Biology:Carbonic anhydrase 9

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Carbonic anhydrase IX (CA9/CA IX) is an enzyme that in humans is encoded by the CA9 gene.[1][2][3] It is one of the 14 carbonic anhydrase isoforms found in humans and is a transmembrane dimeric metalloenzyme with an extracellular active site that facilitates acid secretion in the gastrointestinal tract.[4] CA IX is overexpressed in many types of cancer including clear cell renal cell carcinoma (RCC) as well as carcinomas of the cervix, breast and lung where it promotes tumor growth by enhancing tumor acidosis.[5][6]

Function

Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization.[3]

CA IX is mainly expressed in the gastrointestinal tract where it facilitates acid secretion.[7] The CA IX enzyme, along with the CA II enzyme, binds to Anion Exchanger 2 (AE2) which increases bicarbonate transport and maximizes the rate of acid secretion by gastric parietal cells.[4]

Structure

CA IX is a transmembrane glycoprotein with an extracellular active site.[5] The cytoplasmic tail of the enzyme contains three residues that may be phosphorylated (Thr-443, Ser-448, and Tyr-449) and participate in signal transduction.[5][8] Phosphorylated tyrosine 449 can interact with PI3K which activates protein kinase B to affect cellular glucose metabolism.[9]

Under physiological conditions, the enzyme exists as two nearly identical dimers.[10] Both dimers are stabilized by two hydrogen bonds between Arg-137 and the Ala-127 carbonyl oxygen as well as many Van der Waals interactions.[10] One dimer, however, has additional stabilization due to a disulfide bridge formed by two cysteine residues.[10]

Two hydrogen bonds between Arg-137 and the Ala-127 carbonyl oxygen stabilize the CA IX dimer.

One face of the dimer contains proteoglycan (PG) domains-a feature that is unique from other CA enzymes- and the opposite face contains the C-termini which help the enzyme attach to the cell membrane.[11] CA IX contains an N-linked glycosylation site bearing mannose-type glycan structures on Asn-309 as well as an O-linked glycosylation site on Thr-78.[12]

CA IX dimer with its four distinct pairs of domains labeled: the proteoglycan domain (PG), catalytic domain (blue), transmembrane segment (TM) and the intracellular tail (IC).

Regulation

Expression of CA IX is primarily regulated at the transcriptional level.[13] The promoter region of the CA9 gene contains an HRE (hypoxia responsive element) where HIF-1 can bind, which allows hypoxic conditions to increase CA IX expression.[13] Expression can also be regulated post-translationally by metalloproteinases which cause shedding of the enzyme's ectodomain.[14] Unlike other CA isozymes, CA IX is not inhibited by high lactate concentrations.[15] However, it is inhibited by bicarbonate.[15]

Clinical significance

CA IX is a transmembrane protein and is a tumor-associated carbonic anhydrase isoenzyme. It is over-expressed in VHL mutated clear cell renal cell carcinoma (ccRCC) and hypoxic solid tumors, but is low-expressed in normal kidney and most other normal tissues. It may be involved in cell proliferation and transformation. This gene is mapped to 9p13-p12.[3]

CA IX is a cellular biomarker of hypoxia. Furthermore, recent studies examining the association between CA IX levels and various clinicopathological outcomes suggest that CA IX expression may also be a valuable prognostic indicator for overall survival[16] although this association has been questioned.[17]

CA IX shows high expression in carcinomas of the uterine cervix, kidney, oesophagus, lung, breast, colon, brain, and vulva compared to expression in few noncancerous tissues.[18][7] Its overexpression in cancerous tissues compared to normal ones is due to hypoxic conditions in the tumor microenvironment caused by abnormal vasculature and subsequent transcriptional activation by HIF-1 binding.[13] In clear cell renal carcinomas, CA IX shows high expression under normoxia due to a mutation in the VHL gene that normally negatively regulates HIF-1.[18] Because of its overexpression in many types of cancer and low expression in normal tissues, CAIX has become a useful target for clear cell RCC and breast cancer tumor imaging in mice.[19][20]

CA IX plays a very significant role in tumor acidification as it has very high catalytic activity with the highest rate of proton transfer of the known CAs.[12] The enzyme converts carbon dioxide outside of the tumor into bicarbonate and protons, contributing to extracellular acidosis and promoting tumor growth by regulating the pH of the cytosol.[6]

As a drug target

Because of its low expression in normal tissues and overexpression in many cancer tissues, CA IX has also become a desirable drug target. Girentuximab, an antibody that binds to CA IX, failed to improve disease-free as well as overall survival of patients with clear cell RCC in Phase III clinical trials.[21]

However, a number of small molecules have been used to inhibit CA IX. The main classes of these inhibitors are inorganic anions, sulfonamides, phenols, and coumarins.[11] Anions and sulfonamides inhibit CA IX by coordinating the zinc ion within CA IX while phenols bind to the zinc-coordinated water molecule.[11] Coumarins serve as mechanism-based inhibitors that are hydrolyzed by the enzyme to form a cis-2-hydroxy-cinnamic acid derivative that then binds to the active site.[22]

References

  1. ↑ "Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships". Genomics 33 (3): 480–7. May 1996. doi:10.1006/geno.1996.0223. PMID 8661007. 
  2. ↑ "Radiation hybrid mapping of the human MN/CA9 locus to chromosome band 9p12-p13". Genomics 53 (1): 118–9. October 1998. doi:10.1006/geno.1998.5483. PMID 9787087. 
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: CA9 carbonic anhydrase IX". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=768. 
  4. ↑ 4.0 4.1 "Interactions of transmembrane carbonic anhydrase, CAIX, with bicarbonate transporters". American Journal of Physiology. Cell Physiology 293 (2): C738-48. August 2007. doi:10.1152/ajpcell.00157.2007. PMID 17652430. 
  5. ↑ 5.0 5.1 5.2 Frost, Susan C.; McKenna, Robert (Oct 2013) (in en). Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Springer Science & Business Media. ISBN 9789400773592. https://books.google.com/books?id=2xHHBAAAQBAJ&q=caIX+mechanism&pg=PR5. 
  6. ↑ 6.0 6.1 "Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer". Journal of Cellular and Molecular Medicine 14 (4): 771–94. April 2010. doi:10.1111/j.1582-4934.2009.00994.x. PMID 20015196. 
  7. ↑ 7.0 7.1 "Tissue expression of CA9 - Summary - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000107159-CA9/tissue. 
  8. ↑ "Phosphorylation of carbonic anhydrase IX controls its ability to mediate extracellular acidification in hypoxic tumors". Cancer Research 71 (24): 7558–67. December 2011. doi:10.1158/0008-5472.CAN-11-2520. PMID 22037869. 
  9. ↑ "The role of carbonic anhydrase IX overexpression in kidney cancer" (in en). European Journal of Cancer 41 (18): 2935–47. December 2005. doi:10.1016/j.ejca.2005.09.011. PMID 16310354. 
  10. ↑ 10.0 10.1 10.2 "Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX". Proceedings of the National Academy of Sciences of the United States of America 106 (38): 16233–8. September 2009. doi:10.1073/pnas.0908301106. PMID 19805286. Bibcode: 2009PNAS..10616233A. 
  11. ↑ 11.0 11.1 11.2 "Carbonic anhydrase IX: Biochemical and crystallographic characterization of a novel antitumor target". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1804 (2): 404–9. February 2010. doi:10.1016/j.bbapap.2009.07.027. PMID 19679200. 
  12. ↑ 12.0 12.1 "Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes". The Journal of Biological Chemistry 283 (41): 27799–809. October 2008. doi:10.1074/jbc.M800938200. PMID 18703501. 
  13. ↑ 13.0 13.1 13.2 "Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases". Sub-Cellular Biochemistry. Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications (Springer Netherlands) 75: 221–54. 2014. doi:10.1007/978-94-007-7359-2_12. ISBN 9789400773585. PMID 24146382. 
  14. ↑ "Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17". British Journal of Cancer 93 (11): 1267–76. November 2005. doi:10.1038/sj.bjc.6602861. PMID 16278664. 
  15. ↑ 15.0 15.1 "Carbonic anhydrase inhibitors. Inhibition of isozymes I, II, IV, V, and IX with anions isosteric and isoelectronic with sulfate, nitrate, and carbonate". Bioorganic & Medicinal Chemistry Letters 15 (3): 567–71. February 2005. doi:10.1016/j.bmcl.2004.11.056. PMID 15664814. 
  16. ↑ "Elevated CAIX Expression is Associated with an Increased Risk of Distant Failure in Early-Stage Cervical Cancer". Biomarker Insights 3: 45–55. February 2008. doi:10.4137/bmi.s570. PMID 19578493. 
  17. ↑ "Is carbonic anhydrase IX a validated target for molecular imaging of cancer and hypoxia?". Future Oncology 11 (10): 1531–41. 2015. doi:10.2217/fon.15.11. PMID 25963430. 
  18. ↑ 18.0 18.1 "Molecular mechanisms of carbonic anhydrase IX-mediated pH regulation under hypoxia". BJU International 101 Suppl 4 (s4): 8–15. June 2008. doi:10.1111/j.1464-410X.2008.07642.x. PMID 18430116. 
  19. ↑ "ImmunoPET imaging of renal cell carcinoma with (124)I- and (89)Zr-labeled anti-CAIX monoclonal antibody cG250 in mice". Cancer Biotherapy & Radiopharmaceuticals 28 (7): 510–5. September 2013. doi:10.1089/cbr.2013.1487. PMID 23697926. 
  20. ↑ "Optical imaging of pre-invasive breast cancer with a combination of VHHs targeting CAIX and HER2 increases contrast and facilitates tumour characterization". EJNMMI Research 6 (1): 14. December 2016. doi:10.1186/s13550-016-0166-y. PMID 26860296. PMC 4747965. https://dspace.library.uu.nl/bitstream/1874/344448/1/optical.pdf. 
  21. ↑ "Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial". JAMA Oncology 3 (7): 913–920. July 2017. doi:10.1001/jamaoncol.2016.4419. PMID 27787547. 
  22. ↑ "Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors". Journal of the American Chemical Society 131 (8): 3057–62. March 2009. doi:10.1021/ja809683v. PMID 19206230. 

Further reading

  • "Carbonic anhydrase isozymes in the human pancreas". Digestive and Liver Disease 33 (1): 68–74. 2001. doi:10.1016/s1590-8658(01)80138-9. PMID 11303978. 
  • "A novel quasi-viral agent, MaTu, is a two-component system". Virology 187 (2): 620–6. April 1992. doi:10.1016/0042-6822(92)90464-Z. PMID 1312272. 
  • "Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment". Oncogene 9 (10): 2877–88. October 1994. PMID 8084592. 
  • "Expression of MaTu-MN protein in human tumor cultures and in clinical specimens". International Journal of Cancer 54 (2): 268–74. May 1993. doi:10.1002/ijc.2910540218. PMID 8486430. 
  • "Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts". Gastroenterology 112 (2): 398–408. February 1997. doi:10.1053/gast.1997.v112.pm9024293. PMID 9024293. 
  • "Immunohistochemistry of carbonic anhydrase isozyme IX (MN/CA IX) in human gut reveals polarized expression in the epithelial cells with the highest proliferative capacity". The Journal of Histochemistry and Cytochemistry 46 (4): 497–504. April 1998. doi:10.1177/002215549804600409. PMID 9524195. 
  • "Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes". Proceedings of the National Academy of Sciences of the United States of America 95 (21): 12596–601. October 1998. doi:10.1073/pnas.95.21.12596. PMID 9770531. Bibcode: 1998PNAS...9512596I. 
  • "Molecular cloning and immunogenicity of renal cell carcinoma-associated antigen G250". International Journal of Cancer 85 (6): 865–70. March 2000. doi:10.1002/(SICI)1097-0215(20000315)85:6<865::AID-IJC21>3.0.CO;2-Q. PMID 10709109. 
  • "Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours". Histochemistry and Cell Biology 114 (3): 197–204. September 2000. doi:10.1007/s004180000181. PMID 11083462. 
  • "The catalytic properties of human carbonic anhydrase IX". Biochemical and Biophysical Research Communications 288 (3): 666–9. November 2001. doi:10.1006/bbrc.2001.5824. PMID 11676494. 
  • "Differential expression of cytoplasmic carbonic anhydrases, CA I and II, and membrane-associated isozymes, CA IX and XII, in normal mucosa of large intestine and in colorectal tumors". Digestive Diseases and Sciences 46 (10): 2179–86. October 2001. doi:10.1023/A:1011910931210. PMID 11680594. 
  • "Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy". Clinical Cancer Research 7 (11): 3399–403. November 2001. PMID 11705854. 
  • "Renal cell carcinoma-associated G250 methylation and expression: in vivo and in vitro studies". Urology 60 (2): 357–62. August 2002. doi:10.1016/S0090-4295(02)01711-9. PMID 12137853. 
  • "Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3'-kinase". Cancer Research 62 (15): 4469–77. August 2002. PMID 12154057. 
  • "Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer". Journal of Clinical Oncology 21 (3): 473–82. February 2003. doi:10.1200/JCO.2003.11.132. PMID 12560438. 
  • "Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy". Clinical Cancer Research 9 (2): 802–11. February 2003. PMID 12576453. 




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