Surprise Discovery: A 'Known' TB Gene Springs to Action Under Stress, Revealing a New Drug Target
核心洞察
Researchers at The Herbert Wertheim UF Scripps Institute discovered that the tuberculosis (搜索) gene rv2531c (搜索) encodes an enzyme with a completely unexpected biological role, published in PNAS.
The enzyme, previously thought to build polyamines, instead converts the amino acid glutamate into GABA at a rate of 70 per second once a stress threshold is reached.
The finding could impact TB antibiotic resistance research and new drug development, with implications for pathogens causing leprosy (搜索) and malaria (搜索).
A research group led by biochemist Luiz Pedro Carvalho, Ph.D., of The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology (搜索), has found that one of tuberculosis (搜索)'s supposedly "known" genes has a completely unexpected biological role, with far-reaching implications for drug development and antibiotic resistance.
The discovery, published in the journal Proceedings of the National Academy of Sciences (PNAS) the week of August 17, reveals that the gene rv2531c (搜索) encodes an enzyme whose job is to transform the abundant amino acid glutamate into another substance called GABA, which bacteria need for metabolism, signaling, and defense. Previously, scientists presumed the enzyme played a role in assembling a group of biological molecules called polyamines, essential to protein building and many other functions.
"What scientists thought we knew about this enzyme is just wrong, it acts in a completely different way," Carvalho said. "This expands our understanding of microbial metabolism and opens new avenues for targeting metabolic pathways in several pathogenic organisms."
A Jack-in-the-Box Enzyme
Carvalho's doctoral student, H. Minh Thai, and team, found that the enzyme made by rv2531c (搜索) 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, Carvalho added, because researchers typically expect to see results within a minute with standard methods. His group instead used an hourlong process called nuclear magnetic resonance to study it.
Implications for TB and Beyond
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 (搜索) and malaria (搜索).
Once they saw what the enzyme did, the researchers investigated whether the gene and its cousins appeared in other pathogenic organisms. They did, including the malaria (搜索) parasite Plasmodium, the leprosy (搜索) 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, Carvalho said, raising the odds that this discovery will lead to other new and useful discoveries.
The Unmet Need in Tuberculosis
Globally, TB continues to vex health officials. The germ that causes tuberculosis (搜索) can lie dormant for sometimes years, waiting for an opportune moment like illness or stress to spring to life, making containment nearly impossible. Treatment typically requires TB patients to take strong antibiotics for six months, with side effects that can be serious and compliance that 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 has worked to better understand the pathogen's genetics for more than 15 years. His group's research continues to explore the possibilities raised by this discovery.
"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."