Carb synthesis sheds light on promising tuberculosis drug targetJune 23, 2009MADISON - 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 tuberculosis bacterium, 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 Proceedings of the National Academy of Sciences 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. University of Wisconsin-Madison |
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| Related Tuberculosis Current Events and Tuberculosis News Articles Multiple health concerns surface as winter, vitamin D deficiences arrive A string of recent discoveries about the multiple health benefits of vitamin D has renewed interest in this multi-purpose nutrient, increased awareness of the huge numbers of people who are deficient in it, spurred research and even led to an appreciation of it as "nature's antibiotic." Study reveals why certain drug combinations backfire Combination drug therapy has become a staple for treating many infections. For instance, doctors treat extensively drug resistant forms of tuberculosis with one drug that breaks down the pathogen's protective barriers and opens the door for another to deliver the deathblow. Drug industry, nonprofits join forces to fight world's neglected diseases Drug companies and nonprofit organizations are joining forces to develop new drugs and vaccines to target so-called "neglected" diseases that claim millions of lives in the developing world each year. U.S. and European Experts Applaud Creation of New Transatlantic Task Force on Global Antibiotic Resistance Threat Experts on both sides of the Atlantic applaud President Barack Obama and Swedish Prime Minister Fredrik Reinfeldt, representing the European Union (EU) Presidency, for establishing a transatlantic task force to address antibiotic resistance, an urgent and growing problem that threatens patient safety and public health worldwide. 1930s drug slows tumor growth Drugs sometimes have beneficial side effects. A glaucoma treatment causes luscious eyelashes. A blood pressure drug also aids those with a rare genetic disease. There's a speed limit to the pace of evolution, Penn biologists say Researchers at the University of Pennsylvania have developed a theoretical model that informs the understanding of evolution and determines how quickly an organism will evolve using a catalogue of "evolutionary speed limits." Cell phones become handheld tools for global development Mobile phones are on the verge of becoming powerful tools to collect data on many issues, ranging from global health to the environment. Will genomics help prevent the next pandemic? This week, the Public Library of Science, an open-access publisher, presents the "Genomics of Emerging Infectious Disease," a collection of essays, perspectives, and reviews that explores how genomics-with all its associated tools and techniques-can provide insights into our understanding of emerging infectious disease. Exon-skipping drug prevents muscle wasting, maintains muscle function in dystrophin deficient mice An exon skipping PPMO has demonstrated dramatic effects in the prevention and treatment of severely affected, dystrophin and utrophin-deficient mice, preventing severe deterioration of the treated animals and extending their lifespan. Scientists take step toward simple and portable tuberculosis tests for developing world Two billion people worldwide carry the pathogen that causes tuberculosis (TB), and most of them do not even know they are infected. This is because some 90 percent of people with TB have "latent" infections. They have no symptoms, they can't spread the disease to others and the bug remains dormant in their lungs -- often for years. More Tuberculosis Current Events and Tuberculosis News Articles |
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