Histidine triad nucleotide-binding protein 1 (HINT1)

Histidine triad nucleotide-binding protein 1 (HINT1) is a small, evolutionarily conserved enzyme of the histidine triad (HIT) superfamily found in most eukaryotes[3]. It catalyzes the hydrolysis of purine nucleotide phosphoramidates and functions as a scaffold protein modulating the activity of various transcription factors, such as MITF, AP-1, TFIIH, and USF2, thereby participating in gene expression regulation via the Wnt/β-catenin pathway and others[1][3]. HINT1 acts as a haploinsufficient tumor suppressor and has key roles in suppressing cancer development. It regulates calcium signaling by modulating the expression of Orai1 and STIM1, which are critical for store-operated calcium entry in cells, and influences PKC activity and NMDA/glutamate receptor signaling in neurons[2][3][4]. HINT1's activity has been linked to the pathophysiology of several neuropsychiatric and neurological disorders, including schizophrenia, mood disorders, and inherited neuropathies[2][3]. HINT1 deficiency or mutation has been implicated in axonal neuropathy with neuromyotonia and may modulate behaviors related to depression, anxiety, and drug addiction[3]. No approved drugs directly target HINT1, but it plays a modulatory role in opioid and cannabinoid receptor function[3][4].

Other names

Adenosine 5'-monophosphoramidase HINT1PKCI1PRKCNH1PKCI-1Desumoylating isopeptidase HINT1Protein kinase C inhibitor 1Protein kinase C-interacting protein 1NMANepididymis secretory sperm binding protein

Not established for approved drugs; experimental data implicate HINT1 in the modulation of GPCR (especially μ-opioid receptor and cannabinoid receptor CB1) and NMDA receptor signaling[3][4].