Histidine Triad (HIT) Superfamily

Charles Brenner, Dartmouth Medical School, Lebanon, New Hampshire, USA

Published online: September 2007

DOI: 10.1002/9780470015902.a0020545

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 and deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and carbohydrate metabolism. Four branches of HIT enzymes function as nucleotide hydrolases. These enzymes include homologues and paralogues of histidine triad nucleotide-binding (Hint) protein, fragile histidine triad (Fhit) protein, Aprataxin and scavenger decapping protein (Dcps). One diverse branch of the HIT superfamily contains nucleotide transferases and phosphorylases related to galactose-1-phosphate uridylyltransferase (GalT), AppppA phosphorylase, adenylylsulfate:phosphate adenylyltransferase (APAT), adenosine diphosphate (ADP)-glucose phosphorylase, and Vtc2, the guanosine diphosphate (GDP)-l-galactose phosphorylase. This review provides tools to discern the identities and the probable functions of new HIT enzymes from their sequences.

Keywords: Hint; Fhit; GalT; VTC2; Aprataxin; Dcps

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 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, consisting of or 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, GDP-l-galactose; (d) Aprataxin substrate, 5¢ adenylylated 5¢ phosphorylated DNA; and (e) Dcps substrate, 7-methyl GpppN.
close
 References
    Ahel I, Rass U, El-Khamisy SF et al. (2006) The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature 443: 713–716.
    Barnes LD, Garrison PN, Siprashvili Z et al. (1996) Fhit, a putative tumor suppressor in humans, is a dinucleoside 5¢, 5¢¢¢-P-1,P-3-triphosphate hydrolase. Biochemistry 35: 11529–11535.
    Bieganowski P, Garrison PN, Hodawadekar SC et al. (2002) Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1 and Tfb3. Journal of Biological Chemistry 277: 10852–10860.
    Brenner C (2002) Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Biochemistry 41: 9003–9014.
    Brenner C, Garrison P, Gilmour J et al. (1997) Crystal structures of Hint demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins. Nature Structural Biology 4: 231–238.
    Bruser T, Selmer T and Dahl C (2000) ADP sulfurylase from Thiobacillus denitrificans is an adenylylsulfate:phosphate adenylyltransferase and belongs to a new family of nucleotidyltransferases. Journal of Biological Chemistry 275: 1691–1698.
    Clements PM, Breslin C, Deeks ED et al. (2004) The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. DNA Repair (Amst) 3: 1493–1502.
    Conklin PL, Saracco SA, Norris SR and Last RL (2000) Identification of ascorbic acid-deficient Arabidopsis thaliana mutants. Genetics 154: 847–856.
    Date H, Onodera O, Tanaka H et al. (2001) Early onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nature Genetics 29: 184–188.
    Frey PA (1996) The Leloir pathway: a mechanistic imperative for three enzymes to change the stereochemical configuration of a single carbon in galactose. FASEB Journal 10: 461–470.
    Gu M, Fabrega C, Liu SW et al. (2004) Insights into the structure, mechanism, and regulation of scavenger mRNA decapping activity. Molecular Cell 14: 67–80.
    Ishii H, Vecchione A, Fong LY et al. (2004) Cancer prevention and therapy in a preclinical mouse model: impact of FHIT viruses. Current Gene Therapy 4: 53–63.
    Lee YN, Nechushtan H, Figov N and Razin E (2004) The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of MITF activity in FcepsilonRI-activated mast cells. Immunity 20: 145–151.
    Linster CL, Gomez TA, Christensen KC et al. (2007) Arabidopis VTC2 Encodes GDP-l-galactose phosphorylase, the last unknown enzyme in the Smirnoff-Wheeler Pathway to ascorbic acid in plants. Journal of Biological Chemistry 282: 18879–18885.
    Liu H, Rodgers ND, Jiao X and Kiledjian M (2002) The scavenger mRNA decapping enzyme DcpS is a member of the HIT family of pyrophosphatases. EMBO Journal 21: 4699–4708.
    Luo H, Chan DW, Yang T et al. (2004) A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment. Molecular and Cellular Biology 24: 8356–8365.
    Martin J, Magnino F, Schmidt K et al. (2006) Hint2, a mitochondrial apoptotic sensitizer down-regulated in hepatocellular carcinoma. Gastroenterology 130: 2179–2188.
    McCoy JG, Arabshahi A, Bitto E et al. (2006) Structure and mechanism of an ADP-glucose phosphorylase from Arabidopsis thaliana. Biochemistry 45: 3154–3162.
    Moreira MC, Barbot C, Tachi N et al. (2001) The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nature Genetics 29: 189–193.
    Pace HC, Hodawadekar SC, Draganescu A et al. (2000) Crystal structure of the worm NitFhit Rosetta Stone protein reveals a Nit tetramer binding two Fhit dimers. Current Biology 10: 907–917.
    Parks KP, Seidle H, Wright N et al. (2004) Altered specificity of Hint-W123Q supports a role for Hint inhibition by Asw in avian sex determination. Physiological Genomics 20: 12–14.
    Plateau P, Fromant M, Schmitter JM and Blanquet S (1990) Catabolism of bis(5¢-nucleosidyl) tetraphosphates in Saccharomyces cerevisiae. Journal of Bacteriology 172: 6892–6899.
    Robu ME, Larson JD, Nasevicius A et al. (2007) p53 activation by knockdown technologies. PLoS Genetics 3(5): e78.
    Rubio-Texeira M, Varnum JM, Bieganowski P and Brenner C (2002) Control of dinucleoside polyphosphates by the FHIT-homologous HNT2 gene, adenine biosynthesis and heat shock in Saccharomyces cerevisiae. BMC Molecular Biology 3: 7.
    Seidle HF, Bieganowski P and Brenner C (2005) Disease-associated mutations inactivate AMP-lysine hydrolase activity of Aprataxin. Journal of Biological Chemistry 280: 20927–20931.
    Su T, Suzui M, Wang L et al. (2003) Deletion of histidine triad nucleotide-binding protein 1/PKC-interacting protein in mice enhances cell growth and carcinogenesis. Proceedings of the National Academy of Sciences of the USA 100: 7824–7829.
    Trapasso F, Krakowiak A, Cesari R et al. (2003) Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate-binding. Proceedings of the National Academy of Sciences of the USA 100: 1592–1597.
    Wang Z, Jiao X, Carr-Schmid A and Kiledjian M (2002) The hDcp2 protein is a mammalian mRNA decapping enzyme. Proceedings of the National Academy of Sciences of the USA 99: 12663–12668.
    Weiske J and Huber O (2005) The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF-beta-catenin-mediated transcription. Journal of Cell Science 118: 3117–3129.
 Further Reading
    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.
    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.
    other Calderon FR, Phansalkar AR, Crockett DK, Miller M and Mao R (2007) Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene. Human Mutation [Epub ahead of print].
    Rass U, Ahel I and West SC (2007) Actions of aprataxin in multiple DNA repair pathways. Journal of Biological Chemistry 282(13): 9469–9474.
    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.

Related Sub-Topics:

DNA Damage and Repair | Proteins: Structure, Function, Metabolism | Enzymes: Structure and Action Mechanism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Histidine Triad (HIT) Superfamily
 
How to Cite close
Brenner, Charles(Sep 2007) Histidine Triad (HIT) Superfamily. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020545]