acid anhydride hydrolases


Summary: A group of enzymes that catalyze the hydrolysis of diphosphate bonds in compounds such as nucleoside di- and tri-phosphates, and sulfonyl-containing anhydrides such as adenylylsulfate. (Enzyme Nomenclature, 1992) EC 3.6.

Top Publications

  1. D Agostini F, Izzotti A, Balansky R, Zanesi N, Croce C, De Flora S. Early loss of Fhit in the respiratory tract of rodents exposed to environmental cigarette smoke. Cancer Res. 2006;66:3936-41 pubmed
    ..In conclusion, there is unequivocal evidence that Fhit is an early, critical target in smoke-related lung carcinogenesis in rodents, and that certain chemopreventive agents can attenuate the occurrence of this gene alteration. ..
  2. Balansky R, D Agostini F, Ganchev G, Izzotti A, Di Marco B, Lubet R, et al. Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: chemoprevention by budesonide and N-acetylcysteine. Proc Natl Acad Sci U S A. 2006;103:7823-8 pubmed
    ..In conclusion, heterozygosity for FHIT affects susceptibility of mice to spontaneous alopecia areata and B[a]P-induced preneoplastic lesions of the uterus and does not alter responsiveness to budesonide and NAC. ..
  3. Benarroch D, Smith P, Shuman S. Characterization of a trifunctional mimivirus mRNA capping enzyme and crystal structure of the RNA triphosphatase domain. Structure. 2008;16:501-12 pubmed publisher
    ..The mimivirus TTM-type RTPase-GTase fusion resembles the capping enzymes of amoebae, providing evidence that the ancestral large DNA virus acquired its capping enzyme from a unicellular host. ..
  4. Lee E, Lee B, Kim J, Shim Y, Hoseok I, Han J, et al. Aberrant methylation of Fragile Histidine Triad gene is associated with poor prognosis in early stage esophageal squamous cell carcinoma. Eur J Cancer. 2006;42:972-80 pubmed
    ..Our study suggests that FHIT promoter methylation may be an independent prognostic biomarker in early stage esophageal squamous cell carcinoma. ..
  5. Karpe Y, Lole K. RNA 5'-triphosphatase activity of the hepatitis E virus helicase domain. J Virol. 2010;84:9637-41 pubmed publisher
    ..It is suggested that HEV employs the helicase to mediate the first step of 5' cap synthesis...
  6. Hu B, Wang H, Wang X, Lu H, Huang C, Powell S, et al. Fhit and CHK1 have opposing effects on homologous recombination repair. Cancer Res. 2005;65:8613-6 pubmed
  7. Bianchi F, Tagliabue E, Menard S, Campiglio M. Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections. Cell Cycle. 2007;6:643-6 pubmed
    ..These tumor-free at twenty months twenty months. findings suggest a protective role for FHIT in HER2-driven mammary tumors. Together, these data argue for the cooperation between Fhit and HER2 in breast carcinogenesis. ..
  8. Cantor J, Iliopoulos D, Rao A, Druck T, Semba S, Han S, et al. Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity. Int J Cancer. 2007;120:24-31 pubmed
    ..These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses. ..
  9. Sun J, Okumura H, Yearsley M, Frankel W, Fong L, Druck T, et al. Nit1 and Fhit tumor suppressor activities are additive. J Cell Biochem. 2009;107:1097-106 pubmed publisher
    ..The relevance of Nit1 deficiency to human cancers was examined in human esophageal cancer tissues, and loss of Nit1 expression was observed in 48% of esophageal adenocarcinomas. ..

More Information


  1. Kristensen O, Ross B, Gajhede M. Structure of the PPX/GPPA phosphatase from Aquifex aeolicus in complex with the alarmone ppGpp. J Mol Biol. 2008;375:1469-76 pubmed publisher
    ..The arginines R22 and R267, residing in different domains, are crucial for guanosine pentaphosphate specificity as they interact with the unique 3'-ribose phosphorylation...
  2. Chan K, Palmai Pallag T, Ying S, Hickson I. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol. 2009;11:753-60 pubmed publisher
    ..Our data have general implications concerning the contribution of fragile site loci to chromosomal instability and tumorigenesis. ..
  3. Shears S, Weaver J, Wang H. Structural insight into inositol pyrophosphate turnover. Adv Biol Regul. 2013;53:19-27 pubmed publisher
    ..This work includes the analysis of crystal complexes with substrates, products, transition state analogs, and a novel phosphonoacetate substrate analog. ..
  4. Yanagawa N, Osakabe M, Hayashi M, Tamura G, Motoyama T. Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas. Virchows Arch. 2008;452:377-82 pubmed publisher
    ..Methylation of FHIT gene was frequently found than HPV infection, therefore methylation of the FHIT gene is suggested to play an important role in the pathogenesis of penile squamous cell carcinoma. ..
  5. Zanesi N, Pekarsky Y, Croce C. A mouse model of the fragile gene FHIT: From carcinogenesis to gene therapy and cancer prevention. Mutat Res. 2005;591:103-9 pubmed
    ..Insights into Fhit mouse genetics that have emerged in the last 7 years, and are reviewed in the present article, allowed for development of new tools in carcinogenesis and gene delivery studies. ..
  6. Bougie I, Bisaillon M. Inhibition of a metal-dependent viral RNA triphosphatase by decavanadate. Biochem J. 2006;398:557-67 pubmed
    ..Taken together, these studies provide crucial insights into the inhibition of metal-dependent RNA triphosphatases by decavanadate. ..
  7. Pichiorri F, Okumura H, Nakamura T, Garrison P, Gasparini P, Suh S, et al. Correlation of fragile histidine triad (Fhit) protein structural features with effector interactions and biological functions. J Biol Chem. 2009;284:1040-9 pubmed publisher
  8. Fisher D, McLennan A. Correlation of intracellular diadenosine triphosphate (Ap3A) with apoptosis in Fhit-positive HEK293 cells. Cancer Lett. 2008;259:186-91 pubmed
    ..510pmol/10(6)cells with etoposide. These results support the view that Ap3A is the in vivo Fhit ligand and that an inhibition of Fhit activity is a key element in Fhit-mediated apoptosis. ..
  9. Hsu H, Chen T, Hung C, Wen C, Lin R, Lee H, et al. Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma. Cancer. 2007;110:2019-26 pubmed
    ..This methylation marker panel should improve the detection of cancer or the risk assessment for lung cancer in combination with conventional diagnostic tools. ..
  10. Bekar A, Cecener G, Tunca B, Guler G, Egeli U, Tolunay S. Investigation of mutations and expression of the FHIT gene in Turkish patients with brain metastases derived from non-small cell lung cancer. Tumori. 2007;93:604-7 pubmed
    ..Furthermore, it is not known whether the FHIT gene has a role in the formation of brain metastases...
  11. Neyaz M, Hussain S, Hassan M, Das B, Husain S, Bharadwaj M. Novel missense mutation in FHIT gene: interpreting the effect in HPV-mediated cervical cancer in Indian women. Mol Cell Biochem. 2010;335:53-8 pubmed publisher
    ..We predict that this change, His to Arg substitution in substrate-binding domain may generate catalytically inactive protein with loss of tumor suppressor activity. ..
  12. Thayil S, Morrison N, Schechter N, Rubin H, Karakousis P. The role of the novel exopolyphosphatase MT0516 in Mycobacterium tuberculosis drug tolerance and persistence. PLoS ONE. 2011;6:e28076 pubmed publisher
    ..We conclude that exopolyphosphatase is required for long-term survival of M. tuberculosis in necrotic lung lesions...
  13. Semba S, Han S, Qin H, McCorkell K, Iliopoulos D, Pekarsky Y, et al. Biological functions of mammalian Nit1, the counterpart of the invertebrate NitFhit Rosetta stone protein, a possible tumor suppressor. J Biol Chem. 2006;281:28244-53 pubmed
  14. Saldivar J, Shibata H, Huebner K. Pathology and biology associated with the fragile FHIT gene and gene product. J Cell Biochem. 2010;109:858-65 pubmed publisher
    ..These questions are considered in light of recent investigations of genetic and epigenetic alterations to the locus and in a retrospective consideration of biological roles of the Fhit protein discovered through functional studies. ..
  15. Semba S, Trapasso F, Fabbri M, McCorkell K, Volinia S, Druck T, et al. Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Oncogene. 2006;25:2860-72 pubmed
    ..The results indicate that the Fhit Y114 residue plays a critical role in Fhit-induced apoptosis, occurring through inactivation of the PI3K-Akt-survivin signal pathway. ..
  16. Yin D, Wang L, Sun J, Yin F, Yan Q, Shen R, et al. Association of the promoter methylation and protein expression of Fragile Histidine Triad (FHIT) gene with the progression of differentiated thyroid carcinoma. Int J Clin Exp Pathol. 2010;3:482-91 pubmed
    ..Our results suggest that methylation of the promoter region may play a key role in inactivation of FHIT - possibly leading to subsequent carcinogenesis and progression of DTC. ..
  17. Song X, Tian Z, Wang S, Peng Z, Feng J. Restoration of fragile histidine triad (FHIT) expression inhibits cell growth and induces apoptosis in cutaneous T-cell lymphoma cell line. Cancer Invest. 2010;28:1019-23 pubmed publisher
    ..Tumor formation in vivo was strongly suppressed by FHIT gene restoration. Our data demonstrate restoration of FHIT gene expression inhibit the tumor cell growth and provide an option for the treatment. ..
  18. Guidi E, Uboldi C, Ferretti L. Molecular analysis of the fragile histidine triad (FHIT) tumor suppressor gene in vesical tumors of cattle with chronic enzootic hematuria (CEH). Cytogenet Genome Res. 2008;120:173-7 pubmed publisher
  19. Pichiorri F, Trapasso F, Palumbo T, Aqeilan R, Drusco A, Blaser B, et al. Preclinical assessment of FHIT gene replacement therapy in human leukemia using a chimeric adenovirus, Ad5/F35. Clin Cancer Res. 2006;12:3494-501 pubmed
    ..FHIT restoration in some FHIT-deficient leukemia cells induces both antiproliferative and proapoptotic effects involving the intrinsic caspase apoptotic pathway. ..
  20. Ugochukwu E, Lovering A, Mather O, Young T, White S. The crystal structure of the cytosolic exopolyphosphatase from Saccharomyces cerevisiae reveals the basis for substrate specificity. J Mol Biol. 2007;371:1007-21 pubmed
    ..Structural comparisons with the inorganic pyrophosphatases and analysis of the ligand-bound complexes lead us to propose a hydrolysis mechanism. Finally, we discuss a structural basis for substrate selectivity and processivity. ..
  21. Di Meo G, Perucatti A, Uboldi C, Roperto S, Incarnato D, Roperto F, et al. Comparative mapping of the fragile histidine triad (FHIT) gene in cattle, river buffalo, sheep and goat by FISH and assignment to BTA22 by RH-mapping: a comparison with HSA3. Anim Genet. 2005;36:363-4 pubmed
  22. Neyaz M, Kumar R, Hussain S, Naqvi S, Kohaar I, Thakur N, et al. Effect of aberrant promoter methylation of FHIT and RASSF1A genes on susceptibility to cervical cancer in a North Indian population. Biomarkers. 2008;13:597-606 pubmed publisher
    ..Future studies are underway to examine the practical implications of these findings for use as a biomarker. ..
  23. Arun B, Kilic G, Yen C, Foster B, Yardley D, Gaynor R, et al. Loss of FHIT expression in breast cancer is correlated with poor prognostic markers. Cancer Epidemiol Biomarkers Prev. 2005;14:1681-5 pubmed
    ..Furthermore, loss of FHIT expression is also seen in metastatic axillary lymph node. The prognostic and predictive value of these findings needs to be further evaluated in larger trials with longer follow-up. ..
  24. Hassan M, Naiyer A, Ahmad F. Fragile histidine triad protein: structure, function, and its association with tumorogenesis. J Cancer Res Clin Oncol. 2010;136:333-50 pubmed publisher
    ..Here we have gathered information is known about biological activities of FHIT, the structural and biochemical bases for their functions. Our approach may provide a comparative framework for further investigation of FHIT. ..
  25. Saito K, Ohtomo R, Kuga Uetake Y, Aono T, Saito M. Direct labeling of polyphosphate at the ultrastructural level in Saccharomyces cerevisiae by using the affinity of the polyphosphate binding domain of Escherichia coli exopolyphosphatase. Appl Environ Microbiol. 2005;71:5692-701 pubmed
  26. Fang J, Ruiz F, Docampo M, Luo S, Rodrigues J, Motta L, et al. Overexpression of a Zn2+-sensitive soluble exopolyphosphatase from Trypanosoma cruzi depletes polyphosphate and affects osmoregulation. J Biol Chem. 2007;282:32501-10 pubmed
    ..This was accompanied by a delayed regulatory volume decrease after hyposmotic stress. These results support the role of poly P in T. cruzi osmoregulation. ..
  27. Levin A, Ray A, Zuhlke K, Douglas J, Cooney K. Association between germline variation in the FHIT gene and prostate cancer in Caucasians and African Americans. Cancer Epidemiol Biomarkers Prev. 2007;16:1294-7 pubmed
  28. Xiao Y, Wu D, Xu L, Xin Y. Loss of heterozygosity and microsatellite instabilities of fragile histidine triad gene in gastric carcinoma. World J Gastroenterol. 2006;12:3766-9 pubmed
    ..3%, P < 0.05). LOH of FHIT gene is correlated with invasive depth of gastric carcinoma. MSI of FHIT gene is correlated with lymph node metastases. LOH and MSI of FHIT gene play an important role in carcinogenesis of gastric cancer. ..
  29. Benzaghou I, Bougie I, Picard Jean F, Bisaillon M. Energetics of RNA binding by the West Nile virus RNA triphosphatase. FEBS Lett. 2006;580:867-77 pubmed publisher
    ..Our data indicate that the protein undergoes structural modifications upon RNA binding, although the interaction does not significantly modify the stability of the protein...
  30. McCorkell K, Mancini R, Siprashvili Z, Barnoski B, Iliopoulos D, Siracusa L, et al. Influence of a nonfragile FHIT transgene on murine tumor susceptibility. Cytogenet Genome Res. 2007;118:196-203 pubmed
    ..It is likely that the FHIT transgene is more tightly silenced in female transgenic mice, leading to a lack of protection from tumor induction. ..
  31. Chou T, Sham Y, Wagner C. Impact of the C-terminal loop of histidine triad nucleotide binding protein1 (Hint1) on substrate specificity. Biochemistry. 2007;46:13074-9 pubmed
    ..coli or human lysyl-tRNA synthetase were partially transferable by C-terminal loop exchange. Hence, our results support the critical role of the C-terminal loop of human and E. coli Hint1 on governing substrate specificity. ..
  32. Huebner K, Saldivar J, Sun J, Shibata H, Druck T. Hits, Fhits and Nits: beyond enzymatic function. Adv Enzyme Regul. 2011;51:208-17 pubmed publisher
  33. Liu H, Peng Z, Wang H, Liu S, Zhang C, Tang Q, et al. [Study on the relationship between LOH and MI of FHIT gene and the development of cervical carcinoma]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005;36:506-9 pubmed
    ..The detection of the LOH of FHIT gene might be helpful to the early diagnosis and the screening of cervical carcinoma. It might also be useful for predicting the prognosis of cervical carcinoma. ..
  34. Lu L, Hu B, Yu F, Wang Y. Low dose radiation-induced adaptive response preventing HPRT mutation is Fhit independent. Int J Radiat Biol. 2009;85:532-7 pubmed publisher
    ..Fhit prevents IR-induced HPRT mutation and preventing mutation through low dose of IR-induced adaptive response is Fhit independent. ..
  35. Roa S J, GarcĂ­a M P, Melo A A, Tapia E O, Villaseca H M, Araya O J, et al. [Gene methylation patterns in digestive tumors]. Rev Med Chil. 2008;136:451-8 pubmed publisher
    ..07) y CDKN2A (p= 0.06) were methylated, respectively. An abnormal methylation pattern was associated with morphological features in gastric and gallbladder cancer and with a tendency towards a lower survival in colon and gastric cancer. ..
  36. Bardaweel S, Pace J, Chou T, Cody V, Wagner C. Probing the impact of the echinT C-terminal domain on structure and catalysis. J Mol Biol. 2010;404:627-38 pubmed publisher
    ..Taken together, our results highlight the emerging role of the C-terminus in governing the catalytic function of Hints. ..
  37. Strickler S, Gribenko A, Gribenko A, Keiffer T, Tomlinson J, Reihle T, et al. Protein stability and surface electrostatics: a charged relationship. Biochemistry. 2006;45:2761-6 pubmed
  38. Zanesi N, Mancini R, Sevignani C, Vecchione A, Kaou M, Valtieri M, et al. Lung cancer susceptibility in Fhit-deficient mice is increased by Vhl haploinsufficiency. Cancer Res. 2005;65:6576-82 pubmed
  39. Rimessi A, Marchi S, Fotino C, Romagnoli A, Huebner K, Croce C, et al. Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis. Proc Natl Acad Sci U S A. 2009;106:12753-8 pubmed publisher
    ..This concept, and the identification of the molecular machinery, may provide ways to act on apoptotic cell death and its derangement in cancer. ..
  40. D Arca D, Lenoir J, Wildemore B, Gottardo F, Bragantini E, Shupp Byrne D, et al. Prevention of urinary bladder cancer in the FHIT knock-out mouse with Rofecoxib, a Cox-2 inhibitor. Urol Oncol. 2010;28:189-94 pubmed publisher
    ..003). These findings suggest that rofecoxib provides a therapeutic defense against bladder carcinogenesis in our model and confirmed that the FHIT knock-out mouse is a suitable system to study in vivo bladder carcinogenesis. ..
  41. Becker K, Goldberg M, Helmbold P, Holbach L, Loeffler K, Ballhausen W. Deletions of BRCA1/2 and p53 R248W gain-of-function mutation suggest impaired homologous recombination repair in fragile histidine triad-negative sebaceous gland carcinomas. Br J Dermatol. 2008;159:1282-9 pubmed publisher
    ..However, a significant fraction of periocular sebaceous gland carcinomas exhibits microsatellite stability associated with a frequent loss of the candidate tumour suppressor fragile histidine triad (FHIT)...
  42. Gaudio E, Paduano F, Spizzo R, Ngankeu A, Zanesi N, Gaspari M, et al. Fhit delocalizes annexin a4 from plasma membrane to cytosol and sensitizes lung cancer cells to paclitaxel. PLoS ONE. 2013;8:e78610 pubmed publisher
    ..Moreover, paclitaxel administration in combination with AdFHIT acts synergistically to increase the apoptotic rate of tumor cells both in vitro and in vivo experiments. ..
  43. Massayuki Kikuti C, Tersariol I, Schenkman S. Divalent metal requirements for catalysis and stability of the RNA triphosphatase from Trypanosoma cruzi. Mol Biochem Parasitol. 2006;150:83-95 pubmed
    ..cruzi enzyme, while the T. brucei homologue remains stable in the absence of metal, as shown for other triphosphatases. These findings may be useful to devise specific triphosphatase inhibitors to the T. cruzi enzyme. ..
  44. Pichiorri F, Palumbo T, Suh S, Okamura H, Trapasso F, Ishii H, et al. Fhit tumor suppressor: guardian of the preneoplastic genome. Future Oncol. 2008;4:815-24 pubmed publisher
  45. Guerin L, Hoffman H, Zimmerman M, Robinson R. Decreased fragile histidine triad gene protein expression is associated with worse prognosis in oral squamous carcinoma. Arch Pathol Lab Med. 2006;130:158-64 pubmed
    ..Because genomic alterations involving loss of heterozygosity of the FHIT gene were not associated with protein expression in these tumors, the presence or absence of FHIT expression may be controlled by other factors. ..
  46. Zhang Q, Li Y, Tang C. The role of the exopolyphosphatase PPX in avoidance by Neisseria meningitidis of complement-mediated killing. J Biol Chem. 2010;285:34259-68 pubmed publisher
    ..Instead, expression of PPX modifies the interaction of N. meningitidis with the alternative pathway of complement activation...
  47. Paluszczak J, Misiak P, Wierzbicka M, Wozniak A, Baer Dubowska W. Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa. Oral Oncol. 2011;47:104-7 pubmed publisher
    ..Moreover, evidence is shown for the occurrence of a large epigenetically changed field of epithelial cells in laryngeal cancer patients. Our findings indicate the high prevalence of epigenetic abnormalities in laryngeal tumors. ..
  48. Goldberg M, Rummelt C, Foja S, Holbach L, Ballhausen W. Different genetic pathways in the development of periocular sebaceous gland carcinomas in presumptive Muir-Torre syndrome patients. Hum Mutat. 2006;27:155-62 pubmed
    ..Our data suggest that either somatic inactivation of the FHIT gene associated with MSS or inactivation of the MMR system resulting in MSI contribute to the development of periocular SGCs in presumptive MTS. ..
  49. Joannes A, Bonnomet A, Bindels S, Polette M, Gilles C, Burlet H, et al. Fhit regulates invasion of lung tumor cells. Oncogene. 2010;29:1203-13 pubmed publisher
    ..These results show that Fhit controls the invasive phenotype of lung tumor cells by regulating the expression of genes associated with epithelial-mesenchymal transition. ..
  50. Letessier A, Millot G, Koundrioukoff S, Lachages A, Vogt N, Hansen R, et al. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature. 2011;470:120-3 pubmed publisher
    ..Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates...
  51. Kim J, Kim J, Han J, Shim Y, Park J, Kim D. Cohypermethylation of p16 and FHIT promoters as a prognostic factor of recurrence in surgically resected stage I non-small cell lung cancer. Cancer Res. 2006;66:4049-54 pubmed
    ..In conclusion, the present study suggests that cohypermethylation of p16 and FHIT genes in patients with stage I NSCLC may be a valuable biomarker for predicting the recurrence-associated prognosis of the disease. ..
  52. Giarnieri E, Zanesi N, Bottoni A, Alderisio M, Lukic A, Vecchione A, et al. Oncosuppressor proteins of fragile sites are reduced in cervical cancer. Cancer Lett. 2010;289:40-5 pubmed publisher
    ..Thus, WWOX may be considered as a novel important genetic marker in cervical cancer and the association between the altered expression of FHIT and WWOX may be a critical event in the progression of this neoplasia. ..