Researchers discover how botulinum neurotoxin survives in the stomach

Researchers recently discovered how the botulinum neurotoxin, a deadly potential bioterror agent, can survive its passage through the hostile environment of the human stomach.

Scientists from the Sanford-Burnham Medical Research Institute and the Medical School of Hannover Germany revealed the first three-dimensional structure of the neurotoxin together with its bodyguard, a protein made simultaneously from the same bacterium.

The study, which appears in the journal Science, reveals a possible weak point that may be targeted by future therapeutics.

The botulinum neurotoxin is considered to be one of the most poisonous substances known to man, but it is also an effective therapy and used as popular cosmetic Botox.

The neurotoxin can accomplish both good and bad by using the same process. It paralyzes muscle cells by disrupting their connections with the nerves that tell them when and how to move. Before it can gain access to the muscles and the neurons that control them, however, it must make a journey through the human body that includes surviving the digestive enzymes and extreme acidic environment in the stomach.

The new study breaks the atomic structure of the toxin into three basic parts, a region that recognizes neurons, an enzyme that acts like a pair of scissors to cut neural proteins and a needle that punches holes to help deliver the enzyme to the nerve terminal.

In addition, the researchers were able to map the toxin's relationship to a second bacterial protein, its bodyguard, called nontoxic nonhemagglutinin.

"We were surprised to see that NTNHA, which is not toxic, turned out to be remarkably similar to botulinum neurotoxin," Sanford-Burnham's Dr. Rongsheng Jin said. "It's composed of three parts, just like a copy of the toxin itself. These two proteins hug each other and interlock with what looks like a handshake.

"Now that we better understand the structure of the bacterial machinery that was designed for highly efficient toxin protection and delivery, we can see more clearly how to break it."

NTNHA keeps the botulinum toxin from being degraded throughout its journey in the stomach, but when the toxin punches its way out of the small intestine, a change in PH leads to the molecule's release.

"We now hope we might be able to fool the toxin and its bodyguard using a small molecule that sends the wrong signal-mimicking pH change, prematurely breaking up their protective embrace, and leaving the stomach's digestive enzymes and acid to do their job," Jin said. "We envision this type of therapy-either alone or in combination with other therapies currently in development-could be given preventively at a time when botulinum neurotoxin contamination becomes a public health concern."