Evolution of Structure and Function in the Carbonic Anhydrase Isozymes of Mammals

  • R. E. Tashian
  • D. Hewett-Emmett
  • S. K. Stroup
  • M. Goodman
  • Y.-S. L. Yu
Part of the Proceedings in Life Sciences book series (LIFE SCIENCES)


Comparative studies on the primary structures of the carbonic anhydrase isozymes, designated CA I and CA II, from a number of mammlian species have shown that nearly one half (46%) of the amino acid residues at homologous positions in these isozymes has remained invariant (cf. Tashian, 1977). Because of this high degree of sequence homology between the two carbonic anhydrase isozymes and the fact that the three-dimensional structures of human CA I and CA II are very similar (Kannan et al., 1975; Liljas et al., 1972; Notstrand et al., 1974), it is clear that the structural genes for these isozymes arose from the same ancestral gene. These isozymes are known to differ, sometimes markedly, in their stabilities to heat and denaturing reagents, specific activities, and inhibition by cyclic sulfonamides, halides, and anions (Cf. Lindskog et al., 1971; Maren, 1976; Tashian, 1977). Thus, some critical changes must have evolved in the structures (active site residues?) of these isozymes to account for the observed functional differences (Notstrand et al., 1974; Kannan et al., 1977). Recently, a third isozyme of carbonic anhydrase has been reported, which we have designated CA III, from mammalian skeletal muscle (Holmes, 1977; Koester et al., 1977; Tashian, 1977, 1978; Tashian et al., 1978) some of whose properties differ strikingly from those of CA I and II. For example, the CO2 hydratase and esterase activities and sulfonamide binding affinity of the CA III isozymes are much lower than those of the CA I and II isozymes, especially the esterase activity and sulfon­amide binding affinity (Holmes, 1977; Koester et al., 1977; Tashian et al., 1978; Carter et al., 1979). In addition, the conformational properties of CA III appear to be uniquely different from CA I and CA II (Koester and Noltmann, 1979).


Carbonic Anhydrase Esterase Activity Active Site Residue Carbonic Anhy Carbonic Anhydrase Isozyme 
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  1. Andersson B, Nyman PO, Strid L (1972) Amino acid sequence of human erythrocyte CA B. Biochem Biophys Res Commun 48: 670–677CrossRefGoogle Scholar
  2. Argos P, Garavito RM, Eventoff W, Rossmann MG, Branden CI (1978) Similarities in active center geometries of zinc-containing enzymes, proteases and dehydrogenases. J Mol Biol 126: 141–158CrossRefGoogle Scholar
  3. Armstrong J McD, Myers DV, Verpoorte JA, Edsall JT (1966) Purification and properties of human erythrocyte carbonic anhydrases. J Biol Chem 241: 5137–5149Google Scholar
  4. Carter MJ (1971) The carbonic anhydrase of the rumen epithelial tissue of the ox. Biochim Biophys Acta 235: 222–236Google Scholar
  5. Carter ND (1972) Carbonic anhydrase isozymes in Cavia porcellus, Carvia aperea and their hybrids. Comp Biochem Physiol 43 B: 743–747Google Scholar
  6. Carter ND, Jeffery S, Shiels A, Edwards Y, Tipler T, Hopkinson DA (1979) Characterization of human carbonic anhydrase III from skeletal muscle. Biochem Genet 17: 837–854CrossRefGoogle Scholar
  7. Cherniack NS, Longobardo GS, Fishman AP (1974) The behavior of carbon dioxide stores of the body during unsteady states. In: Nahas G, Schaefer KE (eds) Topics in environmental physiology and medicine: Carbon dioxide and metabolic regulation. Springer, Berlin Heidelberg New York, pp 324–338CrossRefGoogle Scholar
  8. Dayhoff MO (1972) Atlas of protein sequence and structure, vol V. National Biomedical Research Foundation, Washington DCGoogle Scholar
  9. Dayhoff MO (1976) Atlas of protein sequence and structure, vol V, Suppl 2. National Biomedical Research Foundation, Washington DCGoogle Scholar
  10. De Simone J, Linde M, Tashian RE (1973) Evidence for linkage of carbonic anhydrase isozyme genes in the pig-tailed macaque, Macaca nemestrina. Nature (New Biol) 242: 55–56CrossRefGoogle Scholar
  11. Eicher EM, Stern RH, Womack JE, Davisson MT, Roderick TH, Reynolds SC (1976) Evolution of mammalian carbonic anhydrase loci by tandem duplication: Close linkage of Car-1 and Car-2 to the centromere region of chromosome 3 of the mouse. Biochem Genet 14: 651–660CrossRefGoogle Scholar
  12. Ferrell RE, Stroup SK, Tanis RJ, Tashian RE (1978) Amino acid sequence of rabbit carbonic anhydrase II. Biochim Biophys Acta 553: 1–11Google Scholar
  13. Giraud N, Marriq C, Laurent-Tabusse G (1974) Structure primaire de l’anhydrase carbonique érythrocytaire B humaine. III. Séquence des fragments ICNBr et III CNBr (résidus 149–260) Biochimie 56: 1031–1043Google Scholar
  14. Goodman M, Czelusniak J, Moore GW, Romero-Herrera AE, Matsuda G (1979) Fitting the gene lineage into its species lineage, a parsinomy strategy illustrated by cladograms constructed from globin sequences. Syst Zool 28: 132–163CrossRefGoogle Scholar
  15. Henderson LE, Henriksson D, Nyman PO (1973) Amino acid sequence of human erythrocyte carbonic anhydrase C. Biochem Biophys Res Commun 52: 1388–1393CrossRefGoogle Scholar
  16. Henderson LE, Henriksson D, Nyman PO (1976) Primary structure of human carbonic anhydrase C. J Biol Chem 251: 5457–5463Google Scholar
  17. Holmes RS (1976) Mammalian carbonic anhydrase isozymes: evidence for a third locus. J Exp Zool 197: 289–295CrossRefGoogle Scholar
  18. Holmes RS (1977) Purification, molecular properties and ontogeny of carbonic anhydrase isozymes. Evidence for A, B and C isozymes in avian and mammalian tissues. Eur J Biochem 78: 511–520CrossRefGoogle Scholar
  19. Kannan KK, Notstrand B, Fridburg K, Lövgren S, Ohlsson A, Petef M (1975) Crystal structure of human erythrocyte carbonic anhydrase B. Three-dimensional structure at a nominal 2.2 A resolution. Proc Natl Acad Sci USA 72: 51–55ADSCrossRefGoogle Scholar
  20. Kannan KK, Vaara I, Notstrand B, Lovgren S, Borell A, Friedborg K, Petef M (1977) Structure and function of carbonic anhydrase: comparative studies of sulphonamide binding to human erythrocyte carbonic anhydrases B and C. In: Roberts GCK (ed) Drug action at the molecular level. University Park Press, Baltimore, pp 73–91Google Scholar
  21. Koester MK (1979) Is carbonic anhydrase III also an acid phosphatase? Fed Proc 38: 727Google Scholar
  22. Koester MK, Noltmann EA (1979) Unique conformational properties of muscle carbonic anhy- drase III as demonstrated by circular dichroism spectrometry. Biochemistry 18: 343–348CrossRefGoogle Scholar
  23. Koester MK, Register AM, Noltmann EA (1977) Basic muscle protein, a third genetic locus iso-Google Scholar
  24. enzyme of carbonic anhydrase? Biochem Biophys Res Commun 76: 196–204Google Scholar
  25. Liljas A, Kannan KK, Bergstén P.-C, Waara I, Fridborg K, Strandberg B, Carlbom U, Järup L, Lövgren S, Petef M (1972) Crystal structure of human carbonic anhydrase C. Nature (Lon-don) 235: 131–137Google Scholar
  26. Lin K-TD, Deutsch HF (1973) Human carbonic anhydrases. XI. The complete primary structure of carbonic anhydrase B. J Biol Chem 248: 1885–1893Google Scholar
  27. Lin K-TD, Deutsch HF (1974) Human carbonic anhydrases. XII. The complete primary structure of the C isozyme. J Biol Chem 249: 2339–2337Google Scholar
  28. Lindskog S, Henderson LE, Kannan KK, Liljas A, Nyman PO, Strandberg B (1971) Carbonic anhydrase. In: Boyer PD (ed) The enzymes, vol V. Academic Press, London New York, pp 587–665Google Scholar
  29. Maren TH, Rayburn CS, Liddell ME (1976) Inhibition by anions of human red cell carbonic anhydrase B: physiological and biological implications. Science 191: 469–472ADSCrossRefGoogle Scholar
  30. McKenna MC (1969) The origin and early differentiation of therian mammals. Ann NY Acad Sci 167: 217–240ADSCrossRefGoogle Scholar
  31. Moore GW (1977) Proof of the populous path algorithm for missing mutations in parsimony trees. J Theoret Biol 66: 95–106MathSciNetCrossRefGoogle Scholar
  32. Moynihan JB (1977) Carbonic anhydrase activity in mammalian skeletal muscle and cardiac muscle. Biochem J 168: 567–569Google Scholar
  33. Notstrand B, Vaara I, Kannan KK (1974) Structural relationship of human erythrocyte carbonic anhydrase isozymes B and C. In: Markert CL (ed) Isozymes, vol I. Academic Press, London New York, pp 575-599Google Scholar
  34. Nyman PO (1963) A spectrophotometric method for the assay of carbonic anhydrase activity. Acta Chem Scand 17: 429–435CrossRefGoogle Scholar
  35. Osborne WRA, Tashian RE (1975) An improved method for the purification of carbonic anhydrase isozymes by affinity chromatogrphy. Anal Biochem 64; 297–303CrossRefGoogle Scholar
  36. Riordan JF, McElvany KD, Borders CL, Jr (1977) Arginyl residues: anion recognition sites in enzymes. Science 195: 884–886ADSCrossRefGoogle Scholar
  37. Schulz GE, Elzinga M, Marx F, Schirmer RH (1974) Three-dimensional structure of adenyl kinase. Nature (London) 250: 120–123ADSCrossRefGoogle Scholar
  38. Sciaky M, Limozin N, Filippi-Foveau D, Gullian J-M, Laurent-Tabusse G (1976) Structure primaire de l’anhydrase carbonique érythrocytaire bovine CI. Séquence complete. Biochimie 58: 1071–1082Google Scholar
  39. Tanis RJ, Ferrell RE, Tashian RE (1974) Amino acid sequence of sheep carbonic anhydrase C. Biochim Biophys Acta 371: 534–548Google Scholar
  40. Tashian RE (1977) Evolution and regulation of the carbonic anhydrase isozymes. In: Rattazzi MC, Scandalios JG, Whitt GS (eds) Isozymes: Current topics in biological and medical research, vol II. Alan R Liss Inc, New York, pp 21–62Google Scholar
  41. Tashian RE (1978) Evolution of the carbonic anhydrases. In: Matsubara H, Yamanaka T (eds) Evolution of protein molecules. Japan Scientific Societies Press, Tokyo, pp 343–360Google Scholar
  42. Tashian RE, Carter ND (1976) Biochemical genetics of carbonic anhydrase. In: Harris H, Hirsch-horn K (eds) Advances in human genetics, vol VII. Plenum Publishing Corp, New York, pp 1–56Google Scholar
  43. Tashian RE, Riggs SK, Yu Y-SL (1966) Characterization of a mutant human erythrocyte carbo-nic anhydrase: carbonic anhydrase le Guam. The amino acid substitution and carboxyl esterase and hydratase activities. Arch Biochem Biophys 117: 320–327CrossRefGoogle Scholar
  44. Tashian RE, Stroup SK, Yu Y-SL, Henriksson D (1978) Primary structure of an isozyme of carbonic anhydrase isolated from bovine skeletal muscle. Fed Proc 37: 1797Google Scholar
  45. Van Goor H (1940) Die Verbreitung und Bedeutung der Carbonanhydrase. Enzymologia 8: 113–128Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1980

Authors and Affiliations

  • R. E. Tashian
    • 1
  • D. Hewett-Emmett
    • 1
  • S. K. Stroup
    • 1
  • M. Goodman
    • 2
  • Y.-S. L. Yu
    • 1
  1. 1.Department of Human GeneticsUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of AnatomyWayne State University School of MedicineDetroitUSA

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