HINT1 Human
Description
Structure and Enzymatic Activity
-
Catalytic Triad: The HIT motif enables hydrolysis of nucleoside phosphoramidates (e.g., adenosine 5′-monophosphoramidate) .
-
Dimerization: Functions as a homodimer, with dimerization critical for substrate recognition .
-
Substrate Specificity: Hydrolyzes substrates including AMP-morpholidate, AMP-NH₂, and lysyl-adenylate .
Table 1: Molecular Properties of HINT1
| Property | Details | Source |
|---|---|---|
| Gene Location | Chromosome 5 (5q31.2) | |
| Protein Length | 126 amino acids (13.8 kDa) | |
| Catalytic Motif | His-X-His-X-His-XX | |
| Key Domains | N-terminal β-sheet, C-terminal α-helices |
Tumor Suppression
-
Inhibits Wnt/β-catenin signaling and MITF transcriptional activity, acting as a haploinsufficient tumor suppressor .
-
Downregulated in cancers (e.g., colon, liver), promoting apoptosis and reducing metastasis .
Neurological Roles
-
Neuropsychiatric Disorders: Modulates opioid receptor signaling and is implicated in depression, bipolar disorder, and schizophrenia .
-
Peripheral Neuropathy: Biallelic HINT1 mutations cause autosomal recessive axonal neuropathy with neuromyotonia (NMAN) .
Table 2: Key Biological Pathways Involving HINT1
Genetic Mutations and Neuropathy
-
Over 9 HINT1 mutations (e.g., p.Arg37Pro, p.Arg95Gln) destabilize the protein, leading to axonal neuropathy .
-
Loss of enzymatic function correlates with neuromuscular symptoms (e.g., muscle cramps, motor deficits) .
Cancer and Mental Health
-
Reduced HINT1 expression is observed in tumor tissues and postmortem brains of bipolar disorder patients .
-
Potential therapeutic target for depression (via PKC ε/ALDH-2 inhibition) and antiviral prodrug activation (e.g., sofosbuvir) .
Table 3: Clinically Relevant HINT1 Mutations
| Mutation | Effect on Protein | Associated Disease |
|---|---|---|
| p.Arg37Pro | Proteasomal degradation | NMAN |
| p.Arg95Gln | Reduced stability | NMAN |
| c.110G > C | Founder allele in European populations | Axonal neuropathy |
Therapeutic Applications
-
Antiviral ProTides: HINT1 activates prodrugs like sofosbuvir and remdesivir by hydrolyzing phosphoramidate bonds .
-
Cancer Therapy: HINT1 restoration suppresses tumor growth via transcriptional regulation (e.g., β-catenin inhibition) .
Table 4: Substrate Catalysis by HINT1
Product Specs
Product Science Overview
Histidine Triad Nucleotide Binding Protein 1 (HINT1) is a highly conserved protein that belongs to the histidine triad superfamily. This family is characterized by the presence of a histidine triad motif (His-X-His-X-His-X, where X is a hydrophobic amino acid) which is crucial for its function . HINT1 is involved in various biological processes and has been studied for its potential therapeutic applications.
HINT1 is a small protein with a molecular mass of approximately 13.8 kDa . It hydrolyzes purine nucleotide phosphoramidates substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2 . The protein interacts with these substrates via its histidine triad motif, which is essential for its enzymatic activity .
HINT1 has been implicated in several biological pathways and processes:
- Tumor Suppression: HINT1 is considered a tumor suppressor gene. Loss of HINT1 function increases susceptibility to carcinogenesis in mice .
- Neurological Functions: HINT1 plays important roles in diverse neuropsychiatric diseases, including schizophrenia, mood disorders, drug addiction, and inherited peripheral neuropathies .
- Liver Fibrosis: Recombinant human HINT1 (rhHint1) has been shown to attenuate liver fibrosis induced by carbon tetrachloride (CCl4) in rats. This effect is achieved by inhibiting the TGF-β/Smad and Wnt/β-catenin signaling pathways .
