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Carbonic anhydrase 9

(Redirected from CAIX)

Carbonic anhydrase IX (CA9/CA IX) is an enzyme that in humans is encoded by the CA9 gene.[5][6][7] 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.[8] 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.[9][10]

CA9
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCA9, CAIX, MN, carbonic anhydrase 9
External IDsOMIM: 603179; MGI: 2447188; HomoloGene: 20325; GeneCards: CA9; OMA:CA9 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

768

230099

Ensembl

ENSG00000107159

ENSMUSG00000028463

UniProt

Q16790

Q8VHB5

RefSeq (mRNA)

NM_001216

NM_139305

RefSeq (protein)

NP_001207

NP_647466

Location (UCSC)Chr 9: 35.67 – 35.68 MbChr 4: 43.51 – 43.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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.[7]

CA IX is mainly expressed in the gastrointestinal tract where it facilitates acid secretion.[11] 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.[8]

Structure

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CA IX is a transmembrane glycoprotein with an extracellular active site.[9] 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.[9][12] Phosphorylated tyrosine 449 can interact with PI3K which activates protein kinase B to affect cellular glucose metabolism.[13]

Under physiological conditions, the enzyme exists as two nearly identical dimers.[14] 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.[14] One dimer, however, has additional stabilization due to a disulfide bridge formed by two cysteine residues.[14]

 
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.[15] 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.[16]

 
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

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Expression of CA IX is primarily regulated at the transcriptional level.[17] 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.[17] Expression can also be regulated post-translationally by metalloproteinases which cause shedding of the enzyme's ectodomain.[18] Unlike other CA isozymes, CA IX is not inhibited by high lactate concentrations.[19] However, it is inhibited by bicarbonate.[19]

Clinical significance

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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.[7]

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[20] although this association has been questioned.[21]

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.[22][11] 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.[17] 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.[22] 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.[23][24]

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.[16] 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.[10]

As a drug target

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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.[25]

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.[15] Anions and sulfonamides inhibit CA IX by coordinating the zinc ion within CA IX while phenols bind to the zinc-coordinated water molecule.[15] Coumarins serve as mechanism-based inhibitors that are hydrolyzed by the enzyme to form a cis-2-hydroxycinnamic acid derivative that then binds to the active site.[26]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000107159 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028463 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Opavský R, Pastoreková S, Zelník V, Gibadulinová A, Stanbridge EJ, Závada J, Kettmann R, Pastorek J (May 1996). "Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships". Genomics. 33 (3): 480–7. doi:10.1006/geno.1996.0223. PMID 8661007.
  6. ^ Nakagawa Y, Uemura H, Hirao Y, Yoshida K, Saga S, Yoshikawa K (October 1998). "Radiation hybrid mapping of the human MN/CA9 locus to chromosome band 9p12-p13". Genomics. 53 (1): 118–9. doi:10.1006/geno.1998.5483. PMID 9787087.
  7. ^ a b c "Entrez Gene: CA9 carbonic anhydrase IX".
  8. ^ a b Morgan PE, Pastoreková S, Stuart-Tilley AK, Alper SL, Casey JR (August 2007). "Interactions of transmembrane carbonic anhydrase, CAIX, with bicarbonate transporters". American Journal of Physiology. Cell Physiology. 293 (2): C738-48. doi:10.1152/ajpcell.00157.2007. PMID 17652430.
  9. ^ a b c Frost, Susan C.; McKenna, Robert (Oct 2013). Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Springer Science & Business Media. ISBN 9789400773592.
  10. ^ a b Chiche J, Brahimi-Horn MC, Pouysségur J (April 2010). "Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer". Journal of Cellular and Molecular Medicine. 14 (4): 771–94. doi:10.1111/j.1582-4934.2009.00994.x. PMC 3823111. PMID 20015196.
  11. ^ a b "Tissue expression of CA9 - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2019-03-14.
  12. ^ Ditte P, Dequiedt F, Svastova E, Hulikova A, Ohradanova-Repic A, Zatovicova M, Csaderova L, Kopacek J, Supuran CT, Pastorekova S, Pastorek J (December 2011). "Phosphorylation of carbonic anhydrase IX controls its ability to mediate extracellular acidification in hypoxic tumors". Cancer Research. 71 (24): 7558–67. doi:10.1158/0008-5472.CAN-11-2520. PMID 22037869.
  13. ^ Dorai T, Sawczuk IS, Pastorek J, Wiernik PH, Dutcher JP (December 2005). "The role of carbonic anhydrase IX overexpression in kidney cancer". European Journal of Cancer. 41 (18): 2935–47. doi:10.1016/j.ejca.2005.09.011. PMID 16310354.
  14. ^ a b c Alterio V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S, Scaloni A, Pastorek J, Pastorekova S, Pedone C, Scozzafava A, Monti SM, De Simone G (September 2009). "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. Bibcode:2009PNAS..10616233A. doi:10.1073/pnas.0908301106. PMC 2752527. PMID 19805286.
  15. ^ a b c De Simone G, Supuran CT (February 2010). "Carbonic anhydrase IX: Biochemical and crystallographic characterization of a novel antitumor target". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1804 (2): 404–9. doi:10.1016/j.bbapap.2009.07.027. PMID 19679200.
  16. ^ a b Hilvo M, Baranauskiene L, Salzano AM, Scaloni A, Matulis D, Innocenti A, Scozzafava A, Monti SM, Di Fiore A, De Simone G, Lindfors M, Jänis J, Valjakka J, Pastoreková S, Pastorek J, Kulomaa MS, Nordlund HR, Supuran CT, Parkkila S (October 2008). "Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes". The Journal of Biological Chemistry. 283 (41): 27799–809. doi:10.1074/jbc.M800938200. PMID 18703501.
  17. ^ a b c Tafreshi NK, Lloyd MC, Bui MM, Gillies RJ, Morse DL (2014). "Carbonic Anhydrase IX as an Imaging and Therapeutic Target for Tumors and Metastases". Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry. Vol. 75. Springer Netherlands. pp. 221–54. doi:10.1007/978-94-007-7359-2_12. ISBN 9789400773585. PMC 4282494. PMID 24146382.
  18. ^ Zatovicova M, Sedlakova O, Svastova E, Ohradanova A, Ciampor F, Arribas J, Pastorek J, Pastorekova S (November 2005). "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. doi:10.1038/sj.bjc.6602861. PMC 2361518. PMID 16278664.
  19. ^ a b Innocenti A, Vullo D, Scozzafava A, Supuran CT (February 2005). "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. doi:10.1016/j.bmcl.2004.11.056. PMID 15664814.
  20. ^ Kirkpatrick JP, Rabbani ZN, Bentley RC, Hardee ME, Karol S, Meyer J, Oosterwijk E, Havrilesky L, Secord AA, Vujaskovic Z, Dewhirst MW, Jones EL (February 2008). "Elevated CAIX Expression is Associated with an Increased Risk of Distant Failure in Early-Stage Cervical Cancer". Biomarker Insights. 3: 45–55. doi:10.4137/bmi.s570. PMC 2688355. PMID 19578493.
  21. ^ Li J, Zhang G, Wang X, Li XF (2015). "Is carbonic anhydrase IX a validated target for molecular imaging of cancer and hypoxia?". Future Oncology. 11 (10): 1531–41. doi:10.2217/fon.15.11. PMC 4976829. PMID 25963430.
  22. ^ a b Pastorekova S, Ratcliffe PJ, Pastorek J (June 2008). "Molecular mechanisms of carbonic anhydrase IX-mediated pH regulation under hypoxia". BJU International. 101 Suppl 4 (s4): 8–15. doi:10.1111/j.1464-410X.2008.07642.x. PMID 18430116. S2CID 8780292.
  23. ^ Stillebroer AB, Franssen GM, Mulders PF, Oyen WJ, van Dongen GA, Laverman P, Oosterwijk E, Boerman OC (September 2013). "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. doi:10.1089/cbr.2013.1487. PMC 3741422. PMID 23697926.
  24. ^ Kijanka MM, van Brussel AS, van der Wall E, Mali WP, van Diest PJ, van Bergen En Henegouwen PM, Oliveira S (December 2016). "Optical imaging of pre-invasive breast cancer with a combination of VHHs targeting CAIX and HER2 increases contrast and facilitates tumour characterization" (PDF). EJNMMI Research. 6 (1): 14. doi:10.1186/s13550-016-0166-y. PMC 4747965. PMID 26860296.
  25. ^ Chamie K, Donin NM, Klöpfer P, Bevan P, Fall B, Wilhelm O, Störkel S, Said J, Gambla M, Hawkins RE, Jankilevich G, Kapoor A, Kopyltsov E, Staehler M, Taari K, Wainstein AJ, Pantuck AJ, Belldegrun AS (July 2017). "Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial". JAMA Oncology. 3 (7): 913–920. doi:10.1001/jamaoncol.2016.4419. PMC 5824229. PMID 27787547.
  26. ^ Maresca A, Temperini C, Vu H, Pham NB, Poulsen SA, Scozzafava A, Quinn RJ, Supuran CT (March 2009). "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. doi:10.1021/ja809683v. hdl:2158/594272. PMID 19206230. S2CID 207136680.

Further reading

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