A new study was conducted to understand the biochemistry and structure of a protein-cleaving complex (proteasome) that is essential to the TB bacterium's survival. The findings were published in the journal Molecular Microbiology. The study's main aim was to design effective treatment for the disease tuberculosis (TB). The study was done by scientists from the U.S. Department of Energy's Brookhaven National Laboratory and collaborating institutions. Biophysicist Huilin Li, who led Brookhaven's role in the research, said that the study also plans to analyze the difference present in the structure and biochemistry of the TB bacterial proteasome from those found in human cells. This would greatly improve prospects for developing specific proteasome-based anti-tuberculosis treatments.
Mycobacterium tuberculosis is the bacterium that causes TB in man. Statistics show that one out of three people is infected with the disease. Largely the infected person is not aware of the presence of the disease as it does not manifest any observable symptoms. This is due to the fact that the bacteria is kept in check within immune system cells known as macrophages by compounds such as nitric oxide that kills or disables most of the bacteria. Inside the macrophage the immune cells damages and destroys the bacterial proteins. These accumulated proteins have to be removed otherwise it will in turn destroy the cell.
But the TB bacteria remove the damaged proteins with the help of a protein-cleaving complex known as a proteasome. It is highly specific for degrading protein parts. This protein allows Mycobacterium tuberculosis to remain in macrophages, and possibly go on to cause active TB infections. Hence Li said this protein should be made as a major target for the production of new anti-TB drugs. By this technique TB microbes can be eradicated from infected individuals who show no signs of infection. But the major drawback is that human cells also contain proteasomes for degrading unneeded proteins. This process is essential for human cell survival. So any drug targeting the TB proteasome would have to be extremely specific. Hence studies should be very specific in identifying the unique characteristics that would allow such a targeted drug design.
The studies reveal highly specific details of the proteasome active site and mechanism, which will be invaluable to designing TB specific inhibitors. The proteasome structure was revealed by Guiqing Hu and collaborators using cryo electron microscopy in Brookhaven Lab's Biology Department and by x-ray crystallography at the Lab's National Synchrotron Light Source. The biochemical studies were conducted at Weill Medical College of Cornell University by Gang Lin in a group led by Carl Nathan. Other collaborating institutions included the Max Planck Institute of Biochemistry, Cold Spring Harbor Laboratory, and Millennium Pharmaceuticals. This research was funded by the Office of Biological and Environmental Research within the U.S. Department of Energy's Office of Science, the National Institutes of Health, and Brookhaven's Laboratory Directed Research and Development program.