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Gene Review

CA12  -  carbonic anhydrase XII

Homo sapiens

Synonyms: CA-XII, CAXII, Carbonate dehydratase XII, Carbonic anhydrase 12, Carbonic anhydrase XII, ...
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Disease relevance of CA12


High impact information on CA12

  • By using GroEL-containing extracts from a DeltanifHDK strain of A. vinelandii CA12 along with FeMoco, Fe protein, and MgATP, we were able to supply all required proteins and/or factors and obtained a fully active reconstituted E146D nifH MoFe protein [7].
  • We have determined the three-dimensional structure of the extracellular catalytic domain of human CA XII by x-ray crystallographic methods at 1.55-A resolution [8].
  • Purification and kinetic analysis of recombinant CA XII, a membrane carbonic anhydrase overexpressed in certain cancers [9].
  • The catalysis of CO(2) hydration by soluble CA XII has a maximal value of k(cat)/K(m) at 34 microM(-1) small middle dots(-1), which is similar to those of the membrane-associated CA IV and to soluble CA I [9].
  • These observations suggest a role for CA XII in CO(2)/HCO(3)(-) homeostasis in cells in which it is normally expressed [9].

Chemical compound and disease context of CA12

  • A spontaneous mutant derivative of Azotobacter vinelandii CA12 (delta nif HDK), which vanadium-dependent nitrogen fixation is not inhibited by molybdenum (A. vinelandii CARR), grows profusely on BNF-agar containing 1 microM Na2MoO4, alone or supplemented with 1 microM V2O5 [10].

Biological context of CA12

  • We mapped CA12 and CA9 loci to chromosome bands 15q22 and 17q21.2 respectively, regions prone to amplification in some human cancers [1].
  • Additional experiments are needed to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth [1].
  • A series of such aromatic/heterocyclic sulfonamides incorporating 2,3,5,6-tetrafluorobenzoyl-, 2,3,5,6-tetrafluorophenylsulfonyl- and pentafluorophenylureido moieties has been investigated for its interaction with the catalytic domain of the human isozymes hCA IX and hCA XII [11].
  • The newly identified CA IX (previously called MN) and CA XII are related to cell proliferation and oncogenesis [12].
  • Tn5 insertions were obtained in this clone and the mutagenized plasmid was used for marker exchange with A. vinelandii strain CA12 (delta nifHDK) to obtain Tn5 mutants [13].

Anatomical context of CA12


Associations of CA12 with chemical compounds

  • In addition, topiramate and zonisamide were observed to behave as weak hCA XII inhibitors, while zonisamide was an effective hCA IX inhibitor (K(I) of 5.1 nM) [16].
  • The full-length hCA XIV is an enzyme showing a medium-low catalytic activity, quite similar to that of hCA XII, with the following kinetic parameters at 20 degrees C and pH 7.5, for the CO2 hydration reaction: k(cat) = 3.12 x 10(5) s(-1) and k(cat)/K(M) = 3.9 x 10(7) M(-1) s(-1) [16].
  • One study localizes CA XII to the distal nephron, while another places it in proximal tubules and inner medullary collecting ducts; confirmatory studies are needed for CA XII [17].
  • These mutants exhibited a Nif- phenotype in the presence of vanadium, unlike CA12 which was Nif+ on vanadium-containing medium [13].
  • The adenine auxotrophic mutants, which were readily isolated after UV irradiation of C. albicans CA12, were proved to be the segregants of mitotic recombination as they remained as diploid, not hemizygous or haploid, cells and were homozygous for ade2 [18].

Other interactions of CA12

  • Membrane polarity is apical for CAXIV, basolateral for CAXII, and apical and basolateral for CAIV [19].
  • In the epididymal duct, CA XII was detected only in sporadic cells, which also contained CA II, thus suggesting that they are apical mitochondria-rich cells [20].
  • CA XII expression was present in 77 out of 103 (75%) cases and was associated with lower grade (P=0.001), positive estrogen receptor status (P<0.001), and negative epidermal growth factor receptor status (P<0.001) [21].
  • RESULTS: On univariate Cox regression analysis certain markers were statistically significant predictors of survival, namely CA9 (p < 0.00001), p53 (p = 0.0072), gelsolin (p = 0.030), Ki67 (p = 0.036) and CA12 (p = 0.043) [22].
  • These studies and initial results with docking to the crystal structure of the extracellular domain of hCAXII indicate that the STS sulphamate ester inhibitors should also be interesting candidates to pursue as inhibitors of CA isozymes that are over-expressed in human tumours [23].

Analytical, diagnostic and therapeutic context of CA12


  1. Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Ivanov, S.V., Kuzmin, I., Wei, M.H., Pack, S., Geil, L., Johnson, B.E., Stanbridge, E.J., Lerman, M.I. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  2. Expression of von Hippel-Lindau tumor suppressor and tumor-associated carbonic anhydrases IX and XII in normal and neoplastic colorectal mucosa. Kivela, A.J., Parkkila, S., Saarnio, J., Karttunen, T.J., Kivela, J., Parkkila, A.K., Bartosova, M., Mucha, V., Novak, M., Waheed, A., Sly, W.S., Rajaniemi, H., Pastorekova, S., Pastorek, J. World J. Gastroenterol. (2005) [Pubmed]
  3. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Wykoff, C.C., Beasley, N.J., Watson, P.H., Turner, K.J., Pastorek, J., Sibtain, A., Wilson, G.D., Turley, H., Talks, K.L., Maxwell, P.H., Pugh, C.W., Ratcliffe, P.J., Harris, A.L. Cancer Res. (2000) [Pubmed]
  4. Tumor carbonic anhydrase 9 expression is associated with the presence of lymph node metastases in uterine cervical cancer. Lee, S., Shin, H.J., Han, I.O., Hong, E.K., Park, S.Y., Roh, J.W., Shin, K.H., Kim, T.H., Kim, J.Y. Cancer Sci. (2007) [Pubmed]
  5. Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Wykoff, C.C., Beasley, N., Watson, P.H., Campo, L., Chia, S.K., English, R., Pastorek, J., Sly, W.S., Ratcliffe, P., Harris, A.L. Am. J. Pathol. (2001) [Pubmed]
  6. Identification of an alternatively spliced isoform of carbonic anhydrase XII in diffusely infiltrating astrocytic gliomas. Haapasalo, J., Hilvo, M., Nordfors, K., Haapasalo, H., Parkkila, S., Hyrskyluoto, A., Rantala, I., Waheed, A., Sly, W.S., Pastorekova, S., Pastorek, J., Parkkila, A.K. Neuro-oncology (2008) [Pubmed]
  7. The chaperone GroEL is required for the final assembly of the molybdenum-iron protein of nitrogenase. Ribbe, M.W., Burgess, B.K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  8. Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells. Whittington, D.A., Waheed, A., Ulmasov, B., Shah, G.N., Grubb, J.H., Sly, W.S., Christianson, D.W. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  9. Purification and kinetic analysis of recombinant CA XII, a membrane carbonic anhydrase overexpressed in certain cancers. Ulmasov, B., Waheed, A., Shah, G.N., Grubb, J.H., Sly, W.S., Tu, C., Silverman, D.N. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  10. Characterization of a spontaneous mutant of Azotobacter vinelandii in which vanadium-dependent nitrogen fixation is not inhibited by molybdenum. Bageshwar, U.K., Raina, R., Das, H.K. FEMS Microbiol. Lett. (1998) [Pubmed]
  11. Carbonic anhydrase inhibitors: Inhibition of the tumor-associated isozymes IX and XII with polyfluorinated aromatic/heterocyclic sulfonamides. Pastorekova, S., Vullo, D., Casini, A., Scozzafava, A., Pastorek, J., Nishimori, I., Supuran, C.T. Journal of enzyme inhibition and medicinal chemistry. (2005) [Pubmed]
  12. The cellular physiology of carbonic anhydrases. Breton, S. JOP (2001) [Pubmed]
  13. Characterization of the gene for the Fe-protein of the vanadium dependent alternative nitrogenase of Azotobacter vinelandii and construction of a Tn5 mutant. Raina, R., Reddy, M.A., Ghosal, D., Das, H.K. Mol. Gen. Genet. (1988) [Pubmed]
  14. Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma. Liao, S.Y., Ivanov, S., Ivanova, A., Ghosh, S., Cote, M.A., Keefe, K., Coca-Prados, M., Stanbridge, E.J., Lerman, M.I. J. Med. Genet. (2003) [Pubmed]
  15. Identification of carbonic anhydrase XII as the membrane isozyme expressed in the normal human endometrial epithelium. Karhumaa, P., Parkkila, S., Türeci, O., Waheed, A., Grubb, J.H., Shah, G., Parkkila, A., Kaunisto, K., Tapanainen, J., Sly, W.S., Rajaniemi, H. Mol. Hum. Reprod. (2000) [Pubmed]
  16. Carbonic anhydrase inhibitors: inhibition of the transmembrane isozyme XIV with sulfonamides. Nishimori, I., Vullo, D., Innocenti, A., Scozzafava, A., Mastrolorenzo, A., Supuran, C.T. Bioorg. Med. Chem. Lett. (2005) [Pubmed]
  17. Physiology and molecular biology of renal carbonic anhydrase. Schwartz, G.J. J. Nephrol. (2002) [Pubmed]
  18. Loss of heterozygosity, by mitotic gene conversion and crossing over, causes strain-specific adenine mutants in constitutive diploid Candida albicans. Tsang, P.W., Cao, B., Siu, P.Y., Wang, J. Microbiology (Reading, Engl.) (1999) [Pubmed]
  19. The role of carbonic anhydrases in renal physiology. Purkerson, J.M., Schwartz, G.J. Kidney Int. (2007) [Pubmed]
  20. Expression of the transmembrane carbonic anhydrases, CA IX and CA XII, in the human male excurrent ducts. Karhumaa, P., Kaunisto, K., Parkkila, S., Waheed, A., Pastoreková, S., Pastorek, J., Sly, W.S., Rajaniemi, H. Mol. Hum. Reprod. (2001) [Pubmed]
  21. Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma. Watson, P.H., Chia, S.K., Wykoff, C.C., Han, C., Leek, R.D., Sly, W.S., Gatter, K.C., Ratcliffe, P., Harris, A.L. Br. J. Cancer (2003) [Pubmed]
  22. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma Kim HL, Seligson D, Liu X, Janzen N, Bui MHT, Yu H, Shi T, Belldegrun AS, Horvath S, Figlin RA, Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, NY. Flanigan, R. Urol. Oncol. (2006) [Pubmed]
  23. Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates. Ho, Y.T., Purohit, A., Vicker, N., Newman, S.P., Robinson, J.J., Leese, M.P., Ganeshapillai, D., Woo, L.W., Potter, B.V., Reed, M.J. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  24. Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Ivanov, S., Liao, S.Y., Ivanova, A., Danilkovitch-Miagkova, A., Tarasova, N., Weirich, G., Merrill, M.J., Proescholdt, M.A., Oldfield, E.H., Lee, J., Zavada, J., Waheed, A., Sly, W., Lerman, M.I., Stanbridge, E.J. Am. J. Pathol. (2001) [Pubmed]
  25. Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. Türeci, O., Sahin, U., Vollmar, E., Siemer, S., Göttert, E., Seitz, G., Parkkila, A.K., Shah, G.N., Grubb, J.H., Pfreundschuh, M., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
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