researchers acknowledge the funding for this work which is supported by a Sir Henry Dale fellowship awarded to Dr Elizabeth Fullam, jointly funded by the Wellcome Trust and The Royal Society.
The paper, ‘Structural basis of trehalose recognition by the mycobacterial LpqY-SugABC transporter’, is published in the Journal of Biological Chemistry.
More information online:
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MND Risk Factor Identified in Junk DNA
Scientists at the University of Sheffield have identified a new genetic risk factor for Motor Neurone Disease (MND), which if treated could halt or prevent the degenerative condition. The pioneering research focused on genetic mutations in non-coding DNA, often known as junk DNA because it does not directly encode protein sequences. Non-coding DNA makes up more than 99 per cent of the human genome, but currently is relatively unexplored.
This research includes new methods for studying mutations in non- coding DNA which could be applied to other diseases.
Experts from the Neuroscience Institute at the University of Sheffield also found that an existing neuroprotective drug developed at the University of California San Diego (UCSD) called SynCav1 could help MND patients carrying the newly discovered genetic mutation said to be present in up to one percent of MND patients.
MND, or Amyotrophic Lateral Sclerosis (ALS) as it is also known, is a disorder that affects the nerves - motor neurons - in the brain and spinal cord that form the connection between the nervous system and muscles to enable movement of the body. The messages from these nerves gradually stop reaching the muscles, leading them to weaken, stiffen and eventually waste.
Dr Johnathan Cooper-Knock, lead author of the study and NIHR Clinical Lecturer in Neurology at the Neuroscience Institute at the University of Sheffield, said: “Until now scientists have never systematically explained non-coding or junk DNA in relation to the development of MND.
“Not only have we identified a mutation in junk DNA which puts
people at risk of developing a certain form of the MND, but we have also found that by targeting the mutated gene with the established neuroprotective drug called SynCav1, it might be possible to halt or potentially prevent the disease progressing in those patients. This is a significant breakthrough in terms of genetic risk factors driving personalised medicine for MND patients.”
The research was made possible due to unprecedented amounts of patient data collected by Project MinE, an international genetic database which aims to map the full DNA profiles of at least 15,000 MND patients and 7,500 control subjects to perform comparative analyses.
Dr Nicholas Cole, Head of Research at the Motor Neurone Disease Association said: “The findings are encouraging further developments in this largely unknown area. The MND Association is delighted to provide continued support to both SITraN and Johnathan Cooper- Knock and we are grateful to them for keeping us updated on their research. Delving into so-called ‘junk DNA’ is extremely difficult to do and we are incredibly proud that Project MinE, which is also funded by the MND Association, has aided this discovery.
“The hope of course is that through continuing public support, collaboration and partnership working we will find solutions to unpick the complex nature of MND which will lead to an effective treatment.”
Published in the journal Cell Reports
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