Tryptophan hydroxylase 2 (TPH2) (TPH2)

Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme responsible for the synthesis of serotonin (5-HT) within the central nervous system, distinct from the peripheral isoform TPH1 [1, 8]. It is primarily expressed in the serotonergic neurons of the brain, particularly in the raphe nuclei, where it catalyzes the conversion of L-tryptophan to 5-hydroxytryptophan (5-HTP) [2, 8]. TPH2 plays a critical role in regulating brain serotonin levels, which are essential for mood regulation, cognition, and the stress response [4, 5]. Genetic variations and dysregulation of TPH2 activity have been strongly implicated in various neuropsychiatric conditions, including major depressive disorder, bipolar disorder, ADHD, and suicide risk [5, 6]. While traditional antidepressants like SSRIs target serotonin reuptake, TPH2 is an emerging therapeutic target for modulating serotonin production at its source [3, 7]. Therapeutic strategies under investigation include TPH2 inhibitors for conditions of serotonin excess and pharmacological chaperones to stabilize mutant forms of the enzyme in cases of serotonin deficiency [1, 6]. Additionally, certain drugs of abuse such as MDMA and methamphetamine can lead to long-term reductions in TPH2 levels, contributing to post-use serotonin depletion [8].

Other names

Tryptophan 5-hydroxylase 2Neuronal tryptophan hydroxylaseADHD7NTPH

Inhibition of serotonin synthesis by binding to the active site of the enzyme; stabilization of enzyme structure and function via pharmacological chaperones; modulation of gene expression by antidepressant therapies.