Carbonic anhydrase 9

Last updated
CA9
Protein CA9 PDB 2HKF.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CA9 , CAIX, MN, carbonic anhydrase 9
External IDs OMIM: 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 Mb Chr 4: 43.51 – 43.51 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Contents

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. [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

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. Caix pymol h bonding.png
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). CA IX.png
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. [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

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

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]

Related Research Articles

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironments in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumor vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

<span class="mw-page-title-main">Aldolase A</span> Mammalian protein found in Homo sapiens

Aldolase A, also known as fructose-bisphosphate aldolase, is an enzyme that in humans is encoded by the ALDOA gene on chromosome 16.

Tumor M2-PK is a synonym for the dimeric form of the pyruvate kinase isoenzyme type M2 (PKM2), a key enzyme within tumor metabolism. Tumor M2-PK can be elevated in many tumor types, rather than being an organ-specific tumor marker such as PSA. Increased stool (fecal) levels are being investigated as a method of screening for colorectal tumors, and EDTA plasma levels are undergoing testing for possible application in the follow-up of various cancers.

<span class="mw-page-title-main">Von Hippel–Lindau tumor suppressor</span> Mammalian protein found in humans

The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.

<span class="mw-page-title-main">Alpha-enolase</span> Protein-coding gene in Homo sapiens

Enolase 1 (ENO1), more commonly known as alpha-enolase, is a glycolytic enzyme expressed in most tissues, one of the isozymes of enolase. Each isoenzyme is a homodimer composed of 2 alpha, 2 gamma, or 2 beta subunits, and functions as a glycolytic enzyme. Alpha-enolase, in addition, functions as a structural lens protein (tau-crystallin) in the monomeric form. Alternative splicing of this gene results in a shorter isoform that has been shown to bind to the c-myc promoter and function as a tumor suppressor. Several pseudogenes have been identified, including one on the long arm of chromosome 1. Alpha-enolase has also been identified as an autoantigen in Hashimoto encephalopathy.

<span class="mw-page-title-main">Carbonic anhydrase II</span> Enzyme found in humans

Carbonic anhydrase II is one of sixteen forms of human α carbonic anhydrases. Carbonic anhydrase catalyzes reversible hydration of carbon dioxide. Defects in this enzyme are associated with osteopetrosis and renal tubular acidosis. Renal carbonic anhydrase allows the reabsorption of bicarbonate ions in the proximal tubule. Loss of carbonic anhydrase activity in bones impairs the ability of osteoclasts to promote bone resorption, leading to osteopetrosis.

<span class="mw-page-title-main">Carbonic anhydrase III, muscle specific</span> Enzyme found in humans

Carbonic anhydrase 3 is an enzyme that in humans is encoded by the CA3 gene.

<span class="mw-page-title-main">Carbonic anhydrase 4</span> Enzyme found in humans

Carbonic anhydrase 4 is an enzyme that in humans is encoded by the CA4 gene.

<span class="mw-page-title-main">Carbonic anhydrase 12</span> Enzyme found in humans

Carbonic anhydrase 12 is an enzyme that in humans is encoded by the CA12 gene.

<span class="mw-page-title-main">BHLHB2</span> Protein-coding gene in the species Homo sapiens

Class E basic helix-loop-helix protein 40 is a protein that in humans is encoded by the BHLHE40 gene.

<span class="mw-page-title-main">Carbonic anhydrase VI</span> Enzyme found in humans

Carbonic anhydrase 6 is an enzyme that in humans is encoded by the CA6 gene. It is also called 'gustin' because of its presence in saliva, and lower-than-normal levels of salivary zinc in individuals with hypogeusia.

<span class="mw-page-title-main">PTPRG</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase gamma is an enzyme that in humans is encoded by the PTPRG gene.

<span class="mw-page-title-main">CA10</span> Protein-coding gene in humans

Carbonic anhydrase-related protein 10 is an enzyme that in humans is encoded by the CA10 gene.

<span class="mw-page-title-main">TKTL1</span> Mammalian protein found in Homo sapiens

Transketolase-like-1 (TKTL1) is a gene closely related to the transketolase gene (TKT). It emerged in mammals during the course of evolution and, according to the latest research findings, is considered one of the key genes that distinguishes modern humans from Neanderthals. However, some modern humans also exhibit the "archaic" transketolase-like-1 allele attributed to Neanderthals, with no known effects.

<span class="mw-page-title-main">Carbonic anhydrase 14</span> Enzyme found in humans

Carbonic anhydrase 14 is an enzyme that in humans is encoded by the CA14 gene.

<span class="mw-page-title-main">Carbonic anhydrase 7</span> Enzyme found in humans

Carbonic anhydrase 7 (CA7) is an enzyme that in humans is encoded by the CA7 gene.

Girentuximab is a chimeric IgG1 monoclonal antibody to carbonic anhydrase IX (CAIX). CAIX is expressed on the surface of most renal cancer cells and is hypothesized to be on the surface of other tumor cells. It is investigational agent in clinical trials for renal cell carcinoma. Its development was suspended as a "naked" or unconjugated antibody during phase III trials due to efficacy.

<span class="mw-page-title-main">Carbonic anhydrase</span> Class of enzymes

The carbonic anhydrases form a family of enzymes that catalyze the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid. The active site of most carbonic anhydrases contains a zinc ion. They are therefore classified as metalloenzymes. The enzyme maintains acid-base balance and helps transport carbon dioxide.

<span class="mw-page-title-main">Carbonic anhydrase 13</span> Human protein

Carbonic anhydrase 13 is a protein that in humans is encoded by the CA13 gene.

Catharine West is a British cancer researcher who specialised in radiation biology. She is an emeritus professor at the University of Manchester, where she worked from 2002 until 2022.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000107159 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 "Entrez Gene: CA9 carbonic anhydrase IX".
  8. 1 2 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. 1 2 3 Frost, Susan C.; McKenna, Robert (Oct 2013). Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Springer Science & Business Media. ISBN   9789400773592.
  10. 1 2 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. 1 2 "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. 1 2 3 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. 1 2 3 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. 1 2 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. 1 2 3 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. 1 2 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. 1 2 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.

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