Tph2

What is TPH2 protein?

Tryptophan Hydroxylase 2 (TPH2) plays a substantial role in numerous biological mechanisms.The journal Science made the first credible reference to the TPH2 protein in 2003, describing it as an isoform of the Tryptophan Hydroxylase (TPH) gene. It was an exciting discovery as TPH1, the first isoform, was much known, whereas TPH2 was completely unheard of before 2003. It was Walther and Bader who found this novel isoform and describe it as being expressed predominantly in the brain, mainly in serotonergic neurons of the raphe nuclei.

Located on chromosome 12q21.1, TPH2 spans around 93.4 kilobases in humans, with 11 exons. The protein structure of TPH2 is intricate, having a tetramer structure with four identical subunits. Each subunit consists of three domains: an N-terminal regulatory domain, a central catalytic domain, and a C-terminal tetramerization domain. The uniqueness of TPH2 resides significantly in its detailed structured making it an ideal target for various drug design studies.

What is the function of TPH2 protein?

As an enzyme, TPH2 catalyzes the conversion of the amino acid tryptophan to 5-hydroxytryptophan (5-HTP) in the biosynthetic pathway of serotonin (5-HT). Serotonin, a well-known neurotransmitter, is significantly involved in various human body functions, ranging from mood regulation, sleep, appetite, to body temperature and pain perception. It is the exclusive enzyme for serotonin synthesis within the neurons of the central nervous system. Therefore, TPH2 plays a crucial role in maintaining serotonin levels in the brain.

TPH2 Protein-related Signal Pathway

The signal pathway associated with TPH2 is mainly the Serotonin Synthesis Pathway. TPH2 catalyzes the rate-limiting step in this pathway. The conversion of tryptophan to 5-HTP by TPH2 is an initial and significant step in the serotonergic pathway. Thereafter, the enzyme aromatic L-amino acid decarboxylase (AADC) converts 5-HTP into serotonin.

TPH2 Protein-related Diseases

The TPH2 protein and its functionality have been associated with various diseases. The most prominent of these diseases include psychiatric disorders like depression, anxiety, obsessive-compulsive disorder (OCD), and schizophrenia. These disorders have been observed in individuals carrying a gene variant of TPH2, promoting the disruption of TPH2 functionality and resulting in reduced serotonin levels in the brain. Consequently, this decrease leads to mood changes and other symptoms notable within the mentioned disorders.

Moreover, TPH2 is also associated with autism spectrum disorder (ASD), bipolar disorder, posttraumatic stress disorder (PTSD), and the Parkinsonian disorder. The correlation between TPH2 and these diseases is primarily established given the role TPH2 plays in serotonin production, a neurotransmitter essential for neuro-development, mood modification, and effective neurotransmission.

•  Major Depressive Disorder (MDD): Reduced levels of serotonin, resulting from Tph2 dysfunction, have been implicated in the development and progression of MDD. Serotonin is an important neurotransmitter that regulates mood, and alterations in its levels can lead to depressive symptoms.
•  Anxiety Disorders: Similar to MDD, dysregulation of serotonin due to Tph2 dysfunction has also been linked to various anxiety disorders, such as generalized anxiety disorder, panic disorder, and social anxiety disorder. Serotonin plays a crucial role in modulating anxiety levels and its imbalance can contribute to the development of anxiety disorders.
•  Obsessive-Compulsive Disorder (OCD): Tph2 dysfunction has been implicated in OCD, a disorder characterized by unwanted and intrusive thoughts (obsessions) and repetitive behaviors (compulsions). Serotonin is involved in regulating the neural circuits associated with OCD symptoms, and alterations in serotonin levels can contribute to the development of these symptoms.
•  Major depressive disorder: Serotonin deficiency is believed to contribute to the development of depression. Studies have shown that variations in the TPH2 gene can affect serotonin levels and increase the risk of developing depression.
•  Anxiety disorders: Similar to depression, serotonin imbalance is also implicated in anxiety disorders. Dysregulation of TPH2 gene expression or activity may contribute to an increased susceptibility to anxiety disorders.
•  Autism spectrum disorders (ASD): Serotonin is involved in neuronal development and synaptic transmission, both of which are implicated in ASD. Abnormalities in TPH2 gene function has been found in individuals with ASD, suggesting a potential role in the pathogenesis of the disorder.

Given the involvement of TPH2 in various disease processes, it has numerous applications in medical research and treatment strategies. Its primary relevance is seen in neuropsychiatric disorders where dysregulated serotonergic transmission is considered to underline the pathophysiology of these disorders.

TPH2 inhibitors and activators, when developed and studied meticulously, can hold significant therapeutic potential in managing disorders associated with the serotonergic system. Drug design studies targeting the unique molecular structure of TPH2 are crucial for improving the effectiveness of treatment strategies for common psychiatric disorders such as depression, schizophrenia, ADHD, and anxiety disorders.

•  Major depressive disorder: Serotonin deficiency is believed to contribute to the development of depression. Studies have shown that variations in the TPH2 gene can affect serotonin levels and increase the risk of developing depression.
•  Anxiety disorders: Similar to depression, serotonin imbalance is also implicated in anxiety disorders. Dysregulation of TPH2 gene expression or activity may contribute to an increased susceptibility to anxiety disorders.
•  Autism spectrum disorders (ASD): Serotonin is involved in neuronal development and synaptic transmission, both of which are implicated in ASD. Abnormalities in TPH2 gene function has been found in individuals with ASD, suggesting a potential role in the pathogenesis of the disorder.