Researchers at The Scripps Research Institute (TSRI) have identified and characterized a bacterial enzyme that shows promise as a potential therapeutic to aid smoking cessation.
Kim Janda, the Ely R. Callaway Jr. Professor of Chemistry and a member of the Skaggs Institute for Chemical Biology at TSRI, emphasized that the work remains in the early stages of drug development but that the enzyme displays the biochemical qualities that could make it a viable treatment option.
The study, published online in the Journal of the American Chemical Society in early August, explores an alternative approach to existing smoking cessation aids, which studies indicate can fail for a large percentage of smokers. Rather than acting on brain receptors, the proposed enzyme therapy would degrade nicotine in the bloodstream before it reaches the brain, thereby removing the rewarding stimulus that often triggers relapse.
For decades, Janda and his team attempted to engineer an effective nicotine-degrading enzyme in the laboratory. Their breakthrough came with the discovery of a naturally occurring enzyme, NicA2, produced by the soil bacterium Pseudomonas putida. This bacterium, originally isolated from a tobacco field, uses nicotine as its sole source of carbon and nitrogen, effectively metabolizing the compound.
“The bacterium behaves like a tiny Pac-Man,” Janda said, “moving through its environment and consuming nicotine.”
In the reported experiments, TSRI researchers purified and characterized NicA2 and then evaluated its potential for therapeutic development. They performed a series of biochemical and stability tests and studied the byproducts of nicotine degradation to assess safety.
One key experiment mixed mouse serum with an amount of nicotine comparable to a single cigarette and then added NicA2. The enzyme dramatically shortened nicotine’s half-life in serum from roughly two to three hours down to approximately 9–15 minutes. According to the researchers, higher enzyme concentrations combined with targeted chemical modifications could reduce nicotine levels even more rapidly and limit or prevent nicotine from entering the brain.
The team subjected NicA2 to rigorous screening designed to evaluate whether the enzyme meets the criteria needed for a drug candidate. These assessments included kinetic measurements, thermostability, serum stability, and analysis of the chemical products formed during nicotine breakdown. “This was a long shot,” Janda noted. “If the enzyme didn’t show the right properties, it would not be feasible as a therapeutic.”
Results were encouraging: NicA2 retained activity and structural stability for more than three weeks at 98°F (about 37°C), a notable finding for a protein-based candidate. Equally important, the degradation products produced during nicotine catabolism showed no signs of toxic metabolites in the assays performed, supporting the enzyme’s safety profile in preliminary tests.
“The enzyme is relatively stable in serum, which is an important factor for any therapeutic candidate,” said Song Xue, a TSRI graduate student and first author of the study. Serum stability increases the likelihood that an administered enzyme could persist long enough to have a meaningful clinical effect.
Looking ahead, the researchers plan to modify the enzyme’s bacterial elements to reduce potential immune responses and to optimize pharmacokinetic properties. These modifications aim to improve circulation time in blood and reduce immunogenicity, with the goal of achieving sustained activity from a single administration.
“With further engineering, our hope is to extend serum stability so that a single injection might provide protection for weeks rather than hours or days,” Xue added. Such improvements would simplify dosing and could make enzyme therapy a practical adjunct to behavioral and pharmacological interventions for nicotine dependence.
The study, titled “A new strategy for smoking cessation: Characterization of a bacterial enzyme for the degradation of nicotine,” lists Song Xue and Joel E. Schlosburg of TSRI as co-authors along with Kim D. Janda. Funding for the research was provided by the Skaggs Institute for Chemical Biology at TSRI.
Funding: Supported by the Skaggs Institute for Chemical Biology at The Scripps Research Institute.
Source: Scripps Research Institute
Image Source: Public domain image
Original Research: Abstract for “A New Strategy for Smoking Cessation: Characterization of a Bacterial Enzyme for the Degradation of Nicotine” by Song Xue, Joel E. Schlosburg, and Kim D. Janda in Journal of the American Chemical Society. Published online August 3, 2015. doi:10.1021/jacs.5b06605
Abstract
A New Strategy for Smoking Cessation: Characterization of a Bacterial Enzyme for the Degradation of Nicotine
Smoking remains the leading cause of preventable illness worldwide, and more effective cessation tools are needed. This study evaluates NicA2, a flavin-containing nicotine-degrading enzyme from Pseudomonas putida, as a possible therapeutic. Researchers performed kinetic analyses, measuring parameters such as Km and kcat, and assessed buffer and serum half-life along with thermostability. They also characterized the enzyme’s catabolic pathway to determine whether nicotine-derived products posed toxicity risks. The results revealed a favorable biochemical profile for NicA2, including rapid nicotine degradation in serum, strong thermostability, and a lack of detected toxic metabolites in the experimental settings. Altogether, these findings support further development of NicA2 as a prospective therapeutic strategy for nicotine addiction.