HINT1 gene

The HINT1 gene (HINT1 stands for: Histidine Triad Nucleotide Binding Protein 1) is a protein-coding gene located on chromosome 5q23.3. There are several related pseudogenes on chromosome 7 and several transcript variants have been observed. An important paralog of this gene is HINT2.

The HINT1 gene encodes a protein that hydrolyzes purine nucleotide phosphoramidate substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl-lysine methyl ester and AMP-NH2. The encoded HINT1 protein interacts with these substrates via a histidine triad motif. The HINT1 gene is considered a tumor suppressor gene. In addition, mutations in this gene can cause autosomal recessive neuromyotonia and axonal neuropathy.

The encoded protein exhibits adenosine 5'-monophosphoramidase activity, hydrolyzes purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'-monophosphoramidate (AMP-NH2) to yield AMP and NH2 (Strom A et al. 2020).

Hydrolyzes adenosine 5'monophosphomorpholidate (AMP-morpholidate) and guanosine 5'monophosphomorpholidate (GMP-morpholidate) (Weiske J et al. 2006).

Hydrolyzes lysyl-AMP (AMP-N-epsilon-(N-alpha-acetyl-lysine methyl ester)) produced by lysine tRNA ligase, as well as Met-AMP, His-AMP and Asp-AMP, lysyl-GMP (GMP-N-epsilon-(N-alpha-acetyl-lysine methyl ester)) and AMP-N-alanine methyl ester.

Hydrolyzes 3-indolepropionic acid acyl adenylate, tryptamine adenosine phosphoramidate monoesters and other fluorogenic purine nucleoside tryptamine phosphoramidates in vitro.

Can also convert adenosine 5'-O-phosphorothioate and guanosine 5'-O-phosphorothioate into the corresponding nucleoside 5'-O-phosphates, simultaneously releasing hydrogen sulfide.

In addition, it functions as a scaffold protein that modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex and by the complex formed with MITF and CTNNB1 (Genovese G et al. 2012).

Modulates p53/TP53 levels and p53/TP53-mediated apoptosis (PubMed:16835243). Modulates proteasomal degradation of target proteins by the E3 ubiquitin-protein ligase complex SCF (SKP2-CUL1-F-box protein).

Also exhibits SUMO-specific isopeptidase activity and deconjugates SUMO1 from RGS17 (Cortés-Montero E et al. 2019). Deconjugates SUMO1 from RANGAP1

Diseases associated with HINT1 include neuromyotonia and axonal neuropathy, autosomal recessive and diseases of the peripheral nervous system. Related pathways include MITF-M-dependent gene expression and remdesivir pathway.

1. Cortés-Montero E et al. (2019) The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease. Antioxid Redox Signal 31:503-520.
2. Genovese G et al. (2012) The tumor suppressor HINT1 regulates MITF and β-catenin transcriptional activity in melanoma cells. Cell Cycle 11:2206-2215.
3. Strom A et al. (2020) Histidine triad nucleotide-binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A. FEBS Lett 594:1497-1505.
4. Weiske J et al. (2006) The histidine triad protein Hint1 triggers apoptosis independent of its enzymatic activity. J Biol Chem 281:27356-27366)