Carb synthesis sheds light on promising tuberculosis drug target

Jun 22, 2009

A fundamental question about how sugar units are strung together into long carbohydrate chains has also pinpointed a promising way to target new medicines against tuberculosis.

Working with components of the , researchers from the University of Wisconsin-Madison identified an unusual process by which the pathogen builds an important structural carbohydrate. In addition to its implications for human health, the mechanism 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," says Laura Kiessling, a professor of chemistry and biochemistry at UW-Madison. "There's not much known about how length is controlled in these carbohydrate polymers."

Kiessling is senior author, along with graduate students John May and Rebecca Splain and postdoctoral fellow Christine Brotschi, of a new study appearing in the online Early Edition of the the week of June 22.

Most carbohydrates exist as many sugar molecules linked into long chains, or polymers. The right number of sugars in the chain is vital for them to work properly, but different types of carbohydrate polymers range from a few dozen sugars in some bacterial molecules to tens of thousands of sugar links in cellulose, a common plant material.

Despite its importance, it's not clear how carbohydrate length is determined, Kiessling says. 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.

"Nature has strategies to generate polymers of different lengths, but we know very little about those strategies," she says. "If you make something too short, it's probably not going to function in the role that you want, and if you make something too long, you're wasting energy that you need to use elsewhere."

The research team focused on an enzyme called GlfT2 that is responsible for building a critical carbohydrate component of the TB bacterial cell wall.

The researchers 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 unwieldy.

"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, Kiessling says, 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.

The current report is 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, Kiessling says, though it may prove to be common among other organisms as well.

In addition to providing insight into what may be a general mechanism for designing and building carbohydrates, the work gives insight into developing new therapeutics against TB. The GlfT2 enzyme is essential for bacterial survival and growth but has never yet been targeted by potential treatment methods. Knowing that the enzyme has two binding sites — one for each end of the growing carbohydrate — makes it an especially appealing candidate.

"Our mechanism provides a blueprint for strategies to block a new anti-mycobacterial target," Kiessling says.

New drug targets will be critical in the fight against tuberculosis, as drug-resistant strains are becoming increasingly widespread. The carbohydrate-synthesizing enzyme represents an untapped and promising resource for crippling even strains that are resistant to current drugs.

The prevalence of carbohydrate polymers in biological systems also means that understanding how their length is controlled has many possible applications, ranging from designing more potent and effective vaccines to facilitating the production of useful fuels from plant materials.

"It's a nice illustration of how basic research can lead to applications that are very practical," says Kiessling.

Source: University of Wisconsin-Madison (news : web)

Explore further: US scientists make embryonic stem cells from adult skin

add to favorites email to friend print save as pdf

Related Stories

Waistline growth on high-carb diets linked to liver gene

Dec 04, 2007

Experts have been warning for years that foods loaded with high-fructose corn syrup and other processed carbohydrates are making us fatter. Now, a University of Wisconsin-Madison study has uncovered the genetic basis for ...

Fat, thin caterpillars are studied

Sep 21, 2006

A U.S.-led international team of scientists says there's no obesity epidemic among insects and the researchers believe they now know why.

Structural study of anthrax yields new antibiotic target

Jan 28, 2008

Researchers studying anthrax knew they were onto something when they discovered an opponent the bacterium couldn’t outwit. Probing a bit deeper, they discovered this was because the attacker was interacting ...

Chemists synthesizes carbohydrates

Apr 01, 2009

Carbohydrates are part of our daily vocabulary. We all know they're part of a healthy diet. We know they're in breads and pastas. We know they have something to do with starches and sugars. But, even though ...

Green diesel: New process makes fuel from plants

Jun 03, 2005

College of Engineering researchers have discovered a new way to make a diesel-like liquid fuel from carbohydrates commonly found in plants. Reporting in the June 3 issue of the Journal Science, Steenbock ...

Recommended for you

Leeches help save woman's ear after pit bull mauling

Apr 18, 2014

(HealthDay)—A pit bull attack in July 2013 left a 19-year-old woman with her left ear ripped from her head, leaving an open wound. After preserving the ear, the surgical team started with a reconnection ...

New pain relief targets discovered

Apr 17, 2014

Scientists have identified new pain relief targets that could be used to provide relief from chemotherapy-induced pain. BBSRC-funded researchers at King's College London made the discovery when researching ...

User comments : 0

More news stories

Filipino tests negative for Middle East virus

A Filipino nurse who tested positive for the Middle East virus has been found free of infection in a subsequent examination after he returned home, Philippine health officials said Saturday.

Study says we're over the hill at 24

(Medical Xpress)—It's a hard pill to swallow, but if you're over 24 years of age you've already reached your peak in terms of your cognitive motor performance, according to a new Simon Fraser University study.

NASA's space station Robonaut finally getting legs

Robonaut, the first out-of-this-world humanoid, is finally getting its space legs. For three years, Robonaut has had to manage from the waist up. This new pair of legs means the experimental robot—now stuck ...

Ex-Apple chief plans mobile phone for India

Former Apple chief executive John Sculley, whose marketing skills helped bring the personal computer to desktops worldwide, says he plans to launch a mobile phone in India to exploit its still largely untapped ...

Egypt archaeologists find ancient writer's tomb

Egypt's minister of antiquities says a team of Spanish archaeologists has discovered two tombs in the southern part of the country, one of them belonging to a writer and containing a trove of artifacts including reed pens ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.