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Gene Review

CA2  -  carbonic anhydrase II

Homo sapiens

Synonyms: CA-II, CAC, CAII, Car2, Carbonate dehydratase II, ...
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Disease relevance of CA2


Psychiatry related information on CA2

  • Quantitative study of neurofibrillary tangles in subdivisions of the hippocampus. CA2 as a special area in normal aging and senile dementia of the Alzheimer type [7].
  • The decreased density of GAD(65) mRNA-positive neurons in subjects with bipolar disorder was significant in sectors CA2/3 and dentate gyrus, and that of GAD(67) mRNA-positive neurons was significant in CA4, but not other hippocampal sectors [8].
  • Synapse loss was most strongly correlated with dementia when it occurred in the molecular layers of the dentate fasciculus and stratum lacunosum, CA2/3, and CA4; synapse loss in these subregions appeared significantly clustered on factor analysis [9].
  • The amnesia was very severe for both old and newly acquired memories and the critical lesions defined by MRI were circumscribed areas confined to CA1 and CA2 fields of both hippocampi [10].
  • Recessive mixed proximal-distal RTA accompanied by osteopetrosis and mental retardation is associated with mutations in cytoplasmic carbonic anhydrase II [11].

High impact information on CA2


Chemical compound and disease context of CA2


Biological context of CA2


Anatomical context of CA2


Associations of CA2 with chemical compounds

  • Here, we present evidence that CA II in red cell lysates can be quantitated by measuring CO2 hydratase activity in the presence of inhibitors that selectively inhibit the activity of CA I to a much greater extent than that of CA II [2].
  • The CA activity in membrane fractions of normal urine was found to comprise two components--(i) a vesicle-enclosed, sodium dodecyl sulfate (SDS)-sensitive fraction, which was shown immunochemically to be the 29-kDa CA II, and (ii) an SDS-resistant fraction, which was due to native and cleaved forms of the 35-kDa, membrane-anchored isozyme CA IV [1].
  • A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers [21].
  • The valproyl derivative of acetazolamide (5-valproylamido-1,3,4-thiadiazole-2-sulfonamide, 6M) was one of the best hCA I and hCA II inhibitor in the series and exhibited very strong anticonvulsant properties in an MES test in mice [24].
  • Finally, the affinity of CA IV for sulfonamide inhibitors is decreased up to 65-fold compared to CA II as demonstrated by fluorescence titration [3].
  • If the H(+) gradient was set to dominate the rate of lactate transport by applying low concentrations of lactate at a high H(+) concentration, the effect of CAII was largest [25].

Physical interactions of CA2

  • Here, we report the X-ray crystal structures of three novel thieno[3,2-e]-1,2-thiazine-6-sulfonamides complexed with CAII and the computationally predicted structures of the same compounds complexed with CAIV [26].
  • First crystal structures of human carbonic anhydrase II in complex with dual aromatase-steroid sulfatase inhibitors [27].
  • A novel carbonic anhydrase II binding site regulates NHE1 activity [28].
  • A significant correlation between the magnitude of CAII binding and kNBC1-mediated flux was shown [29].
  • However, DRA differs from other bicarbonate transport proteins because its transport activity is not stimulated by direct interaction with CAII [14].

Regulatory relationships of CA2

  • NBC1-mediated pH(i) recovery rate after acid load was inhibited by 40 +/- 7% when coexpressed with the inactive human CAII mutant, V143Y [30].
  • AE1 activity was maximally inhibited 61 +/- 4% in the presence of V143Y CAII [21].
  • Our study suggests that NHE1 transport efficiency is influenced by CAII, likely through a direct interaction at the C-terminal region [31].
  • The release of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) by human monocytes stimulated with whole heat-killed Candida albicans CA3 (a clinical isolate) and CA2 (a germ tube-negative mutant) either treated or not treated with amphotericin B was investigated [32].
  • CA II immunoreactivity was not detected in untreated controls but appeared after 2 days of TNF-alpha exposure, peaking on day 6 [33].

Other interactions of CA2

  • The surface epithelium of the colon contained both CA I and CA II [22].
  • CA IV activity and immunoreactivity were present in normal amounts in urinary membranes from CA II-deficient patients [1].
  • The finding of this silent allelic polymorphism together with the finding of an electrophoretically detectable polymorphism of CA II permits us to test the linkage of the CA II and CA III genes which appear to have been formed by gene duplication more than 300 million years ago [34].
  • The hypoxia-ischemia group showed decreased MAP2 immunostaining in the hippocampal areas CA2-CA4 (P<0.05) and in cortical layers II-VI (P<0.001) compared to controls [35].
  • Some of these compounds showed excellent inhibitory properties against isozymes I, II, and IX, with several inhibitors also presenting selectivity for the inhibition of CA IX over that of the ubiquitous isozyme CA II [36].

Analytical, diagnostic and therapeutic context of CA2


  1. Carbonic anhydrase isozymes IV and II in urinary membranes from carbonic anhydrase II-deficient patients. Sato, S., Zhu, X.L., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  2. Carbonic anhydrase II deficiency: diagnosis and carrier detection using differential enzyme inhibition and inactivation. Sundaram, V., Rumbolo, P., Grubb, J., Strisciuglio, P., Sly, W.S. Am. J. Hum. Genet. (1986) [Pubmed]
  3. Catalysis and inhibition of human carbonic anhydrase IV. Baird, T.T., Waheed, A., Okuyama, T., Sly, W.S., Fierke, C.A. Biochemistry (1997) [Pubmed]
  4. Carbonic anhydrase II in the cerebrospinal fluid: its value as a disease marker. Parkkila, A.K., Parkkila, S., Reunanen, M., Niemelä, O., Tuisku, S., Rautakorpi, I., Rajaniemi, H. Eur. J. Clin. Invest. (1997) [Pubmed]
  5. Evaluation of carbonic anhydrase isozymes in disorders involving osteopetrosis and/or renal tubular acidosis. Sly, W.S., Sato, S., Zhu, X.L. Clin. Biochem. (1991) [Pubmed]
  6. Carbonic anhydrase II in the endothelium of glial tumors: a potential target for therapy. Haapasalo, J., Nordfors, K., Järvelä, S., Bragge, H., Rantala, I., Parkkila, A.K., Haapasalo, H., Parkkila, S. Neuro-oncology (2007) [Pubmed]
  7. Quantitative study of neurofibrillary tangles in subdivisions of the hippocampus. CA2 as a special area in normal aging and senile dementia of the Alzheimer type. Mizutani, T., Shimada, H. Acta Pathol. Jpn. (1991) [Pubmed]
  8. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Heckers, S., Stone, D., Walsh, J., Shick, J., Koul, P., Benes, F.M. Arch. Gen. Psychiatry (2002) [Pubmed]
  9. Hippocampal connectivity and Alzheimer's dementia: effects of synapse loss and tangle frequency in a two-component model. Samuel, W., Masliah, E., Hill, L.R., Butters, N., Terry, R. Neurology (1994) [Pubmed]
  10. Bilateral lesions of CA1 and CA2 fields of the hippocampus are sufficient to cause a severe amnesic syndrome in humans. Kartsounis, L.D., Rudge, P., Stevens, J.M. J. Neurol. Neurosurg. Psychiatr. (1995) [Pubmed]
  11. Genetic diseases of acid-base transporters. Alper, S.L. Annu. Rev. Physiol. (2002) [Pubmed]
  12. Catalysis by metal-activated hydroxide in zinc and manganese metalloenzymes. Christianson, D.W., Cox, J.D. Annu. Rev. Biochem. (1999) [Pubmed]
  13. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Sly, W.S., Whyte, M.P., Sundaram, V., Tashian, R.E., Hewett-Emmett, D., Guibaud, P., Vainsel, M., Baluarte, H.J., Gruskin, A., Al-Mosawi, M. N. Engl. J. Med. (1985) [Pubmed]
  14. The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II. Sterling, D., Brown, N.J., Supuran, C.T., Casey, J.R. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  15. Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia. Wiard, R.P., Dickerson, M.C., Beek, O., Norton, R., Cooper, B.R. Stroke (1995) [Pubmed]
  16. Ischemia-induced neuronal cell loss is associated with loss of atypical angiotensin type-1 receptor expression in the gerbil hippocampal formation. Häuser, W., Jöhren, O., de Oliveira, A.M., Shibata, S., Saavedra, J.M. Brain Res. (1999) [Pubmed]
  17. Effects of memantine on synaptic transmission in the hippocampus in vitro. Dimpfel, W. Arzneimittel-Forschung. (1995) [Pubmed]
  18. Inhibition by anions of human red cell carbonic anhydrase B: physiological and biochemical implications. Maren, T.H., Rayburn, C.S., Liddell, N.E. Science (1976) [Pubmed]
  19. The gene for human carbonic anhydrase II (CA2) is located at chromosome 8q22. Nakai, H., Byers, M.G., Venta, P.J., Tashian, R.E., Shows, T.B. Cytogenet. Cell Genet. (1987) [Pubmed]
  20. Proficiency in interscalene anesthesia-how many blocks are necessary? Rosenblatt, M.A., Fishkind, D. Journal of clinical anesthesia. (2003) [Pubmed]
  21. A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers. Sterling, D., Reithmeier, R.A., Casey, J.R. J. Biol. Chem. (2001) [Pubmed]
  22. Amount and distribution of carbonic anhydrases CA I and CA II in the gastrointestinal tract. Lönnerholm, G., Selking, O., Wistrand, P.J. Gastroenterology (1985) [Pubmed]
  23. Membrane-bound carbonic anhydrase IV is expressed in the luminal plasma membrane of the human gallbladder epithelium. Parkkila, S., Parkkila, A.K., Juvonen, T., Waheed, A., Sly, W.S., Saarnio, J., Kaunisto, K., Kellokumpu, S., Rajaniemi, H. Hepatology (1996) [Pubmed]
  24. Carbonic anhydrase inhibitors: anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties. Masereel, B., Rolin, S., Abbate, F., Scozzafava, A., Supuran, C.T. J. Med. Chem. (2002) [Pubmed]
  25. Nonenzymatic proton handling by carbonic anhydrase II during H+-lactate cotransport via monocarboxylate transporter 1. Becker, H.M., Deitmer, J.W. J. Biol. Chem. (2008) [Pubmed]
  26. Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV. Kim, C.Y., Whittington, D.A., Chang, J.S., Liao, J., May, J.A., Christianson, D.W. J. Med. Chem. (2002) [Pubmed]
  27. First crystal structures of human carbonic anhydrase II in complex with dual aromatase-steroid sulfatase inhibitors. Lloyd, M.D., Thiyagarajan, N., Ho, Y.T., Woo, L.W., Sutcliffe, O.B., Purohit, A., Reed, M.J., Acharya, K.R., Potter, B.V. Biochemistry (2005) [Pubmed]
  28. A novel carbonic anhydrase II binding site regulates NHE1 activity. Li, X., Liu, Y., Alvarez, B.V., Casey, J.R., Fliegel, L. Biochemistry (2006) [Pubmed]
  29. Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal tubule cells. Pushkin, A., Abuladze, N., Gross, E., Newman, D., Tatishchev, S., Lee, I., Fedotoff, O., Bondar, G., Azimov, R., Ngyuen, M., Kurtz, I. J. Physiol. (Lond.) (2004) [Pubmed]
  30. Direct extracellular interaction between carbonic anhydrase IV and the human NBC1 sodium/bicarbonate co-transporter. Alvarez, B.V., Loiselle, F.B., Supuran, C.T., Schwartz, G.J., Casey, J.R. Biochemistry (2003) [Pubmed]
  31. Carbonic anhydrase II binds to and enhances activity of the Na+/H+ exchanger. Li, X., Alvarez, B., Casey, J.R., Reithmeier, R.A., Fliegel, L. J. Biol. Chem. (2002) [Pubmed]
  32. Preincubation of Candida albicans strains with amphotericin B reduces tumor necrosis factor alpha and interleukin-6 release by human monocytes. Raponi, G., Ghezzi, M.C., Mancini, C., Filadoro, F. Antimicrob. Agents Chemother. (1993) [Pubmed]
  33. Differentiation of pancreatic ductal carcinoma cells associated with selective expression of protein kinase C isoforms. Franz, M.G., Norman, J.G., Fabri, P.J., Gower, W.R. Ann. Surg. Oncol. (1996) [Pubmed]
  34. A widespread silent polymorphism of human carbonic anhydrase III (31 Ile in equilibrium Val): implications for evolutionary genetics. Hewett-Emmett, D., Welty, R.J., Tashian, R.E. Genetics (1983) [Pubmed]
  35. Microtubule-associated protein 2 (MAP2)--a promising approach to diagnosis of forensic types of hypoxia-ischemia. Kühn, J., Meissner, C., Oehmichen, M. Acta Neuropathol. (2005) [Pubmed]
  36. Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating thioureido-sulfanilyl scaffolds. Puccetti, L., Fasolis, G., Cecchi, A., Winum, J.Y., Gamberi, A., Montero, J.L., Scozzafava, A., Supuran, C.T. Bioorg. Med. Chem. Lett. (2005) [Pubmed]
  37. DNA polymorphism in the 5' flanking region of the human carbonic anhydrase II gene on chromosome 8. Lee, B.L., Venta, P.J., Tashian, R.E. Hum. Genet. (1985) [Pubmed]
  38. Carbonic anhydrase isoenzyme II is located in corticotrophs of the human pituitary gland. Parkkila, A.K., Parkkila, S., Rajaniemi, H. J. Histochem. Cytochem. (1996) [Pubmed]
  39. Gene expression for carbonic anhydrase isoenzymes in human nasal mucosa. Tarun, A.S., Bryant, B., Zhai, W., Solomon, C., Shusterman, D. Chem. Senses (2003) [Pubmed]
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