Histidine Triad (HIT) Superfamily


Histidine triad (HIT) enzymes are an ancient superfamily of nucleotide hydrolases and transferases that catalyse mechanistically similar but biologically distinct reactions on nucleotide‐containing substrates in pathways important for cellular growth, apoptosis, deoxyribonucleic acid, ribonucleic acid, vitamin and carbohydrate metabolism. Four branches of HIT enzymes function as nucleotide hydrolases. These enzymes include homologues and paralogues of histidine triad nucleotide‐binding protein, fragile histidine triad protein, APRATAXIN and scavenger decapping protein, which act in various cellular compartments. One diverse branch of the HIT superfamily contains nucleotide transferases and phosphorylases related to galactose‐1‐phosphate uridylyltransferase, AppppA phosphorylase, adenylylsulfate: phosphate adenylyltransferase, adenosine diphosphate‐glucose phosphorylase and VTC2, the guanosine diphosphate‐l‐galactose phosphorylase. This review provides tools to discern the identities and the probable functions of HIT enzymes from their sequences.

Key Concepts:

  • Histidine triad enzymes act on substrates containing a nucleoside monophosphate linked to distinct leaving groups.

  • HINT, FHIT, APRATAXIN and DCPS are HIT hydrolases.

  • GALT and VTC2 are HIT transferases.

  • Particular HIT enzymes are targeted to different cellular compartments to carry out their functions.

  • HIT enzymes remove nucleotide adducts from proteins and DNA and transform low‐molecular‐weight metabolites in cells.


Figure 1.

Catalysis by HIT enzymes. HIT substrates consist of nucleoside monophosphates varying in the base, 2′ substituent (X=OH or H) and leaving group (Y). In the first step, the enzymes form a covalent nucleotidylylated active site His intermediate with the α phosphate of the substrate, releasing the leaving group, YH. In the case of HIT hydrolases (branch 1, 2, 4 and 5 enzymes), the intermediate is hydrolysed to produce the nucleoside monophosphate (product 1). In the case of HIT transferases (branch 3 enzymes), the enzyme transfers the nucleoside monophosphate to a specific second substrate, containing phosphate (Z=O or a phosphate monoester substituent) to form product 2.

Figure 2.

Preferred substrates of HIT enzymes. (a) HINT substrate, AMP‐lysine residue; (b) Fhit substrate, ApppA; (c) GALT substrates, UDP‐glucose and galactose‐1‐phosphate; AppppA phosphorylase substrate, AppppA; APAT substrate, AMP‐SO4; ADP‐glucose phosphorylase substrate, ADP‐glucose; VTC2 substrate, GDPl‐galactose; (d) APRATAXIN substrate, 5′ adenylylated 5′ phosphorylated DNA; and (e) DCPS substrate, 7‐methyl GpppN.



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Further Reading

Bianchi F, Tagliabue E, Ménard S and Campiglio M (2007) Fhit expression protects against HER2‐driven breast tumor development: unraveling the molecular interconnections. Cell Cycle 6(6): 643–646.

Calderon FR, Phansalkar AR, Crockett DK, Miller M and Mao R (2007) Mutation database for the galactose‐1‐phosphate uridyltransferase (GALT) gene. Human Mutation 28(10): 939–943.

Chen N, Walsh MA, Liu Y, Parker R and Song H (2005) Crystal structures of human DcpS in ligand‐free and m7GDP‐bound forms suggest a dynamic mechanism for scavenger mRNA decapping. Journal of Molecular Biology 347(4): 707–718.

Rass U, Ahel I and West SC (2007) Actions of aprataxin in multiple DNA repair pathways. Journal of Biological Chemistry 282(13): 9469–9474.

Wang L, Zhang Y, Li H et al. (2007) Hint1 inhibits growth and activator protein‐1 activity in human colon cancer cells. Cancer Research 67(10): 4700–4708.

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Brenner, Charles(Aug 2014) Histidine Triad (HIT) Superfamily. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020545.pub2]