Abstract
Carbonic anhydrases are ubiquitous enzymes that catalyze the reversible hydration of carbon dioxide. These enzymes are of ancient origin as they are found in the deepest of branches of the evolutionary tree. Of the five different classes of carbonic anhydrases, the alpha class has perhaps received the most attention because of its role in human pathology. This review focuses on the physiological function of this class of carbonic anhydrases organized by their cellular location.
Susan C. Frost and Robert McKenna (eds.). Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Gilmour KM (2010) Perspectives on carbonic anhydrase. Comp Biochem Physiol A Mol Integr Physiol 157:193–197
Henry RP (1996) Multiple roles of carbonic anhydrase in cellular transport and metabolism. Annu Rev Physiol 58:523–538
Henry RP, Swenson ER (2000) The distribution and physiological significance of carbonic anhydrase in vertebrate gas exchange organs. Respir Physiol 121:1–12
Frasseto F, Parisotto TM, Peres RC, Marques MR, Line SR, Nobre Dos Santos M (2012) Relationship among salivary carbonic anhydrase VI activity and flow rate, biofilm pH and caries in primary dentition. Caries Res 46:194–200
Chaput CD, Dangott LJ, Rahm MD, Hitt KD, Stewart DS, Wayne Sampson H (2012) A proteomic study of protein variation between osteopenic and age-matched control bone tissue. Exp Biol Med (Maywood) 237:491–498
Biswas UK, Kumar A (2012) Study on the changes of carbonic anhydrase activity in insulin resistance and the effect of methylglyoxal. J Pak Med Assoc 62:417–421
Brown BF, Quon A, Dyck JR, Casey JR (2012) Carbonic anhydrase II promotes cardiomyocyte hypertrophy. Can J Physiol Pharmacol 90:1599–1610
Sterling D, Reithmeier RA, Casey JR (2001) Carbonic anhydrase: in the driver’s seat for bicarbonate transport. JOP 2:165–170
Purkerson JM, Schwartz GJ (2007) The role of carbonic anhydrases in renal physiology. Kidney Int 71:103–115
Kuo WH, Yang SF, Hsieh YS, Tsai CS, Hwang WL, Chu SC (2005) Differential expression of carbonic anhydrase isoenzymes in various types of anemia. Clin Chim Acta 351:79–86
Thiry A, Dogne JM, Masereel B, Supuran CT (2006) Targeting tumor-associated carbonic anhydrase IX in cancer therapy. Trends Pharmacol Sci 27:566–573
Whittington DA, Waheed A, Ulmasov B, Shah GN, Grubb JH, Sly WS, Christianson DW (2001) Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells. Proc Natl Acad Sci U S A 98:9545–9550
Supuran CT (2008) Carbonic anhydrase: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181
Pastorekova S, Pastorek J (2004) Cancer-related carbonic anhydrase isozymes and their inhibition. In: Supuran CT, Scozzafava A, Conway J (eds) Carbonic anhydrase: its inhibitors and activators. CRC Press, Bocal Raton, pp 255–281
Ditte P, Dequiedt F, Svastova E, Hulikova A, Ohradanova-Repic A, Zatovicova M, Csaderova L, Kopacek J, Supuran CT, Pastorekova S, Pastorek J (2011) Phosphorylation of carbonic anhydrase IX controls its ability to mediate extracellualr acidification in hypoxic tumors. Cancer Res 71:7558–7567
Chegwidden WR, Dodgson SJ, Spencer IM (2000) The roles of carbonic anhydrase in metabolism, cell growth and cancer in animals. EXS 90:343–363
Supuran CT (2008) Carbonic anhydrases–an overview. Curr Pharm Des 14:603–614
Hilvo M, Innocenti A, Monti SM, De Simone G, Supuran CT, Parkkila S (2008) Recent advances in research on the most novel carbonic anhydrases, CA XIII and XV. Curr Pharm Des 14:672–678
Aspatwar A, Tolvanen ME, Parkkila S (2010) Phylogeny and expression of carbonic anhydrase-related proteins. BMC Mol Biol 11:25
Silverman DN, Lindskog S (1988) The catalytic mechanism of carbonic anhydrase – implication of a rate limiting protolysis of water. Acc Chem Res 21:30–36
Jewell DA, Tu C, Paranawithana SR, Tanhauser SM, LoGrasso PV, Laipis PJ, Silverman DN (1991) Enhancement of the catalytic properties of human carbonic anhydrase III by site-directed mutagenesis. Biochemistry 30:1484–1490
Sly WS (2000) The membrane carbonic anhydrases: from CO2 transport to tumor markers. EXS 90:95–104
Maren TH, Swenson ER (1980) A comparative study of the kinetics of the Bohr effect in vertebrates. J Physiol 303:535–547
Esbaugh AJ, Tufts BL (2006) The structure and function of carbonic anhydrase isozymes in the respiratory system of vertebrates. Respir Physiol Neurobiol 154:185–198
Swenson ER (2000) Respiratory and renal roles of carbonic anhydrase in gas exchange and acid–base regulation. EXS 90:281–341
Chegwidden WR, Carter ND (2000) Introduction to the carbonic anhydrases. EXS 90:14–28
Chiang WL, Lai JC, Yang SF, Chiou HL, Hsieh YS (2001) Alternations in quantity and activities of erythrocyte cytosolic carbonic anhydrase isoenzymes in glucose-6-phosphate dehydrogenase individuals. Clin Chim Acta 314:195–201
Brown D, Kumpulainen T, Roth J, Orci L (1983) Immunohistochemical localization of carbonic anhydrase in postnatal and adult rat kidney. Am J Physiol 245:F110–F118
Lonnerholm G, Wistrand PJ, Barany E (1986) Carbonic anhydrase isoenzymes in the rat kidney. Effects of chronic acetazolamide treatment. Acta Physiol 126:51–60
Sly WS, Hewett-Emmett D, Whyte MP, Yu YS, Tashian RE (1983) Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci U S A 80:2752–2756
Lewis SE, Erickson RP, Barnett LB, Venta PJ, Tashian RE (1988) N-ethyl-N-nitrosourea-induced null mutation at the mouse Car-2 locus: an animal model for human carbonic anhydrase II deficiency syndrome. Proc Natl Acad Sci U S A 85:1962–1966
Breton S, Alper SL, Gluck SL, Sly WS, Barker JE, Brown D (1995) Depletion of intercalated cells from collecting ducts of carbonic anhydrase II-deficient (CAR2 null) mice. Am J Physiol 269:F761–F774
Bagnis C, Marshansky V, Breton S, Brown D (2001) Remodeling the cellular profile of collecting ducts by chronic carbonic anhydrase inhibition. Am J Physiol Renal Physiol 280:F437–F448
Vince JW, Reithmeier RAF (1998) Carbonic anhydrase II binds to the carboxyl-terminus of human band 3, the erythrocyte Cl−/HCO3 − Exchanger. J Biol Chem 273:28430–28437
McMurtrie HL, Cleary HJ, Alvarez BV, Loiselle FB, Sterling D, Morgan PE, Johnson DE, Casey JR (2004) The bicarbonate transport metabolon. J Enzyme Inhib Med Chem 19:231–236
Pushkin A, Abuladze N, Gross E, Newman D, Tatishchev S, Lee I, Fedotoff O, Bondar G, Azimov R, Ngyuen M, Kurtz I (2004) Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal tubule cells. J Physiol 559:55–65
Becker HM, Deitmer JW (2007) Carbonic anhydrase II increases the activity of the human electrogenic Na+/HCO3 − cotransporter. J Biol Chem 282:13508–13521
Li X, Alvarez B, Casey JR, Reithmeier RA, Fliegel L (2002) Carbonic anhydrase II binds to and enhances activity of the Na+/H+ exchanger. J Biol Chem 277:36085–36091
Li X, Liu Y, Alvarez BV, Casey JR, Fliegel L (2006) A novel carbonic anhydrase II binding site regulates NHE1 activity. Biochemistry 45:2414–2424
Vince JW, Carlsson U, Reithmeier RAF (2002) Localization of the Cl−/HCO3 − anion exchanger binding site to the amino-terminal region of carbonic anhydrase II. Biochemistry 39:13344–13349
Becker HM, Hirnet D, Fecher-Trost C, Sultemeyer D, Deitmer JW (2005) Transport activity of MCT1 expressed in Xenopus oocytes is increased by interaction with carbonic anhydrase. J Biol Chem 280:39882–39889
Becker HM, Klier M, Deitmer JW (2010) Nonenzymatic augmentation of lactate transport via monocarboxylate transporter isoform 4 by carbonic anhydrase II. J Membr Biol 234:125–135
Stridh MH, Alt MD, Wittmann S, Heidtmann H, Aggarwal M, Riederer B, Seidler U, Wennemuth G, McKenna R, Deitmer JW, Becker HM (2012) Lactate flux in astrocytes is enhanced by a non-catalytic action of carbonic anhydrase II. J Physiol 590:2333–2351
Becker HM, Klier M, Schuler C, McKenna R, Deitmer JW (2011) Intramolecular proton shuttle supports not only catalytic but also noncatalytic function of carbonic anhydrase II. Proc Natl Acad Sci U S A 108:3071–3076
Becker HM, Deitmer JW (2008) Nonenzymatic proton handling by carbonic anhydrase II during H + −lactate cotransport via monocarboxylate transporter 1. J Biol Chem 283:21655–21667
Carter ND (1991) Hormonal and neuronal control of carbonic anhydrase III gene expression in skeletal muscle. In: Dodgson SJ, Tashian RE, Gross G, Carter ND (eds) The carbonic anhydrases: cellular physiology and moledular genetics. Plenum Publishing, New York, pp 247–256
Stanton LW, Ponte PA, Coleman RT, Snyder MA (1991) Expression of CA III in rodent models of obesity. Mol Endocrinol 5:860–866
Lyons GE, Buckingham ME, Tweedie S, Edwards YH (1991) Carbonic anhydrase III, an early mesodermal marker, is expressed in embryonic mouse skeletal muscle and notochord. Development 111:233–244
Chai YC, Jung CH, Lii CK, Ashraf SS, Hendrich S, Wolf B, Sies H, Thomas JA (1991) Identification of an abundant S-thiolated rat liver protein as carbonic anhydrase III; characterization of S-thiolation and dethiolation reactions. Arch Biochem Biophys 284:270–278
Lii CK, Chai YC, Zhao W, Thomas JA, Hendrich S (1994) S-thiolation and irreversible oxidation of sulfhydryls on carbonic anhydrase III during oxidative stress: a method for studying protein modification in intact cells and tissues. Arch Biochem Biophys 308:231–239
Thomas JA, Poland B, Honzatko R (1995) Protein sulfhydryls and their role in the antioxidant function of protein S-thiolation. Arch Biochem Biophys 319:1–9
Raisanen SR, Lehenkari P, Tasanen M, Rahkila P, Harkonen PL, Vaananen HK (1999) Carbonic anhydrase III protects cells from hydrogen peroxide-induced apoptosis. FASEB J 13:513–522
Mallis RJ, Hamann MJ, Zhao W, Zhang T, Hendrich S, Thomas JA (2002) Irreversible thiol oxidation in carbonic anhydrase III: protetion by S-glutathiolation and detection in aging rats. Biol Chem 383:649–662
Thomas JA, Mallis RJ (2001) Aging and oxidation of reactive protein sulfhydryls. Exp Gerontol 36:1519–1526
Kim G, Lee TH, Wetzel P, Geers C, Robinson MA, Myers TG, Owens JW, Wehr NB, Eckhaus MW, Gros G, Wynshaw-Boris A, Levine RL (2004) Carbonic anhydrase III is not required in the mouse for normal growth, development, and life span. Mol Cell Biol 24:9942–9947
Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847–853
Barnard T (1969) The ultrastructural differentiation of brown adipose tissue in the rat. J Ultrastruct Res 29:311–322
Cinti S, Cigolini M, Bosello O, Bjorntorp P (1984) A morphological study of the adipocyte precursor. J Submicrosc Cytol 16:243–251
Hausman GJ, Campion DR, Martin RJ (1980) Search for the adipocyte precursor cell and factors that promote its differentiation. J Lipid Res 21:657–670
Amos PJ, Shang H, Bailey AM, Taylor A, Katz AJ, Peirce SM (2008) IFATS collection: the role of human adipose-derived stromal cells in inflammatory microvascular remodeling and evidence of a perivascular phenotype. Stem Cells 26:2682–2690
Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313
Traktuev DO, Merfeld-Clauss S, Li J, Kolonin M, Arap W, Pasqualini R, Johnstone BH, March KL (2008) A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res 102:77–85
Zannettino AC, Paton S, Arthur A, Khor F, Itescu S, Gimble JM, Gronthos S (2008) Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J Cell Physiol 214:413–421
Zimmerlin L, Donnenberg VS, Pfeifer ME, Meyer EM, Peault B, Rubin JP, Donnenberg AD (2010) Stromal vascular progenitors in adult human adipose tissue. Cytometry A 77:22–30
Gupta RK, Mepani RJ, Kleiner S, Lo JC, Khandekar MJ, Cohen P, Frontini A, Bhowmick DC, Ye L, Cinti S, Spiegelman BM (2012) Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab 15:230–239
Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, Tallquist MD, Graff JM (2008) White fat progenitor cells reside in the adipose vasculature. Science 322:583–586
Lynch CJ, Hazen SA, Horetsky RL, Carter ND, Dodgson SJ (1993) Differentiation-dependent expression of carbonic anhydrase II and III in 3T3 adipocytes. Am J Physiol 265:C234–C243
Cao TP, Rous S (1978) Inhibitory effect of acetazolamide on the activity of acetyl CoA carboxylase of mouse liver. Life Sci 22:2067–2072
Lynch CJ, Brennan WA Jr, Vary TC, Carter N, Dodgson SJ (1993) Carbonic anhydrase III in obese Zucker rats. Am J Physiol 264:E621–E630
Bray GA, York DA (1979) Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol Rev 59:719–809
Mitterberger MC, Kim G, Rostek U, Levine RL, Zwerschke W (2012) Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-gamma2. Exp Cell Res 318:877–886
Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440:944–948
Montgomery JC, Venta PJ, Eddy RL, Fukushima YS, Shows TB, Tashian RE (1991) Characterization of the human gene for a newly discovered carbonic anhydrase, CA VII, and its localization to chromosome 16. Genomics 11:835–848
Lakkis MM, Bergenhem NC, Tashian RE (1996) Expression of mouse carbonic anhydrase VII in E. coli and demonstration of its CO2 hydrase activity. Biochem Biophys Res Commun 226:268–272
Truppo E, Supuran CT, Sandomenico A, Vullo D, Innocenti A, Di Fiore A, Alterio V, De Simone G, Monti SM (2012) Carbonic anhydrase VII is S-glutathionylated without loss of catalytic activity and affinity for sulfonamide inhibitors. Bioorg Med Chem Lett 22:1560–1564
Bootorabi F, Janis J, Smith E, Waheed A, Kukkurainen S, Hytonen V, Valjakka J, Supuran CT, Vullo D, Sly WS, Parkkila S (2010) Analysis of a shortened form of human carbonic anhydrase VII expressed in vitro compared to the full-length enzyme. Biochimie 92:1072–1080
Thiry A, Dogne JM, Supuran CT, Masereel B (2007) Carbonic anhydrase inhibitors as anticonvulsant agents. Curr Top Med Chem 7:855–864
Ruusuvuori E, Li H, Huttu K, Palva JM, Smirnov S, Rivera C, Kaila K, Voipio J (2004) Carbonic anhydrase isoform VII acts as a molecular switch in the development of synchronous gamma-frequency firing of hippocampal CA1 pyramidal cells. J Neurosci 24:2699–2707
Asiedu M, Ossipov MH, Kaila K, Price TJ (2010) Acetazolamide and midazolam act synergistically to inhibit neuropathic pain. Pain 148:302–308
Lehtonen J, Shen B, Vihinen M, Casini A, Scozzafava A, Supuran CT, Parkkila A, Saarnio J, Kivela AJ, Waheed A, Sly WS, Parkkila S (2004) Characterization of CA XIII, a novel member of the carbonic anhydrase isozyme family. J Biol Chem 279:2719–2727
Lehtonen JM, Parkkila S, Vullo D, Casini A, Scozzafava A, Supuran CT (2004) Carbonic anhydrase inhibitors. Inhibition of cytosolic isozyme XIII with aromatic and heterocyclic sulfonamides: a novel target for the drug design. Bioorg Med Chem Lett 14:3757–3762
Kummola L, Hamalainen JM, Kivela J, Kivela AJ, Saarnio J, Karttunen T, Parkkila S (2005) Expression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colrectal mucosa. BMC Cancer 4:1–7
Wandernoth PM, Raubuch M, Mannowetz N, Becker HM, Deitmer JW, Sly WS, Wennemuth G (2010) Role of carbonic anhydrase IV in the bicarbonate-mediated activation of murine and human sperm. PLoS One 5:e15061
Chappell JB, Crofts AR (1966) Ion transport and reversible volume changes of isolated mitochondria. In: Tager JM, Papa S, Qualiariello E, Slater EC (eds) Regulation of metabolic processes in mitochondria. Elsevier, Amsterdam, pp 293–316
Elder JA (1972) Energy-linked accumulation of bicarbonate by rat liver mitochondria. FASEB J 31:856
Elder JA, Lehninger AL (1973) Respiration-dependent transport of carbon dioxide into rat liver mitochondria. Biochemistry 12:976–982
Dodgson SJ, Forster RE 2nd (1986) Inhibition of CA V decreases glucose synthesis from pyruvate. Arch Biochem Biophys 251:198–204
Dodgson SJ, Forster RE 2nd (1986) Carbonic anhydrase: inhibition results in decreased urea production by hepatocytes. J Appl Physiol 60:646–652
Dodgson SJ (1987) Inhibition of mitochondrial carbonic anhydrase and ureagenesis: a discrepancy examined. J Appl Physiol 63:2134–2141
Amor-Gueret M, Levi-Strauss M (1990) Nucleotide and derived amino-acid sequence of a cDNA encoding a new mouse carbonic anhydrase. Nucleic Acids Res 18:1646
Nagao Y, Srinivasan M, Platero JS, Svendrowski M, Waheed A, Sly WS (1994) Mitochondrial carbonic anhydrase (isozyme V) in mouse and rat: cDNA cloning, expression, subcellular localization, processing, and tissue distribution. Proc Natl Acad Sci U S A 91:10330–10334
Nagao Y, Platero JS, Waheed A, Sly WS (1993) Human mitochondrial carbonic anhydrase: cDNA cloning, expression, subcellular localization, and mapping to chromosome 16. Proc Natl Acad Sci U S A 90:7623–7627
Shah GN, Hewett-Emmett D, Grubb JH, Migas MC, Fleming RE, Waheed A, Sly WS (2000) Mitochondrial carbonic anhydrase CA VB: differences in tissue distribution and pattern of evolution from those of CA VA suggest distinct physiological roles. Proc Natl Acad Sci U S A 97:1677–1682
Fujikawa-Adachi K, Nishimori I, Taguchi T, Onishi S (1999) Human mitochondrial carbonic anhydrase VB. cDNA cloning, mRNA expression, subcellular localization, and mapping to chromosome x. J Biol Chem 274:21228–21233
Nagao Y, Batanian JR, Clemente MF, Sly WS (1995) Genomic organization of the human gene (CA5) and pseudogene for mitochondrial carbonic anhydrase V and their localization to chromosomes 16q and 16p. Genomics 28:477–484
Lusty CJ (1978) Carbamyl phosphate synthetase. Bicarbonate-dependent hydrolysis of ATP and potassium activation. J Biol Chem 253:4270–4278
Cohen PP (1981) The ornithine-urea cycle: biosynthesis and regulation of carbamyl phosphate synthetase I and ornithine transcarbamylase. Curr Top Cell Regul 18:1–19
McGivan JD, Bradford NM, Mendes-Mourao J (1976) The regulation of carbamoyl phosphate synthase activity in rat liver mitochondria. Biochem J 154:415–421
Lusty CJ (1978) Carbamoylphosphate synthetase I of rat-liver mitochondria. Purification, properties, and polypeptide molecular weight. Eur J Biochem/FEBS 85:373–383
Dodgson SJ, Forster RE 2nd, Schwed DA, Storey BT (1983) Contribution of matrix carbonic anhydrase to citrulline synthesis in isolated guinea pig liver mitochondria. J Biol Chem 258:7696–7701
Cao TP, Rous S (1978) Action of acetazolamide on liver pyruvate carboxylase activity, glycogenolysis and gluconeogenesis of mice. Int J Biochem 9:603–605
Hazen SA, Waheed A, Sly WS, LaNoue KF, Lynch CJ (1996) Differentiation-dependent expression of CA V and the role of carbonic anhydrase isozymes in pyruvate carboxylation in adipocytes. FASEB J 10:481–490
Mohammadi A, Leibfritz D (2009) Inhibitory effect of carbonic anhydrase inhibitors on the de novo lipogenesis. A study with 13C-NMR spectroscopy. Proc Int Soc Magn Reson Med 17:2374
Lynch CJ, Fox H, Hazen SA, Stanley BA, Dodgson S, Lanoue KF (1995) Role of hepatic carbonic anhydrase in de novo lipogenesis. Biochem J 310(Pt 1):197–202
Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488
Oommen KJ, Mathews S (1999) Zonisamide: a new antiepileptic drug. Clin Neuropharmacol 22:192–200
Gadde KM, Franciscy DM, Wagner HR II, Krishnan KR (2003) Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA 289:1820–1825
De Simone G, Di Fiore A, Menchise V, Pedone C, Antel J, Casini A, Scozzafava A, Wurl M, Supuran CT (2005) Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies. Bioorg Med Chem Lett 15:2315–2320
Poulsen SA, Wilkinson BL, Innocenti A, Vullo D, Supuran CT (2008) Inhibition of human mitochondrial carbonic anhydrases VA and VB with para-(4-phenyltriazole-1-yl)-benzenesulfonamide derivatives. Bioorg Med Chem Lett 18:4624–4627
Arechederra RL, Waheed A, Sly WS, Supuran CT, Minteer SD (2013) Effect of sulfonamides as carbonic anhydrase VA and VB inhibitors on mitochondrial metabolic energy conversion. Bioorg Med Chem 21:1544–1548
Nishimori I, Vullo D, Innocenti A, Scozzafava A, Mastrolorenzo A, Supuran CT (2005) Carbonic anhydrase inhibitors. The mitochondrial isozyme VB as a new target for sulfonamide and sulfamate inhibitors. J Med Chem 48:7860–7866
Kivela J, Parkkila S, Parkkila AK, Leinonen J, Rajaniemi H (1999) Salivary carbonic anhydrase isoenzyme VI. J Physiol 520(Pt 2):315–320
Fernley RT, Wright RD, Coghlan JP (1979) A novel carbonic anhydrase from ovine parotid glands. FEBS Lett 105:299–302
Feldstein JB, Silverman DN (1984) Purification and characterization of carbonic anhydrase from the saliva of the rat. J Biol Chem 259:5447–5453
Murakami H, Sly WS (1987) Purification and characterization of human salivary carbonic anhydrase. J Biol Chem 262:1382–1388
Parkkila S, Parkkila AK, Rajaniemi H (1995) Circadian periodicity in salivary carbonic anhydrase VI concentration. Acta Physiol Scand 154:205–211
Karhumaa P, Lienonen J, Parkkila S, Kaunisto K, Tapanainen J, Rajanemi H (2001) The identification of secreted carbonic anydrase VI as a constitutive glycoprotein of human and rat milk. Proc Natl Acad Sci U S A 98:11604–11608
Ogawa Y, Matsumoto K, Maeda T, Tamai R, Suzuki T, Sasano H, Fernley RT (2002) Characterization of lacrimal gland carbonic anhydrase VI. J Histochem Cytochem 50:821–827
Leinonen JS, Saari KA, Seppanen JM, Myllyla HM, Rajaniemi HJ (2004) Immunohistochemical demonstration of carbonic anhydrase isoenzyme VI (CA VI) expression in rat lower airways and lung. J Histochem Cytochem 52:1107–1112
Kaseda M, Ichihara N, Nishita T, Amasaki H, Asari M (2006) Immunohistochemistry of the bovine secretory carbonic anhydrase isozyme (CA-VI) in bovine alimentary canal and major salivary glands. J Vet Med Sci 68:131–135
Smith CE, Nanci A, Moffatt P (2006) Evidence by signal peptide trap technology for the expression of carbonic anhydrase 6 in rat incisor enamel organs. Eur J Oral Sci 114(Suppl 1):147–153
Kivela J, Parkkila S, Waheed A, Parkkila AK, Sly WS, Rajaniemi H (1997) Secretory carbonic anhydrase isoenzyme (CA VI) in human serum. Clin Chem 43:2318–2322
Ship JA (2003) Diabetes and oral health: an overview. J Am Dent Assoc 134 Spec No:4S–10S
Dowd FJ (1999) Saliva and dental caries. Dent Clin North Am 43:579–597
Kimoto M, Kishino M, Yura Y, Ogawa Y (2006) A role of salivary carbonic anhydrase VI in dental plaque. Arch Oral Biol 51:117–122
Kivela J, Parkkila S, Parkkila AK, Rajaniemi H (1999) A low concentration of carbonic anhydrase isoenzyme VI in whole saliva is associated with caries prevalence. Caries Res 33:178–184
Peres RC, Camargo G, Mofatto LS, Cortellazzi KL, Santos MC, Nobre-dos-Santos M, Bergamaschi CC, Line SR (2010) Association of polymorphisms in the carbonic anhydrase 6 gene with salivary buffer capacitiy, dental plaque pH, and caries index in children aged 7–9 years. Pharmacogenomics J 10:114–119
Ozturk K, Ulucan K, Akyuz S, Furuncuoglu H, Bayer H, Yarat A (2012) The investigation of genetic polymorphisms in the carbonic anhydrase VI gene exon 2 and salivary parameters in type 2 diabetic patients and healthy adults. Mol Biol Rep 39:5677–5682
Henkin RI, Martin BM, Agarwal RP (1999) Decreased parotid saliva gustin/carbonic anhydrase VI secretion: an enzyme disorder manifested by gustatory and olfactory dysfunction. Am J Med Sci 318:380–391
Henkin RI, Lippoldt RE, Bilstad J, Edelhoch H (1975) A zinc protein isolated from human parotid saliva. Proc Natl Acad Sci U S A 72:488–492
Shatzman AR, Henkin RI (1980) Metal-binding characteristics of the parotid salivary protein gustin. Biochim Biophys Acta 623:107–118
Shatzman AR, Henkin RI (1981) Gustin concentration changes relative to salivary zinc and taste in humans. Proc Natl Acad Sci U S A 78:3867–3871
Henkin RI, Schechter PJ, Hoye R, Mattern CF (1971) Idiopathic hypogeusia with dysgeusia, hyposmia, and dysosmia. A new syndrome. JAMA 217:434–440
Ortho-McNeil-Janssen Pharmaceuticals I (2013) Topomax: drug summary. Physicians’ desk reference http://www.pdr.net
Pilka ES, Kochan G, Oppermann U, Yue WW (2012) Crystal structure of the secretory isozyme of mammalian carbonic anhydrases CA VI: implications for biological assembly and inhibitor development. Biochem Biophys Res Commun 419:485–489
Hilvo M, Tolvanen M, Clark A, Shen B, Shah GN, Waheed A, Halmi P, Hanninen M, Hamalainen JM, Vihinen M, Sly WS, Parkkila S (2005) Characterization of CA XV, a new GPI-anchored from of carbonic anhydrase. Biochem J 392:83–92
Whitney PL, Briggle TV (1982) Membrane-associated carbonic anhydrase purified from bovine lung. J Biol Chem 257:12056–12059
Wistrand PJ (1984) Properties of membrane-bound carbonic anhydrase. Ann N Y Acad Sci 429:195–206
Zhu XL, Sly WS (1990) Carbonic anhydrase IV from human lung. Purification, characterization, and comparison with membrane carbonic anhydrase from human kidney. J Biol Chem 265:8795–8801
Okuyama T, Sato S, Zhu XL, Waheed A, Sly WS (1992) Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression in COS cell membranes. Proc Natl Acad Sci U S A 89:1315–1319
Baird TT Jr, Waheed A, Okuyama T, Sly WS, Fierke CA (1997) Catalysis and inhibition of human carbonic anhydrase IV. Biochemistry 36:2669–2678
Sender S, Decker B, Fenske CD, Sly WS, Carter ND, Gros G (1998) Localization of carbonic anhydrase IV in rat and human heart muscle. J Histochem Cytochem 46:855–861
Brion LP, Suarez C, Zhang H, Cammer W (1994) Up-regulation of carbonic anhydrase isozyme IV in CNS myelin of mice genetically deficient in carbonic anhydrase II. J Neurochem 63:360–366
Hageman GS, Zhu XL, Waheed A, Sly WS (1991) Localization of carbonic anhydrase IV in a specific capillary bed of the human eye. Proc Natl Acad Sci U S A 88:2716–2720
Wistrand PJ, Carter ND, Conroy CW, Mahieu I (1999) Carbonic anhydrase IV activity is localized on the exterior surface of human erythrocytes. Acta Physiol Scand 165:211–218
Conroy CW, Wynns GC, Maren TH (1996) Synthesis and properties of two new membrane-impermeant high-molecular-weight carbonic anhydrase inhibitors. Bioorg Chem 24:262–272
Maren TH, Conroy CW, Wynns GC, Godman DR (1997) Renal and cerbrospinal fluid formation pharmacology of a high molecular weight carbonic anhydrase inhibitor. J Pharmacol Exp Ther 280:98–104
Maren TH (1969) Renal carbonic anhydrase and the pharmacology of sulfonamide inhibitors. Springer-Verlag, Berlin
Sly WS, Whyte MP, Krupin T, Sundaram V (1985) Positive renal response to intravenous acetazolamide in patients with carbonic anhydrase II deficiency. Pediatr Res 19:1033–1036
Tureci O, Sahin U, Vollmar E, Siemer S, Gottert E, Seitz G, Parkkila A, Shah GN, Grubb JH, Pfreundschuh M, Sly WS (1998) Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal location of a carbonic anhydrase gene that is overexpressed in some renal cancers. Proc Natl Acad Sci U S A 93:7608–7613
Schwartz GL, Kittelberger AM, Watkins RH, O’Reilly MA (2003) Carbonic anhydrase XII mRNA encodes a hydratase that is differentially expressed along the rabbit nephron. Am J Physiol 284:F399–F410
Sterling D, Alvarez BV, Casey JR (2002) The extracellular component of a transport metabolon: extracellular loop 4 of the human AE1 Cl−/HCO3 − exchanger binds carbonic anhydrase IV. J Biol Chem 277:25239–25246
Yang Z, Alvarez B, Chakarova C, Jiang L, Karan G, Frederick JM, Zhao Y, Sauve Y, Zrenner E, Wissinger B, Den Hollander AI, Katz B, Baehr W, Cremers FP, Casey JR, Bhattacharya SS, Zhang K (2005) Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration. Hum Mol Genet 14:255–265
Rebello G, Ramesar R, Vorster A, Roberts L, Ehrenreich L, Oppon E, Gama D, Bardien S, Greenberg J, Bonapace G, Waheed A, Shah GN, Sly WS (2004) Apoptosis-inducing signal sequence mutation in carbonic anhydrase IV identified in patients with the RP17 form of retinitis pigmentosa. Proc Natl Acad Sci U S A 101:6617–6622
Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, Zavada J, Waheed A, Sly W, Lerman MI, Stanbridge EJ (2001) Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905–919
Pastorekova S, Parkkila S, Parkkila A, Opavsky R, Zelnik V, Saarnio J, Pastorek J (1997) Carbonic anhydrase IX, MN/CAIX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 112:398–408
Saarnio J, Parkkila S, Parkkila AK, Waheed A, Casey MC, Zhou XY, Pastorekova S, Pastorek J, Karttunen T, Haukipuro K, Kairaluoma MI, Sly WS (1998) Immunohistochemistry of carbonic anhydrase isozyme IX (MN/CA IX) in human gut reveals polarized expression in epithelial cells with the highest proliferative capacity. J Histochem Cytochem 46:497–504
Parkkila S, Rajaniemi H, Parkkila A, Kivela J, Waheed A, Pastorekova S, Pastorek J, Sly WS (2000) Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci U S A 97:2220–2224
Robertson N, Potter C, Harris AL (2004) Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res 64:6160–6165
Svastova E, Zilka N, Zatovicova M, Gibadulinova A, Ciampor F, Pastorek J, Pastorekova S (2003) Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with á-catenin. Exp Cell Res 290:332–345
Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, auf dem Keller U, Leung S, Huntsman D, Clarke B, Sutherland BW, Waterhouse D, Bally M, Roskelley C, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum J, Supuran CT, Dedhar S (2011) Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 71:3364–3376
Swietach P, Hulikova A, Vaughan-Jones RD, Harris AL (2010) New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene 29:6509–6521
Chiche J, Ilc K, Brahimi-Horn MC, Pouyssegur J (2010) Membrane-bound carbonic anhydrases are key pH regulators controlling tumor growth and cell migration. Adv Enzyme Regul 50:20–33
Svastova E, Hulikova A, Rafajova M, Zatovicova M, Gibadulinova A, Casini A, Cecchi A, Scozzafava A, Supuran CT, Pastorek J, Pastorekova S (2004) Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 577:439–445
Li Y, Tu C, Wang H, Silverman DN, Frost SC (2011) Catalysis and pH control by membrane-associated carbonic anhydrase IX in MDA-MB-231 breast cancer cells. J Biol Chem 286:15789–15796
Pastorek J, Pastorekova S, Callebaut I, Mornon JP, Zeln¡k V, Opavsky R, Zat’ovicov M, Liao S, Portetelle D, Stanbridge EJ, Zá-vada J, Burny A, Kettmann R (1994) 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 9:2877–2888
Opavsky R, Pastorekova S, Zeln¡k V, Gibadulinov A, Stanbridge EJ, Zá-vada J, Kettmann R, Pastorek J (1996) Human MN/CA9 Gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 33:480–487
Hilvo M, Baranauskiene L, Salzano AM, Scaloni A, Matulis D, Innocenti A, Scozzafava A, Monti SM, Di Fiore A, De Simone G, Lindfors M, Janis J, Valjakka J, Pastorekova S, Pastorek J, Kulomaa MS, Mordlund HR, Supuran CT, Parkkila S (2008) Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J Biol Chem 283:27799–27809
Li Y, Wang H, Tu C, Shiverick KT, Silverman DN, Frost SC (2011) Role of hypoxia and EGF on expression, activity, localization, and phosphorylation of carbonic anhydrase IX in MDA-MB-231 breast cancer cells. Biochim Biophys Acta 1813:159–167
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 (2009) Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci U S A 106:16233–16238
Orlowski A, De Giusti VC, Morgan PE, Aiello EA, Alvarez BV (2012) Binding of carbonic anhydrase IX to extracellular loop 4 of the NBCe1 Na +/HCO3 − cotransporter enhances NBCe1-medicated HCO3 − influx in the heart. Am J Physiol Cell Physiol 303:C69–C80
Wingo T, Tu C, Laipis PJ, Silverman DN (2001) The catalytic properties of human carbonic anhydrase IX. Biochem Biophys Res Commun 288:666–669
Wykoff CC, Beasley NJP, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrase. Cancer Res 60:7075–7083
Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, Harris AL (2001) Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast cancer. J Clin Oncol 19:3660–3668
Generali D, Fox SB, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield SM, Bruzzi P, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Bottini A, Harris AL (2006) Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer. Endocr Relat Cancer 13:921–930
Span PM, Bussink J, Manders P, Beex LVAM, Sweep CGJ (2003) Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome. Br J Cancer 89:271–276
Nordfors K, Haapasalo J, Korja M, Niemela A, Laine J, Parkkila A, Pastorekova S, Pastorek J, Waheed A, Sly WS, Parkkila S, Haapasalo H (2010) The tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a group of medulloblastomas and supratentorial primitive neuroectodermal tumours: an association of CA IX with poor prognosis. BMC Cancer 10:148
Ulmasov B, Waheed A, Shah GN, Grubb JH, Sly WS, Tu C, Silverman DN (2000) Purification and kinetic analysis of recombinant CAXII, a membrane carbonic anhydrase overexpressed in certain cancers. Proc Natl Acad Sci U S A 97:14212–14217
Vullo D, Innocenti A, Nishimori I, Pastorek J, Scozzafava A, Pastorekova S, Supuran CT (2005) Carbonic anhydrase inhibitors: inhibition of the transmembrane isozyme XII with sulfonamides – a new target for the design of antitumor and antiglaucoma drugs. Bioorg Med Chem Lett 15:963–969
Parkkila S, Parkkila AK, Saarnio J, Kivela J, Karttunen TJ, Kaunisto K, Waheed A, Sly WS, Tureci O, Virtanen I, Rajaniemi H (2000) Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors. J Histochem Cytochem 48:1601–1608
Hynninen P, Parkkila S, Huhtala H, Pastorekova S, Pastorek J, Wahl RL, Sly WS, Tomas E (2011) Carbonic anhydrase isozymes II, IX and XII in uterine tumors. Acta Physiol Microbiol Immunol Scand 120:117–129
Kivela A, Parkkila S, Saarnio J, Karttunen TJ, Kivela J, Parkkila A, Waheed A, Sly WS, Grubb JH, Shah G, Tureci O, Rajaniemi H (2000) Expression of a novel transmembrane carbonic anhydrase XII in normal human gut and colorectal tumors. Am J Pathol 156:577–584
Creighton CJ, Cordero KE, Larios JM, Miller RS, Johnson MD, Chinnaiyan AR, Lippman ME, Rae JM (2006) Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivo in tumor xernografts and human breast tumors. Genome Biol 7(R28):1–13
Barnett DH, Sheng S, Charn TH, Waheed A, Sly WS, Lin CY, Liu ET, Katzenellenbogen BS (2008) Estrogen receptor regulation of carbonic anhydrase XII through a distal enhancer in breast cancer. Cancer Res 68:3505–3515
Wykoff CC, Beasley N, Watson PH, Campo L, Chia SK, English R, Pastorek J, Sly WS, Ratcliffe P, Harris AL (2001) Expression of hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Am J Pathol 158:1011–1019
Watson PH, Chia SK, Wykoff CC, Han C, Leek RD, Sly WS, Gatter KC, Ratcliffe P, Harris AL (2003) Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma. Br J Cancer 88:1065–1070
Ilie MI, Hofman V, Ortholan C, El Ammadi R, Bonnetaud C, Havet K, Venissac N, Mouroux J, Mazure NM, Pouyssegur J, Hofman P (2011) Overexpression of carbonic anhydrase XII in tissues from resectable non-small cell lung cancers is a biomarker of good prognosis. Int J Cancer 128:1614–1623
Chien MH, Ying TH, Hsieh YH, Lin CH, Shih CH, Wei LH, Yang SF (2012) Tumor-associated carbonic anhydrase XII is linked to the growth of primary oral squamous cell carcinoma and its poor prognosis. Oral Oncol 48:417–423
Mirza NS, Alfirevic A, Jorgensen A, Marson AG, Pirmohamed M (2011) Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors. Pharmacogenet Genomics 21:297–302
Muhammad E, Leventhal N, Parvari G, Hanukoglu A, Hanukoglu I, Chalifa-Caspi V, Feinstein Y, Weinbrand J, Jacoby H, Manor E, Nagar T, Beck JC, Sheffield VC, Hershkovitz E, Parvari R (2011) Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of carbonic anhydrase 12. Hum Genet 129:397–405
Fujikawa-Adachi K, Nishimori I, Taguchi T, Onishi S (1999) Human carbonic anhydrase XIV (CA14): cDNA cloning, mRNA expression, and mapping to chromosome 1. Genomics 61:81
Kaunisto K, Parkkila S, Rajaniemi H, Waheed A, Grubb J, Sly WS (2002) Carbonic anhydrase XIV: luminal expression suggests key role in renal acidification. Kidney Int 61:2111–2118
Juel C, Lundby C, Sander M, Calbet JA, Hall G (2003) Human skeletal muscle and erythrocyte proteins involved in acid–base homeostasis: adaptations to chronic hypoxia. J Physiol 548:639–648
Vargas LA, Alvarez BV (2012) Carbonic anhydrase XIV in the normal and hypertrophic myocardium. J Mol Cell Cardiol 52:741–752
Ochrietor JD, Clamp MF, Moroz TP, Grubb JH, Shah GN, Waheed A, Sly WS, Linser PJ (2005) Carbonic anhydrase XIV identified as the membrane CA in mouse retina: strong expression in Muller cells and the RPE. Exp Eye Res 81:492–500
Linser PJ, Mosconna AA (1984) Variable CA II compartmentalization in the vertebrate retina. Ann N Y Acad Sci 429:430–446
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Frost, S.C. (2014). Physiological Functions of the Alpha Class of Carbonic Anhydrases. In: Frost, S., McKenna, R. (eds) Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry, vol 75. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7359-2_2
Download citation
DOI: https://doi.org/10.1007/978-94-007-7359-2_2
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-7358-5
Online ISBN: 978-94-007-7359-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)