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Researchers have made detailed blueprints of the enzyme Lit, allowing them to understand how it helps bacteria sneak past the immune system.
A new study involving Trinity College Dublin has described the mechanisms of an enzyme that builds lipoproteins to suppress the immune system, allowing it to carefully evade our defences.
The study, led by scientists from the School of Biochemistry and Immunology and the Trinity Biomedical Sciences Institute at Trinity, has been published by international journal Nature Communications.
These scientists have produced the first fine-detail molecular blueprints of the bacterial enzyme known as Lit, which is suspected to play a “stealthy” role in the progression of infection by reducing the immune response.
There is a growing list of enzymes responsible for building lipoproteins, including the recently discovered Lit (lipoprotein intramolecular transacylase).
Lipoproteins serve a wide variety of functions in the bacterial cell.
Some are needed for survival while others play an important role in infection by engaging with the innate immune response of the host.
This is the case in the Lit enzyme, which creates a specific lipoprotein that “cools the immune response” – raising the likelihood that Lit enables bacteria to gain a foothold in the host by stealth.
Previous research into the stealthy enzyme used whole cells. In contrast, this research confined the enzyme to a crystal lattice.
“Satisfyingly, the crystal structure matches and rationalises many of the observations made with the protein in its more natural in vivo setting,” the researchers wrote.
Blueprints such as these are useful as they allow drug designers to find potential weaknesses in the bacterial mechanism. This allows for the development of new therapeutic avenues that can help deal with antibiotic resistance.
Combined with other analytical techniques, molecular dynamics simulations and quantum mechanics approaches, the team were able to describe in detail how the enzyme functions.
“We believe Lit is very likely a virulence factor, negatively impacting host immune response to infection,” said Prof Martin Caffrey, senior author of the research.
“As such, it could well turn out to be an important target for the development of critically needed antibiotics against which resistance is much less likely to evolve. And it is no exaggeration to say that antibiotic resistance poses a genuine, growing threat to our society.”
