GTP cyclohydrolase 1 (GCH1) (GCH1)

GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases and aromatic amino acid hydroxylases [4, 12]. The enzyme's catalytic active site contains a zinc ion coordinated by conserved residues (Cys141, His144, and Cys212 in humans), which is critical for the conversion of GTP into 7,8-dihydroneopterin triphosphate [17, 18, 21]. By regulating BH4 availability, GCH1 plays a pivotal role in the synthesis of neurotransmitters such as dopamine and serotonin, as well as the production of nitric oxide for vascular regulation [1, 4, 9]. Mutations in the GCH1 gene are the primary cause of dopa-responsive dystonia and BH4-deficient hyperphenylalaninemia [1, 11]. In drug discovery, GCH1 is a prominent target for chronic pain management, where inhibitors like DAHP aim to reduce pathological BH4 levels in sensory neurons [22, 23, 26]. Conversely, GCH1 activation is explored to restore endothelial function in cardiovascular diseases [8, 15]. Additionally, the enzyme is a target for novel antimalarial therapies because the parasite's folate synthesis pathway relies on its own version of GCH1 [2, 6, 24].

Other names

GTP cyclohydrolase IGTPCHGTPCH1DYT5DYT14GCHHPABH4B

GCH1 is targeted through both inhibition and activation. Inhibitors like 2,4-diamino-6-hydroxypyrimidine (DAHP) competitively bind to the active site to reduce BH4 production, which is used to alleviate neuropathic pain or inhibit parasite growth in malaria [16, 22, 24]. Activators, such as L-phenylalanine (acting via the GFRP regulatory protein), or gene therapies aim to increase GCH1 activity to restore BH4 levels for treating cardiovascular diseases or neurotransmitter deficiencies [8, 15].