InterPro domain: IPR001310

The Histidine Triad (HIT) motif, His-x-His-x-His-x-x (x, ahydrophobic amino acid) was identified as being highly conserved in a variety of organisms [ 1 ]. Crystal structure of rabbit Hint, purified as an adenosine and AMP-binding protein, showed that proteins in the HITsuperfamily are conserved as nucleotide-binding proteins and that Hint homologues, which are found in all forms of life, are structurally related to Fhit homologues and GalT-related enzymes, which have more restricted phylogenetic profiles [ 2 ]. Hint homologues including rabbit Hint and yeastHnt1 hydrolyse adenosine 5' monophosphoramide substrates such as AMP-NH2 andAMP-lysine to AMP plus the amine product and function as positive regulatorsof Cdk7/Kin28 in vivo [ 3 ]. Fhit homologues are diadenosine polyphosphate hydrolases [ 4 ] and function as tumour suppressors in human and mouse [ 5 ] though the tumour suppressing function of Fhit does not depend on ApppA hydrolysis [ 6 ]. The third branch of the HIT superfamily, which includesGalT homologues, contains a related His-X-His-X-Gln motif and transfersnucleoside monophosphate moieties to phosphorylated second substrates ratherthan hydrolysing them [ 7 ].

1. The HIT protein family: a new family of proteins present in prokaryotes, yeast and mammals. DNA Seq. 3, 177-9
2. Crystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins. Nat. Struct. Biol. 4, 231-8
3. Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1, and Tfb3. J. Biol. Chem. 277, 10852-60
4. Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase. Biochemistry 35, 11529-35
5. Muir-Torre-like syndrome in Fhit-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 97, 4742-7
6. Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit. Proc. Natl. Acad. Sci. U.S.A. 95, 5484-9
7. Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Biochemistry 41, 9003-14