French researchers identify structure of key TB enzyme.

French chemists have determined the structure of an enzyme essential to the survival of Mycobacterium tuberculosis, the infectious agent that causes tuberculosis (TB). The structure of this enzyme is slightly different from the version found in humans and it could therefore prove to be an important target for novel TB drugs.

Always a major problem in the developing world, TB was once thought to have been practically eradicated from developed countries. However, the development of strains of Mycobacterium tuberculosis that are resistant to the major TB drugs and the increased risk of co-infection with HIV means that TB is becoming a global health threat. New ways of treating the disease, including novel drug targets, are desperately needed.

Adenylate kinases are small enzymes that play a key role in metabolism and nucleic synthesis in most cells and are therefore vital for their survival. However, the adenylate kinase found in bacteria, including mycobacteria, has a far lower catalytic activity than the versions found in human cells.

Now a team of French researchers from the Centre Universitaire, Orsay, and the Institut Pasteur, Paris, decided to find out whether this inequality in activity was founded on a structural difference and whether the mycobacterial adenylate kinase could be a promising drug target.

Using nuclear magnetic resonance spectroscopy, the team resolved the structure of the adenylate kinase found in mycobacteria and compared it with the structures of the adenylate kinases present in human cells. The researchers discovered that, although the different adenylate kinases had the same basic structure, the mycobacterial version was considerably more compact and therefore had a significantly decreased ability to bind with mononucleotides.

The researchers hope that their findings will help the search for possible specific inhibitors. However, Jeremy Dale, professor of molecular microbiology at Surrey University's School of Biomedical and Molecular Sciences and an expert on TB, questions whether adenylate kinase would make a good drug target. 'It might be possible to design a specific inhibitor with selective toxicity, but it would be much easier with an enzyme that was not present at all in the host.' 

Jon Evans