Structures, catalytic mechanisms, and contribution to pathogenesis of polysaccharide lyases from Streptococcus pneumoniae

Beyond playing an important role in nutrition, carbohydrate building blocks and their biochemistry have been described as the "last frontier of cell and molecular biology." It is easy to see why their study has remained a great challenge: even a simple chain with only six sugar links has over a trillion possible arrangements. This vast structural diversity is reflected in the role of polysaccharides (sugar chains) as the "language of the cell," in that specific arrangements of carbohydrate messages act like dual receivers and transmitters of cell-signaling events. These signals may contribute to friendly cell-cell interactions, lead immune responses, or help to disguise human pathogens from immune detection. Because of the central importance of polysaccharides in signaling events, characterizing the cellular mechanisms responsible for the synthesis, breakdown, and recognition of cell-surface polysaccharides are of vast importance in understanding how the cell works.

Dr. Michael Suits is working to understand how infection by Streptococcus pneumoniae, a human pathogen that is one of the world's leading causes of death, causes infection by recognizing and manipulating the carbohydrate building blocks present on many of our cell surfaces. Certain strains of S. pneumoniae have evolved resistance to antibiotics, are not recognized by human immune defenses even following vaccination, and have the capacity to act in lethal synergy with the Influenza virus. As part of a concerted attack, S. pneumoniae releases proteins, which help the microbe to attach to host cells and short circuit the carbohydrate messages being transmitted. Dr. Suits is directing his research attention towards a pair of carbohydrate-modifying enzymes produced by S. pneumoniae.

Using powerful X-rays to investigate these key enzymes in very precise detail, Dr. Suits hopes to determine how these enzymes interact with an important type of carbohydrate found on the surface of human cells. Additionally, he will use molecular biology tools to "knock out" S. pneumoniae genes encoding important carbohydrate modifying enzymes and then examine how this influences bacterial growth and the ability to cause infection. These research results will help identify potential targets for therapeutic intervention, and provide a platform to develop compounds to inhibit carbohydrate-modifying enzymes.