Skip to main content
SpringerLink
Log in

Catalytic Mechanism of α-Class Carbonic Anhydrases: CO2 Hydration and Proton Transfer

  • Chapter
  • First Online:
Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications

Part of the book series: Subcellular Biochemistry ((SCBI,volume 75))

Abstract

The carbonic anhydrases (CAs; EC 4.2.1.1) are a family of metalloenzymes that catalyze the reversible hydration of carbon dioxide (CO2) and dehydration of bicarbonate (HCO3 −) in a two-step ping-pong mechanism:

$$ \mathrm{C}{{\mathrm{O}}_2} + {{\mathrm{H}}_2}\mathrm{O}\leftrightarrow \mathrm{HC}{{\mathrm{O}}_3}^{-} + {{\mathrm{H}}^{+}} $$

CAs are ubiquitous enzymes and are categorized into five distinct classes (α, β, γ, δ and ζ). The α-class is found primarily in vertebrates (and the only class of CA in mammals), β is observed in higher plants and some prokaryotes, γ is present only in archaebacteria whereas the δ and ζ classes have only been observed in diatoms.

The focus of this chapter is on α-CAs as the structure-function relationship is best understood for this class, in particular for humans. The reader is referred to other reviews for an overview of the structure and catalytic mechanism of the other CA classes. The overall catalytic site structure and geometry of α-CAs are described in the first section of this chapter followed by the kinetic studies, binding of CO2, and the proton shuttle network.

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 to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Eriksson AE, Jones TA, Liljas A (1988) Refined structure of human carbonic anhydrase II at 2.0 A resolution. Proteins 4:274–282

    PubMed  CAS  Google Scholar 

  2. Pocker Y, Sarkanen S (1978) Carbonic anhydrase: structure, catalytic versatility, and inhibition. Adv Enzymol Relat Areas Mol Biol 47:149–274

    Google Scholar 

  3. Krishnamurthy VM, Kaufman GK, Urbach AR, Gitlin I, Gudiksen KL, Weibel DB, Whitesides GM (2008) Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding. Chem Rev 108:946–1051

    PubMed  CAS  Google Scholar 

  4. Tu C, Sanyal G, Wynns GC, Silverman DN (1983) The pH dependence of the hydration of CO2 catalyzed by carbonic anhydrase III from skeletal muscle of the cat. Steady state and equilibrium studies. J Biol Chem 258:8867–8871

    PubMed  CAS  Google Scholar 

  5. An H, Tu C, Duda D, Montanez-Clemente I, Math K, Laipis PJ, McKenna R, Silverman DN (2002) Chemical rescue in catalysis by human carbonic anhydrases II and III. Biochemistry 41:3235–3242

    PubMed  CAS  Google Scholar 

  6. Silverman DN, Tu CK (1975) Buffer dependence of carbonic-anhydrase catalyzed oxygen-18 exchange at equilibrium. J Am Chem Soc 97:2263–2269

    CAS  Google Scholar 

  7. Avvaru BS, Kim CU, Sippel KH, Gruner SM, Agbandje-McKenna M, Silverman DN, McKenna R (2010) A short, strong hydrogen bond in the active site of human carbonic anhydrase II. Biochemistry 49:249–251

    PubMed  CAS  Google Scholar 

  8. Fisher Z, Kovalevsky AY, Mustyakimov M, Silverman DN, McKenna R, Langan P (2011) Neutron structure of human carbonic anhydrase II: a hydrogen-bonded water network “switch” is observed between pH 7.8 and 10.0. Biochemistry 50:9421–9423

    PubMed  CAS  Google Scholar 

  9. Fisher SZ, Kovalevsky AY, Mustyakimov M, McKenna R, Silverman DN, Langan P (2010) The neutron structure of human carbonic anhydrase II: Implications for proton transfer. Biochemistry 49:415–421

    PubMed  CAS  Google Scholar 

  10. Lindskog S, Silverman DN (2000) The catalytic mechanism of mammalian carbonic anhydrases. In: Chegwidden WR, Carter ND, Edwards YH (eds) The carbonic anhdyrases: new horizons. Birkhäuser Verlag, Boston, pp 175–195

    Google Scholar 

  11. Christianson DW, Fierke CA (1996) Carbonic anhydrase: evolution of the zinc binding site by nature and by design. Acc Chem Res 29:331–339

    CAS  Google Scholar 

  12. Aggarwal M, Kondeti B, McKenna R (2013) Insights towards sulfonamide drug specificity in alpha-carbonic anhydrases. Bioorg Med Chem 21:1526–1533

    PubMed  CAS  Google Scholar 

  13. Aggarwal M, McKenna R (2012) Update on carbonic anhydrase inhibitors: a patent review (2008–2011). Expert Opin Ther Pat 22:903–915

    PubMed  CAS  Google Scholar 

  14. Alterio V, Di Fiore A, D’Ambrosio K, Supuran CT, De Simone G (2012) Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chem Rev 112:4421–4468

    PubMed  CAS  Google Scholar 

  15. Boriack PA, Christianson DW, Kingery-Wood J, Whitesides GM (1995) Secondary interactions significantly removed from the sulfonamide binding pocket of carbonic anhydrase II influence inhibitor binding constants. J Med Chem 38:2286–2291

    PubMed  CAS  Google Scholar 

  16. Aggarwal M, Boone CD, Kondeti B, McKenna R (2013) Structural annotation of human carbonic anhydrases. J Enzyme Inhib Med Chem 28:267–277

    Google Scholar 

  17. Håkansson K, Carlsson M, Svensson LA, Liljas A (1992) Structure of native and apo carbonic anhydrase II and structure of some of its anion-ligand complexes. J Mol Biol 227:1192–1204

    PubMed  Google Scholar 

  18. Merz KM (1991) Carbon dioxide binding to human carbonic anhydrase II. J Am Chem Soc 113:406–411

    CAS  Google Scholar 

  19. Tu CK, Silverman DN, Forsman C, Jonsson BH, Lindskog S (1989) Role of histidine 64 in the catalytic mechanism of human carbonic anhydrase II studied with a site-specific mutant. Biochemistry 28:7913–7918

    PubMed  CAS  Google Scholar 

  20. Steiner H, Jonsson BH, Lindskog S (1975) Catalytic mechanism of carbonic-anhydrase – hydrogen-isotope effects on kinetic-parameters of human C isoenzyme. Eur J Biochem 59:253–259

    PubMed  CAS  Google Scholar 

  21. Nair SK, Christianson DW (1991) Unexpected pH-dependent conformation of His-64, the proton shuttle of carbonic anhydrase-II. J Am Chem Soc 113:9455–9458

    CAS  Google Scholar 

  22. Fisher Z, Hernandez Prada JA, Tu C, Duda D, Yoshioka C, An H, Govindasamy L, Silverman DN, McKenna R (2005) Structural and kinetic characterization of active-site histidine as a proton shuttle in catalysis by human carbonic anhydrase II. Biochemistry 44:1097–1105

    PubMed  CAS  Google Scholar 

  23. Shimahara H, Yoshida T, Shibata Y, Shimizu M, Kyogoku Y, Sakiyama F, Nakazawa T, Tate S, Ohki SY, Kato T, Moriyama H, Kishida K, Tano Y, Ohkubo T, Kobayashi Y (2007) Tautomerism of histidine 64 associated with proton transfer in catalysis of carbonic anhydrase. J Biol Chem 282:9646–9656

    PubMed  CAS  Google Scholar 

  24. Nair SK, Ludwig PA, Christianson DW (1994) Two-site binding of phenol in the active site of human carbonic anhydrase II: structural implications for substrate association. J Am Chem Soc 116:3659–3660

    CAS  Google Scholar 

  25. Fisher SZ, Maupin CM, Budayova-Spano M, Govindasamy L, Tu C, Agbandje-McKenna M, Silverman DN, Voth GA, McKenna R (2007) Atomic crystal and molecular dynamics simulation structures of human carbonic anhydrase II: insights into the proton transfer mechanism. Biochemistry 46:2930–2937

    PubMed  CAS  Google Scholar 

  26. Fisher SZ, Tu C, Bhatt D, Govindasamy L, Agbandje-McKenna M, McKenna R, Silverman DN (2007) Speeding up proton transfer in a fast enzyme: kinetic and crystallographic studies on the effect of hydrophobic amino acid substitutions in the active site of human carbonic anhydrase II. Biochemistry 46:3803–3813

    PubMed  CAS  Google Scholar 

  27. Mikulski R, Avvaru BS, Tu C, Case N, McKenna R, Silverman DN (2011) Kinetic and crystallographic studies of the role of tyrosine 7 in the active site of human carbonic anhydrase II. Arch Biochem Biophys 506:181–187

    PubMed  CAS  Google Scholar 

  28. Mikulski R, West D, Sippel KH, Avvaru BS, Aggarwal M, Tu C, McKenna R, Silverman DN (2013) Water networks in fast proton transfer during catalysis by human carbonic anhydrase II. Biochemistry 52:125–131

    PubMed  CAS  Google Scholar 

  29. Mikulski R, Domsic JF, Ling G, Tu C, Robbins AH, Silverman DN, McKenna R (2011) Structure and catalysis by carbonic anhydrase II: role of active-site tryptophan 5. Arch Biochem Biophys 516:97–102

    PubMed  CAS  Google Scholar 

  30. Mikulski RL, Silverman DN (2010) Proton transfer in catalysis and the role of proton shuttles in carbonic anhydrase. Biochim Biophys Acta 1804:422–426

    PubMed  CAS  Google Scholar 

  31. Domsic JF, Williams W, Fisher SZ, Tu C, Agbandje-McKenna M, Silverman DN, McKenna R (2010) Structural and kinetic study of the extended active site for proton transfer in human carbonic anhydrase II. Biochemistry 49:6394–6399

    PubMed  CAS  Google Scholar 

  32. Duda DM, Tu C, Fisher SZ, An H, Yoshioka C, Govindasamy L, Laipis PJ, Agbandje-McKenna M, Silverman DN, McKenna R (2005) Human carbonic anhydrase III: structural and kinetic study of catalysis and proton transfer. Biochemistry 44:10046–10053

    PubMed  CAS  Google Scholar 

  33. Harju AK, Bootorabi F, Kuuslahti M, Supuran CT, Parkkila S (2012) Carbonic anhydrase III: a neglected isozyme is stepping into the limelight. J Enzyme Inhib Med Chem 28:231–239

    PubMed  Google Scholar 

  34. Boriack PA, Heck RW, Laipis PJ, Silverman DN, Christianson DW (1995) Structure determination of murine mitochondrial carbonic anhydrase V at 2.45-A resolution: implications for catalytic proton transfer and inhibitor design. Proc Natl Acad Sci U S A 92:10949–10953

    Google Scholar 

  35. Liu Z, Bartlow P, Dilmore RM, Soong Y, Pan Z, Koepsel R, Ataai M (2009) Production, purification, and characterization of a fusion protein of carbonic anhydrase from Neisseria gonorrhoeae and cellulose binding domain from Clostridium thermocellum. Biotechnol Prog 25:68–74

    PubMed  Google Scholar 

  36. Mårtensson L-G, Karlsson M, Carlsson U (2002) Dramatic stabilization of the native state of human carbonic anhydrase II by an engineered disulfide bond. Biochemistry 41:15867–15875

    PubMed  Google Scholar 

  37. De Luca V, Vullo D, Scozzafava A, Carginale V, Rossi M, Supuran CT, Capasso C (2012) Anion inhibition studies of an alpha-carbonic anhydrase from the thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1. Bioorg Med Chem Lett 22:5630–5634

    PubMed  Google Scholar 

  38. Vullo D, De Luca V, Scozzafava A, Carginale V, Rossi M, Supuran CT, Capasso C (2012) The first activation study of a bacterial carbonic anhydrase (CA). The thermostable alpha-CA from Sulfurihydrogenibium yellowstonense YO3AOP1 is highly activated by amino acids and amines. Bioorg Med Chem Lett 22:6324–6327

    PubMed  CAS  Google Scholar 

  39. Luca VD, Vullo D, Scozzafava A, Carginale V, Rossi M, Supuran CT, Capasso C (2013) An alpha-carbonic anhydrase from the thermophilic bacterium Sulphurihydrogenibium azorense is the fastest enzyme known for the CO(2) hydration reaction. Bioorg Med Chem 21:1465–1469

    PubMed  CAS  Google Scholar 

  40. Syrjanen L, Tolvanen ME, Hilvo M, Vullo D, Carta F, Supuran CT, Parkkila S (2013) Characterization, bioinformatic analysis and dithiocarbamate inhibition studies of two new alpha-carbonic anhydrases, CAH1 and CAH2, from the fruit fly Drosophila melanogaster. Bioorg Med Chem 21:1516–1521

    PubMed  CAS  Google Scholar 

  41. Demirdag R, Comakli V, Senturk M, Ekinci D, Irfan Kufrevioglu O, Supuran CT (2013) Purification and characterization of carbonic anhydrase from sheep kidney and effects of sulfonamides on enzyme activity. Bioorg Med Chem 21:1522–1525

    PubMed  CAS  Google Scholar 

  42. Maresca A, Vullo D, Scozzafava A, Supuran CT (2013) Inhibition of the alpha- and beta-carbonic anhydrases from the gastric pathogen Helycobacter pylori with anions. J Enzyme Inhib Med Chem 28:388–391

    PubMed  Google Scholar 

  43. Demirdag R, Yerlikaya E, Senturk M, Kufrevioglu OI, Supuran CT (2013) Heavy metal ion inhibition studies of human, sheep and fish alpha-carbonic anhydrases. J Enzyme Inhib Med Chem 28:278–282

    PubMed  Google Scholar 

  44. Kolayli S, Karahalil F, Sahin H, Dincer B, Supuran CT (2011) Characterization and inhibition studies of an alpha-carbonic anhydrase from the endangered sturgeon species Acipenser gueldenstaedti. J Enzyme Inhib Med Chem 26:895–900

    PubMed  CAS  Google Scholar 

  45. Cincinelli A, Martellini T, Innocenti A, Scozzafava A, Supuran CT (2011) Purification and inhibition studies with anions and sulfonamides of an alpha-carbonic anhydrase from the Antarctic seal Leptonychotes weddellii. Bioorg Med Chem 19:1847–1851

    PubMed  CAS  Google Scholar 

  46. Ekinci D, Ceyhun SB, Senturk M, Erdem D, Kufrevioglu OI, Supuran CT (2011) Characterization and anions inhibition studies of an alpha-carbonic anhydrase from the teleost fish Dicentrarchus labrax. Bioorg Med Chem 19:744–748

    PubMed  CAS  Google Scholar 

  47. Innocenti A, Supuran CT (2010) Paraoxon, 4-nitrophenyl phosphate and acetate are substrates of alpha- but not of beta-, gamma- and zeta-carbonic anhydrases. Bioorg Med Chem Lett 20:6208–6212

    PubMed  CAS  Google Scholar 

  48. Del Prete S, Isik S, Vullo D, De Luca V, Carginale V, Scozzafava A, Supuran CT, Capasso C (2012) DNA cloning, characterization, and inhibition studies of an alpha-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae. J Med Chem 55:10742–10748

    PubMed  Google Scholar 

  49. Krungkrai J, Supuran CT (2008) The alpha-carbonic anhdyrase from the malaria parasite and its inhibition. Curr Pharm Des 14:631–640

    PubMed  CAS  Google Scholar 

  50. Ohradanova A, Vullo D, Pastorekova S, Pastorek J, Jackson DJ, Worheide G, Supuran CT (2012) Cloning, characterization and sulfonamide inhibition studies of an alpha-carbonic anhydrase from the living fossil sponge Astrosclera willeyana. Bioorg Med Chem 20:1403–1410

    PubMed  CAS  Google Scholar 

  51. Bertucci A, Innocenti A, Scozzafava A, Tambutte S, Zoccola D, Supuran CT (2011) Carbonic anhydrase inhibitors. Inhibition studies with anions and sulfonamides of a new cytosolic enzyme from the scleractinian coral Stylophora pistillata. Bioorg Med Chem Lett 21:710–714

    PubMed  CAS  Google Scholar 

  52. Bertucci A, Tambutte S, Supuran CT, Allemand D, Zoccola D (2011) A new coral carbonic anhydrase in Stylophora pistillata. Mar Biotechnol (NY) 13:992–1002

    CAS  Google Scholar 

  53. Guzel O, Innocenti A, Hall RA, Scozzafava A, Muhlschlegel FA, Supuran CT (2009) Carbonic anhydrase inhibitors. The nematode alpha-carbonic anhydrase of Caenorhabditis elegans CAH-4b is highly inhibited by 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides. Bioorg Med Chem 17:3212–3215

    PubMed  CAS  Google Scholar 

  54. Crocetti L, Maresca A, Temperini C, Hall RA, Scozzafava A, Muhlschlegel FA, Supuran CT (2009) A thiabendazole sulfonamide shows potent inhibitory activity against mammalian and nematode alpha-carbonic anhydrases. Bioorg Med Chem Lett 19:1371–1375

    PubMed  CAS  Google Scholar 

  55. Bergenhem NC, Hallberg M, Wisén S (1998) Molecular characterization of the human carbonic anhydrase-related protein (HCA-RP VIII). Biochim Biophys Acta 1384:294–298

    PubMed  CAS  Google Scholar 

  56. Nishimori I, Vullo D, Minakuchi T, Scozzafava A, Capasso C, Supuran CT (2013) Restoring catalytic activity to the human carbonic anhydrase (CA) related proteins VIII, X and XI affords isoforms with high catalytic efficiency and susceptibility to anion inhibition. Bioorg Med Chem Lett 23:256–260

    PubMed  CAS  Google Scholar 

  57. Lakkis MM, Bergenhem NC, O’Shea S, Tashian RE (1997) Expression of the acatalytic carbonic anhdyrase VIII gene, Car8, during mouse embryonic development. Histochem J 29:135–141

    PubMed  CAS  Google Scholar 

  58. Hirota J, Ando H, Hamada K, Mikoshiba K (2003) Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1. Biochem J 372:435–441

    PubMed  CAS  Google Scholar 

  59. Bosanac I, Alattia JR, Mal TK, Chan J, Talarico S, Tong FK, Tong KI, Yoshikawa F, Furuichi T, Iwai M, Michikawa T, Mikoshiba K, Ikura M (2002) Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand. Nature 420:696–700

    PubMed  CAS  Google Scholar 

  60. Jiao Y, Yan J, Zhao Y, Donahue LR, Beamer WG, Li X, Roe BA, Ledoux MS, Gu W (2005) Carbonic anhydrase-related protein VIII deficiency is associated with a distinctive lifelong gait disorder in waddles mice. Genetics 171:1239–1246

    PubMed  CAS  Google Scholar 

  61. 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

    PubMed  CAS  Google Scholar 

  62. Lindskog S (1997) Structure and mechanism of carbonic anhydrase. Pharmacol Ther 74:1–20

    PubMed  CAS  Google Scholar 

  63. Silverman DN, Lindskog S (1988) The catalytic mechanism of carbonic anhydrase: implications of a rate-limiting protolysis of water. Acc Chem Res 21:30–36

    CAS  Google Scholar 

  64. Khalifah RG (1971) The carbon dioxide hydration activity of carbonic anhydrase I. Stop-flow kinetic studies on the native human isoenzyme B and C. J Biol Chem 246:2561–2573

    PubMed  CAS  Google Scholar 

  65. Silverman DN, McKenna R (2007) Solvent-mediated proton transfer in catalysis by carbonic anhydrase. Acc Chem Res 40:669–675

    PubMed  CAS  Google Scholar 

  66. Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181

    PubMed  CAS  Google Scholar 

  67. Supuran CT, Scozzafava A, Casini A (2003) Carbonic anhydrase inhibitors. Med Res Rev 23:146–189

    PubMed  CAS  Google Scholar 

  68. 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

    PubMed  CAS  Google Scholar 

  69. Nishimori I, Minakuchi T, Onishi S, Vullo D, Scozzafava A, Supuran CT (2007) Carbonic anhydrase inhibitors. DNA cloning, characterization, and inhibition studies of the human secretory isoform VI, a new target for sulfonamide and sulfamate inhibitors. J Med Chem 50:381–388

    PubMed  CAS  Google Scholar 

  70. Vullo D, Voipio J, Innocenti A, Rivera C, Ranki H, Scozzafava A, Kaila K, Supuran CT (2005) Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isozyme VII with aromatic and heterocyclic sulfonamides. Bioorg Med Chem Lett 15:971–976

    PubMed  CAS  Google Scholar 

  71. Vullo D, Franchi M, Gallori E, Pastorek J, Scozzafava A, Pastorekova S, Supuran CT (2003) Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulfonamides. Bioorg Med Chem Lett 13:1005–1009

    PubMed  CAS  Google Scholar 

  72. 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

    PubMed  CAS  Google Scholar 

  73. Lehtonen J, Shen B, Vihinen M, Casini A, Scozzafava A, Supuran CT, Parkkila AK, 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

    PubMed  CAS  Google Scholar 

  74. Whittington DA, Grubb JH, Waheed A, Shah GN, Sly WS, Christianson DW (2004) Expression, assay, and structure of the extracellular domain of murine carbonic anhydrase XIV: implications for selective inhibition of membrane-associated isozymes. J Biol Chem 279:7223–7228

    PubMed  Google Scholar 

  75. Ren X, Jonsson B-H, Millqvist E, Lindskog S (1988) A comparison of the kinetic properties of native bovine muscle carbonic anhydrase and an activated derivative with modified thiol groups. Biochim Biophys Acta (BBA) Protein Struct Mol Enzymol 953:79–85

    CAS  Google Scholar 

  76. Hurt JD, Tu C, Laipis PJ, Silverman DN (1997) Catalytic properties of murine carbonic anhydrase IV. J Biol Chem 272:13512–13518

    PubMed  CAS  Google Scholar 

  77. Feldstein JB, Silverman DN (1984) Purification and characterization of carbonic anhdyrase from the saliva of the rat. J Biol Chem 259:5447–5453

    PubMed  CAS  Google Scholar 

  78. Elleby B, Chirica LC, Tu C, Zeppezauer M, Lindskog S (2001) Characterization of carbonic anhydrase from Neisseria gonorrhoeae. Eur J Biochem 268:1613–1619

    PubMed  CAS  Google Scholar 

  79. Del Prete S, De Luca V, Scozzafava A, Carginale V, Supuran CT, Capasso C (2013) Biochemical properties of a new alpha-carbonic anhydrase from the human pathogenic bacterium, Vibrio cholerae. J Enzyme Inhib Med Chem. doi:10.3109/14756366.2012.747197

  80. Akdemir A, Vullo D, De Luca V, Scozzafava A, Carginale V, Rossi M, Supuran CT, Capasso C (2013) The extremo-alpha-carbonic anhydrase (CA) from Sulfurihydrogenibium azorense, the fastest CA known, is highly activated by amino acids and amines. Bioorg Med Chem Lett 23:1087–1090

    Google Scholar 

  81. Capasso C, De Luca V, Carginale V, Cannio R, Rossi M (2012) Biochemical properties of a novel and highly thermostable bacterial alpha-carbonic anhydrase from Sulfurihydrogenibium yellowstonense YO3AOP1. J Enzyme Inhib Med Chem 27:892–897

    PubMed  CAS  Google Scholar 

  82. Syrjanen L, Tolvanen M, Hilvo M, Olatubosun A, Innocenti A, Scozzafava A, Leppiniemi J, Niederhauser B, Hytonen VP, Gorr TA, Parkkila S, Supuran CT (2010) Characterization of the first beta-class carbonic anhydrase from an arthropod (Drosophila melanogaster) and phylogenetic analysis of beta-class carbonic anhydrases in invertebrates. BMC Biochem 11:28

    PubMed  Google Scholar 

  83. Nishimori I, Minakuchi T, Kohsaki T, Onishi S, Takeuchi H, Vullo D, Scozzafava A, Supuran CT (2007) Carbonic anhydrase inhibitors: the beta-carbonic anhydrase from Helicobacter pylori is a new target for sulfonamide and sulfamate inhibitors. Bioorg Med Chem Lett 17:3585–3594

    PubMed  CAS  Google Scholar 

  84. Nishimori I, Minakuchi T, Morimoto K, Sano S, Onishi S, Takeuchi H, Vullo D, Scozzafava A, Supuran CT (2006) Carbonic anhydrase inhibitors: DNA cloning and inhibition studies of the alpha-carbonic anhydrase from Helicobacter pylori, a new target for developing sulfonamide and sulfamate gastric drugs. J Med Chem 49:2117–2126

    PubMed  CAS  Google Scholar 

  85. Rowlett RS, Tu C, McKay MM, Preiss JR, Loomis RJ, Hicks KA, Marchione RJ, Strong JA, Donovan GS Jr, Chamberlin JE (2002) Kinetic characterization of wild-type and proton transfer-impaired variants of beta-carbonic anhydrase from Arabidopsis thaliana. Arch Biochem Biophys 404:197–209

    PubMed  CAS  Google Scholar 

  86. Alber BE, Colangelo CM, Dong J, Stalhandske CM, Baird TT, Tu C, Fierke CA, Silverman DN, Scott RA, Ferry JG (1999) Kinetic and spectroscopic characterization of the gamma-carbonic anhydrase from the methanoarchaeon Methanosarcina thermophila. Biochemistry 38:13119–13128

    PubMed  CAS  Google Scholar 

  87. Eriksson AE, Kylsten PM, Jones TA, Liljas A (1968) Crystallographic studies of inhibitor binding sites in human carbonic anhydrase II: a pentacoordinated binding of the SCN-ion to the zinc at high pH. Proteins 4:283–293

    Google Scholar 

  88. Lindahl M, Svensson LA, Liljas A (1993) Metal poison inhibition of carbonic anhydrase. Proteins 15:177–182

    PubMed  CAS  Google Scholar 

  89. Williams TJ, Henkens RW (1985) Dynamic carbon-13 NMR investigations of substrate interaction and catalysis by cobalt(II) human carbonic anhydrase I. Biochemistry 24:2459–2462

    PubMed  CAS  Google Scholar 

  90. Bertini I, Luchinat C, Monnanni R, Roelens S, Moratal JM (1987) Interaction of carbon dioxide and copper(II) carbonic anhydrase. J Am Chem Soc 109:7855–7856

    CAS  Google Scholar 

  91. Krebs JF, Rana F, Dluhy RA, Fierke CA (1993) Kinetic and spectroscopic studies of hydrophilic amino acid substitutions in the hydrophobic pocket of human carbonic anhydrase II. Biochemistry 32:4496–4505

    PubMed  CAS  Google Scholar 

  92. Supuran CT (2008) Carbonic anhydrases–an overview. Curr Pharm Des 14:603–614

    PubMed  CAS  Google Scholar 

  93. Supuran CT (2010) Carbonic anhydrase inhibitors. Bioorg Med Chem Lett 20:3467–3474

    PubMed  CAS  Google Scholar 

  94. Supuran CT (2012) Inhibition of carbonic anhydrase IX as a novel anticancer mechanism. World J Clin Oncol 3:98–103

    PubMed  Google Scholar 

  95. Supuran CT, Scozzafava A (2007) Carbonic anhydrases as targets for medicinal chemistry. Bioorg Med Chem 15:4336–4350

    PubMed  CAS  Google Scholar 

  96. Domsic JF, McKenna R (2010) Sequestration of carbon dioxide by the hydrophobic pocket of the carbonic anhydrases. Biochim Biophys Acta 1804:326–331

    PubMed  CAS  Google Scholar 

  97. Liang JY, Lipscomb WN (1990) Binding of substrate CO2 to the active site of human carbonic anhydrase II: a molecular dynamics study. Proc Natl Acad Sci U S A 87:3675–3679

    PubMed  CAS  Google Scholar 

  98. Domsic JF, Avvaru BS, Kim CU, Gruner SM, Agbandje-McKenna M, Silverman DN, McKenna R (2008) Entrapment of carbon dioxide in the active site of carbonic anhydrase II. J Biol Chem 283:30766–30771

    PubMed  CAS  Google Scholar 

  99. Sjoblom B, Polentarutti M, Djinovic-Carugo K (2009) Structural study of X-ray induced activation of carbonic anhydrase. Proc Natl Acad Sci U S A 106:10609–10613

    PubMed  Google Scholar 

  100. Kim CU, Kapfer R, Gruner SM (2005) High-pressure cooling of protein crystals without cryoprotectants. Acta Crystallogr D Biol Crystallogr 61:881–890

    PubMed  Google Scholar 

  101. Xue Y, Vidgren J, Svensson LA, Liljas A, Jonsson BH, Lindskog S (1993) Crystallographic analysis of Thr-200 → His human carbonic anhydrase II and its complex with the substrate, HCO3. Proteins 15:80–87

    PubMed  CAS  Google Scholar 

  102. Huang S, Sjöblom B, Sauer-Eriksson AE, Jonsson B-H (2002) Organization of an efficient carbonic anhydrase: implications for the mechanism based on structure–function studies of a T199P/C206S mutant. Biochemistry 41:7628–7635

    PubMed  CAS  Google Scholar 

  103. West D, Kim CU, Tu C, Robbins AH, Gruner SM, Silverman DN, McKenna R (2012) Structural and kinetic effects on changes in the CO(2) binding pocket of human carbonic anhydrase II. Biochemistry 51:9156–9163

    PubMed  CAS  Google Scholar 

  104. Pocker Y, Sarkanen S (1978) Carbonic anhydrase: structure, catalytic versatility, and inhibition. Adv Enzymol Relat Areas Mol Biol 47:149–274

    PubMed  CAS  Google Scholar 

  105. Tu CK, Silverman DN (1982) Solvent deuterium-isotope effects in the catalysis of O-18 exchange by human carbonic anhydrase-II. Biochemistry 21:6353–6360

    PubMed  CAS  Google Scholar 

  106. Pocker Y, Bjorkquist DW (1977) Comparative studies of bovine carbonic anhydrase in H2O and D2O. Stopped-flow studies of the kinetics of interconversion of CO2 and HCO3. Biochemistry 16:5698–5707

    PubMed  CAS  Google Scholar 

  107. Rowlett RS, Chance MR, Wirt MD, Sidelinger DE, Royal JR, Woodroffe M, Wang YFA, Saha RP, Lam MG (1994) Kinetic and structural characterization of spinach carbonic-anhydrase. Biochemistry 33:13967–13976

    PubMed  CAS  Google Scholar 

  108. Hsu JL, Hsieh Y, Tu C, O’Connor D, Nick HS, Silverman DN (1996) Catalytic properties of human manganese superoxide dismutase. J Biol Chem 271:17687–17691

    PubMed  CAS  Google Scholar 

  109. Bull C, Niederhoffer EC, Yoshida T, Fee JA (1991) Kinetic-studies of superoxide dismutases – properties of the manganese-containing protein from Thermus thermophilus. J Am Chem Soc 113:4069–4076

    CAS  Google Scholar 

  110. Lindskog S, Coleman JE (1973) Catalytic mechanism of carbonic-anhydrase. Proc Natl Acad Sci U S A 70:2505–2508

    PubMed  CAS  Google Scholar 

  111. Campbell ID, Lindskog S, White AI (1975) A study of the histidine residues of human carbonic anhydrase C using 270 MHz proton magnetic resonance. J Mol Biol 98:597–614

    PubMed  CAS  Google Scholar 

  112. Braun-Sand S, Strajbl M, Warshel A (2004) Studies of proton translocations in biological systems: simulating proton transport in carbonic anhydrase by EVB-based models. Biophys J 87:2221–2239

    PubMed  CAS  Google Scholar 

  113. Riccardi D, Konig P, Prat-Resina X, Yu H, Elstner M, Frauenheim T, Cui Q (2006) “Proton holes” in long-range proton transfer reactions in solution and enzymes: a theoretical analysis. J Am Chem Soc 128:16302–16311

    PubMed  CAS  Google Scholar 

  114. Venkatasubban KS, Silverman DN (1980) Carbon-dioxide hydration activity of carbonic-anhydrase in mixtures of water and deuterium-oxide. Biochemistry 19:4984–4989

    PubMed  CAS  Google Scholar 

  115. Krebs JF, Fierke CA, Alexander RS, Christianson DW (1991) Conformational mobility of His-64 in the Thr200Ser mutant of human carbonic anhydrase-II. Biochemistry 30:9153–9160

    PubMed  CAS  Google Scholar 

  116. Riccardi D, Konig P, Guo H, Cui Q (2008) Proton transfer in carbonic anhydrase is controlled by electrostatics rather than the orientation of the acceptor. Biochemistry 47:2369–2378

    PubMed  CAS  Google Scholar 

  117. Silverman DN, Tu C, Chen X, Tanhauser SM, Kresge AJ, Laipis PJ (1993) Rate-equilibria relationships in intramolecular proton transfer in human carbonic anhydrase III. Biochemistry 32:10757–10762

    PubMed  CAS  Google Scholar 

  118. Tu C, Rowlett RS, Tripp BC, Ferry JG, Silverman DN (2002) Chemical rescue of proton transfer in catalysis by carbonic anhydrases in the beta- and gamma-class. Biochemistry 41:15429–15435

    PubMed  CAS  Google Scholar 

  119. Iverson TM, Alber BE, Kisker C, Ferry JG, Rees DC (2000) A closer look at the active site of gamma-class carbonic anhydrases: high-resolution crystallographic studies of the carbonic anhydrase from Methanosarcina thermophila. Biochemistry 39:9222–9231

    PubMed  CAS  Google Scholar 

  120. Jude KM, Wright SK, Tu C, Silverman DN, Viola RE, Christianson DW (2002) Crystal structure of F65A/Y131C-methylimidazole carbonic anhydrase V reveals architectural features of an engineered proton shuttle. Biochemistry 41:2485–2491

    PubMed  CAS  Google Scholar 

  121. Ramaswamy S, Park DH, Plapp BV (1999) Substitutions in a flexible loop of horse liver alcohol dehydrogenase hinder the conformational change and unmask hydrogen transfer. Biochemistry 38:13951–13959

    PubMed  CAS  Google Scholar 

  122. Fisher SZ, Aggarwal M, Kovalesky A, Silverman DN, McKenna R (2012) Neutron-diffraction of acetazolamide-bound human carbonic anhydrase II reveals atomic details of drug binding. J Am Chem Soc 134:14726–14729

    PubMed  CAS  Google Scholar 

  123. Roy A, Taraphder S (2007) Identification of proton-transfer pathways in human carbonic anhydrase II. J Phys Chem B 111:10563–10576

    PubMed  CAS  Google Scholar 

  124. Maupin CM, Voth GA (2010) Proton transport in carbonic anhydrase: Insights from molecular simulation. Biochim Biophys Acta-Proteins Proteomics 1804:332–341

    CAS  Google Scholar 

  125. Maupin CM, McKenna R, Silverman DN, Voth GA (2009) Elucidation of the proton transport mechanism in human carbonic anhydrase II. J Am Chem Soc 131:7598–7608

    PubMed  CAS  Google Scholar 

  126. Cui Q, Karplus M (2003) Is a “proton wire” concerted or stepwise? A model study of proton transfer in carbonic anhydrase. J Phys Chem B 107:1071–1078

    CAS  Google Scholar 

  127. Fisher SZ, Tu CK, Bhatt D, Govindasamy L, Agbandje-McKenna M, McKenna R, Silverman DN (2007) Speeding up proton transfer in a fast enzyme: kinetic and crystallographic studies on the effect of hydrophobic amino acid substitution in the active site of human carbonic anhydrase II. Biochemistry 42:3803–3813

    Google Scholar 

  128. Maupin CM, Saunders MG, Thorpe IF, McKenna R, Silverman DN, Voth GA (2008) Origins of enhanced proton transport in the Y7F mutant of human carbonic anhydrase II. J Am Chem Soc 130:11399–11408

    PubMed  CAS  Google Scholar 

  129. Khalifah RG (1973) Carbon-dioxide hydration activity of carbonic-anhydrase – paradoxical consequences of unusually rapid catalysis. Proc Natl Acad Sci U S A 70:1986–1989

    PubMed  CAS  Google Scholar 

  130. Butler JN (1982) Carbon dioxide equilibria and their applications. Addison-Wesley, Reading

    Google Scholar 

  131. Alberty RA (1962) The interpretation of steady state kinetic data on enzymatic reactions. Brookhaven Symp Biol 15:18

    PubMed  CAS  Google Scholar 

  132. Prince RH, Woolley PR (1973) Mechanism of action of carbonic-anhydrase. Bioorg Chem 2:337–344

    CAS  Google Scholar 

  133. Tu CK, Silverman DN (1975) Mechanism of carbonic-anhydrase studied by C-13 and O-18 labeling of carbon-dioxide. J Am Chem Soc 97:5935–5936

    PubMed  CAS  Google Scholar 

  134. Silverman DN (1982) Carbonic anhydrase: oxygen-18 exchange catalyzed by an enzyme with rate-contributing proton-transfer steps. Methods Enzymol 87:732–752

    PubMed  CAS  Google Scholar 

  135. Rowlett RS, Silverman DN (1982) Kinetics of the protonation of buffer and hydration of Co-2 catalyzed by human carbonic anhydrase-II. J Am Chem Soc 104:6737–6741

    CAS  Google Scholar 

  136. Admiraal SJ, Meyer P, Schneider B, Deville-Bonne D, Janin J, Herschlag D (2001) Chemical rescue of phosphoryl transfer in a cavity mutant: a cautionary tale for site-directed mutagenesis. Biochemistry 40:403–413

    PubMed  CAS  Google Scholar 

  137. Elder I, Tu CK, Ming LJ, McKenna R, Silverman DN (2005) Proton transfer from exogenous donors in catalysis by human carbonic anhydrase II. Arch Biochem Biophys 437:106–114

    PubMed  CAS  Google Scholar 

  138. Maupin CM, Castillo N, Taraphder S, Tu CK, McKenna R, Silverman DN, Voth GA (2011) Chemical rescue of enzymes: proton transfer in mutants of human carbonic anhydrase II. J Am Chem Soc 133:6223–6234

    PubMed  CAS  Google Scholar 

  139. Kresge AJ, Silverman DN (1999) Application of Marcus rate theory to proton transfer in enzyme-catalyzed reactions. Methods Enzymol 308:276–297

    PubMed  CAS  Google Scholar 

  140. Schutz CN, Warshel A (2004) Analyzing free energy relationships for proton translocations in enzymes: carbonic anhydrase revisited. J Phys Chem B 108:2066–2075

    CAS  Google Scholar 

  141. Closs GL, Calcaterra LT, Green NJ, Penfield KW, Miller JR (1986) Distance, stereoelectronic effects, and the Marcus inverted region in intramolecular electron-transfer in organic radical-anions. J Phys Chem 90:3673–3683

    CAS  Google Scholar 

  142. Peters KS, Cashin A, Timbers P (2000) Picosecond dynamics of nonadiabatic proton transfer: a kinetic study of proton transfer within the contact radical ion pair of substituted benzophenones/N, N-dimethylaniline. J Am Chem Soc 122:107–113

    CAS  Google Scholar 

  143. Edwards SJ, Soudackov AV, Hammes-Schiffer S (2009) Driving force dependence of rates for nonadiabatic proton and proton-coupled electron transfer: conditions for inverted region behavior. J Phys Chem B 113:14545–14548

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA

    Christopher D. Boone, Melissa Pinard & Rob McKenna

  2. Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA

    David Silverman

Authors
  1. Christopher D. Boone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melissa Pinard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rob McKenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Silverman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Silverman .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA

    Susan C. Frost

  2. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA

    Robert McKenna

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Boone, C.D., Pinard, M., McKenna, R., Silverman, D. (2014). Catalytic Mechanism of α-Class Carbonic Anhydrases: CO2 Hydration and Proton Transfer. 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_3

Download citation

Publish with us

Policies and ethics

Search

Navigation