The complete genome for the tuberculosis bacterium was sequenced and published in 1998. Since then, scientists have deciphered about two-thirds of TB's genes. Or have they?

A research group led by biochemist Luiz Pedro Carvalho, Ph.D., of The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, has found that one of TB's supposedly "known" genes has a completely unexpected biological role, with far-reaching implications.

Under stress, the normally quiet enzyme pops into action, like a jack-in-the-box. The group's discovery, published in the journal Proceedings of the National Academy of Sciences, or PNAS, the week of August 17, suggests that TB's genome may hold more surprises than previously thought.

The work could impact research on TB antibiotic resistance and new drug development, Carvalho said. The discovery also raises important questions for pathogens that carry similar enzymes, including those that cause leprosy and malaria.

What scientists thought we knew about this enzyme is just wrong, it acts in a completely different way. This expands our understanding of microbial metabolism and opens new avenues for targeting metabolic pathways in several pathogenic organisms." 

Luiz Pedro Carvalho, Ph.D., Biochemist, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology

Carvalho's team found the gene, called rv2531c, encodes an enzyme whose job is to transform the abundant amino acid glutamate into another substance called GABA, something bacteria need for metabolism, signaling and defense. Previously, scientists presumed that the enzyme played a role in assembling a group of biological molecules called polyamines, essential to protein building and many other functions. So, if rv2531c doesn't do that, scientists still have a mystery to solve, said Carvalho, a member of the University of Florida's Emerging Pathogens Institute.

Globally, TB continues to vex health officials. The germ that causes tuberculosis is a wily one that can lie dormant for sometimes years, waiting for an opportune moment like illness or stress to spring to life. That makes containing it nearly impossible. Treatment typically requires TB patients to take strong antibiotics for six months. Side effects can be serious, and compliance can be difficult, raising the need for more effective and benign drugs.

About 11 million people a year become sick with TB, while about 1.25 million people die from it. Antibiotic resistance is a problem, with studies showing that 8% of TB patients have a strain that is resistant to one antibiotic, while more than 3% are sick with a strain resistant to multiple antibiotics.

Carvalho's team has long worked to develop better drugs against TB, and they've worked to better understand the pathogen's genetics for more than 15 years. His doctoral student, H. Minh Thai, and team, found that the enzyme made by rv2531c works in a fascinating way. Like the pathogen itself, it lies quietly, doing little, until some stressor causes it to reach a threshold concentration.

"Then it's just insane, it converts glutamate to GABA at a rate of 70 per second," Carvalho said. "It's one of the quickest enzymes we have."

That slow-starting quality may have helped its real properties elude previous research teams, he added, because researchers typically expect to see results within a minute with standard methods. His group used an hourlong process to study it, called nuclear magnetic resonance. 

Once they saw what it did, they wondered if the gene and its cousins showed up in other pathogenic organisms. They did, including the malaria parasite Plasmodium, the leprosy Mycobacterium, and some marine bacteria that may be involved in controlling phytoplankton, types of algae and cyanobacteria found in the ocean. There are 1,000 sequences similar to the gene, he said, raising the odds that this discovery will lead to other new and useful discoveries. His group's research continues to explore those possibilities.

"Blue-sky science can lead to real-life applications," Carvalho said. "This is a natural product, and we have no idea what it does. If this natural product turns out to be the next anti-cancer drug, or red-tide remedy? A natural molecule that isn't a toxin? You cannot predict the potential usefulness of what's going to come out of this."