On Oct. 10, the Schroeder Lab, led by Prof. Frank Schroeder, chemistry and chemical biology, published a study detailing a new class of serotonin-containing compounds and another serotonin pathway in Nature Chemical Biology.
The study, “Parallel Pathways for Serotonin Biosynthesis and Metabolism in C. elegans,” challenges the existing knowledge of how serotonin is produced and what happens to the neurotransmitter after it is synthesized.
Serotonin is a neurotransmitter that regulates different functions in both vertebrates and invertebrates. Serotonin in vertebrates — animals with spines — regulates several biological processes including sleep, memory and emotions. In invertebrates — animals without spines — serotonin has also been associated with egg laying and movement.
Serotonin is synthesized through tryptophan — an amino acid that produces and maintains proteins, enzymes and neurotransmitters — through two steps.
First, a hydroxyl group (OH) is added to the ring of tryptophan in a process called hydroxylation. Then, decarboxylation occurs where a carboxyl group (COOH) is removed. While the first step is caused by the enzyme TPH-1, decarboxylation occurs with the enzyme BAS-1. These enzymes speed up the reaction in each respective step to synthesize serotonin.
Scientists have considered hydroxylation by tryptophan and enzyme TPH-1 the standard pathway for several decades. However, the Schroeder Lab discovered that TPH-1 is not the only enzyme responsible for catalyzing the hydroxylation process in the production of serotonin.
In their study, they made two different types of mutations in their model organism Caenorhabditis elegans. C. elegans are used as model organisms because they are easier to study because of their shorter lifespans and ethical considerations. They also offer the opportunity to study a full organism instead of a cell and many biosynthesis pathways are similar to humans.
The first group didn’t contain the enzyme BAS-1 while the other didn’t contain the enzyme TPH-1. These two groups were used to test the impacts of removing the key enzyme from each of the two steps of serotonin biosynthesis.
First author and researcher at the Schroeder Lab Jingfang Yu, grad noted that there was still serotonin production in the mutated worm C. elegans that lacked TPH-1.
“We would think that if we look into the [traditional] serotonin biosynthesis negative control mutant, we would not see those newly derived compounds but that wasn’t the case,” Yu said. “We still found these compounds suggesting that there is a different parallel pathway that exists in worms.”
The presence of serotonin even without the key enzyme TPH-1 suggests that TPH-1 is not the only enzyme catalyzing this process. This is important because it disproves the widely held notion that TPH-1 is the sole enzyme in serotonin production.
Using this new information, the team found PAH-1 to be the parallel gene for TPH-1, functioning similarly to TPH-1 and contributing to serotonin biosynthesis as well.
“Everybody knows that TPH-1 makes serotonin, but we showed that this one key pathway contributes about 50 percent. That was really crazy,” Schroedor said.
While investigating what happens to serotonin after it is synthesized, the lab found that not all serotonin is just broken down but a majority of serotonin is used to make larger molecules known as serotonin derivatives.
The study noted a new class of serotonin derivatives named sngl, which remain in the worm more in comparison to the other commonly recognized derivatives NAS and 5-HIAA. As the other derivatives are largely excreted, the retention of sngl indicates that sngl may play an important role within the organism.
Yu also found that the derivatives affect behavior in the worms.
Although it’s known that worms without serotonin explore the food plate more than worms with, the lack of exploration by the worms treated with serotonin derivatives in this study suggest that serotonin derivatives, instead of just serotonin, play an important role in behavior.
However, the study has raised questions on how these new findings relate to humans. Although C. elegans are model organisms, not all human biological processes may be represented. This prompts further research with different organisms, particularly in mice for their similarity to humans.
Schroeder discussed the implications of their discoveries on the field as a whole and the numerous questions that remain unanswered.
“What we did was tell the entire neurotransmitter field that they needed to start over,” Schroeder said. “Not necessarily at zero, but that we have to go back some and then start asking where is serotonin made? What does it get made into? And what do these products, these larger molecules, do?”
This discovery of the new derivatives sngl may provide clues into its role in humans and specifically in serotonin related diseases like depression. This could also even aid in the development of new treatments.
“Serotonin is not the end of the story,” Yu said. “There’s still a lot to do here.”