A new study has revealed that the mechanism behind how carbohydrates are synthesized from small sugar units has shed new light on a promising way to target new medicines against tuberculosis.
While working with components of the tuberculosis bacterium, researchers from the University of Wisconsin-Madison identified an unusual process by which the pathogen builds an important structural carbohydrate.
The mechanism also offers insight into a widespread but poorly understood basic biological function, controlling the length of carbohydrate polymers.
"Carbohydrate polymers are the most abundant organic molecules on the planet, and it's amazing that we don't know more about these are made. There's not much known about how length is controlled in these carbohydrate polymers," said Laura Kiessling, a professor of chemistry and biochemistry at UW-Madison.
Most carbohydrates exist as many sugar molecules linked into long chains, or polymers, but the right number of sugars in the chain is vital for them to work properly.
However, Kiessling has said that not much is known about how carbohydrate length is determined.
Unlike some biological chains, such as DNA and proteins, that are built off a template that guides the length of the final product, carbohydrate-synthesizing enzymes work without templates.
The research team focused on an enzyme called GlfT2 that is responsible for building a critical carbohydrate component of the TB bacterial cell wall, and found that a small fatty component at the starting end binds to the enzyme and helps it track the length of the growing polymer.
As the enzyme adds more and more sugar units to the opposite end, the chain becomes increasingly unmanageable.
Kiessling said that "if the chain gets too long, it gets hard to hold on to both of the ends, so the chain falls off" the synthesizing enzyme, forming a completed carbohydrate polymer.
The researchers believe that the enzymes responsible for building different types of carbohydrates exceed their comfort level at different points, leading to molecules of different prescribed lengths.
He said that the report was the first description of this "tethering" mechanism, named for the fatty lipid that tethers the start of the polymer to the enzyme, in carbohydrate synthesis, though it may prove to be common among other organisms as well.
The work gives significant insight into developing new therapeutics against TB.
The GlfT2 enzyme has two binding sites, one for each end of the growing carbohydrate, that make it an especially appealing candidate.
"Our mechanism provides a blueprint for strategies to block a new anti-mycobacterial target," said Kiessling.
The new study has appeared in the online Early Edition of the Proceedings of the National Academy of Sciences.