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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.

Fisher SZ, Tu C, Bhatt D, Govindasamy L, Agbandje-McKenna M, McKenna R, Silverman DN
Biochemistry 46 3803-13 (2007)
Related entries: 2nwo, 2nwp, 2nwz, 2nxr, 2nxs, 2nxt

Cited: 44 times
EuropePMC logo PMID: 17330962

Abstract

Catalysis of the hydration of CO2 by human carbonic anhydrase isozyme II (HCA II) is sustained at a maximal catalytic turnover of 1 mus-1 by proton transfer between a zinc-bound solvent and bulk solution. This mechanism of proton transfer is facilitated via the side chain of His64, which is located 7.5 A from the zinc, and mediated via intervening water molecules in the active-site cavity. Three hydrophilic residues that have previously been shown to contribute to the stabilization of these intervening waters were replaced with hydrophobic residues (Y7F, N62L, and N67L) to determine their effects on proton transfer. The structures of all three mutants were determined by X-ray crystallography, with crystals equilibrated from pH 6.0 to 10.0. A range of changes were observed in the ordered solvent and the conformation of the side chain of His64. Correlating these structural variants with kinetic studies suggests that the very efficient proton transfer (approximately 7 micros-1) observed for Y7F HCA II in the dehydration direction, compared with the wild type and other mutants of this study, is due to a combination of three features. First, in this mutant, the side chain of His64 showed an appreciable inward orientation pointing toward the active-site zinc. Second, in the structure of Y7F HCA II, there is an unbranched chain of hydrogen-bonded waters linking the proton donor His64 and acceptor zinc-bound hydroxide. Finally, the difference in pKa of the donor and acceptor appears favorable for proton transfer. The data suggest roles for residues 7, 62, and 67 in fine-tuning the properties of His64 for optimal proton transfer in catalysis.

Reviews - 2nwy mentioned but not cited (1)

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

Articles - 2nwy mentioned but not cited (1)

  1. Effect of active-site mutation at Asn67 on the proton transfer mechanism of human carbonic anhydrase II. Maupin CM, Zheng J, Tu C, McKenna R, Silverman DN, Voth GA. Biochemistry 48 7996-8005 (2009)


Reviews citing this publication (5)

  1. Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding. Krishnamurthy VM, Kaufman GK, Urbach AR, Gitlin I, Gudiksen KL, Weibel DB, Whitesides GM. Chem Rev 108 946-1051 (2008)
  2. Proton transfer function of carbonic anhydrase: Insights from QM/MM simulations. Riccardi D, Yang S, Cui Q. Biochim Biophys Acta 1804 342-351 (2010)
  3. Thermostable Carbonic Anhydrases in Biotechnological Applications. Di Fiore A, Alterio V, Monti SM, De Simone G, D'Ambrosio K. Int J Mol Sci 16 15456-15480 (2015)
  4. Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design. Linkuvienė V, Zubrienė A, Manakova E, Petrauskas V, Baranauskienė L, Zakšauskas A, Smirnov A, Gražulis S, Ladbury JE, Matulis D. Q Rev Biophys 51 e10 (2018)
  5. Sequestration of carbon dioxide by the hydrophobic pocket of the carbonic anhydrases. Domsic JF, McKenna R. Biochim Biophys Acta 1804 326-331 (2010)

Articles citing this publication (37)

  1. Structure and metal exchange in the cadmium carbonic anhydrase of marine diatoms. Xu Y, Feng L, Jeffrey PD, Shi Y, Morel FM. Nature 452 56-61 (2008)
  2. A short, strong hydrogen bond in the active site of human carbonic anhydrase II. Avvaru BS, Kim CU, Sippel KH, Gruner SM, Agbandje-McKenna M, Silverman DN, McKenna R. Biochemistry 49 249-251 (2010)
  3. Intramolecular proton shuttle supports not only catalytic but also noncatalytic function of carbonic anhydrase II. Becker HM, Klier M, Schüler C, McKenna R, Deitmer JW. Proc Natl Acad Sci U S A 108 3071-3076 (2011)
  4. Elucidation of the proton transport mechanism in human carbonic anhydrase II. Maupin CM, McKenna R, Silverman DN, Voth GA. J Am Chem Soc 131 7598-7608 (2009)
  5. Neutron structure of human carbonic anhydrase II: implications for proton transfer. Fisher SZ, Kovalevsky AY, Domsic JF, Mustyakimov M, McKenna R, Silverman DN, Langan PA. Biochemistry 49 415-421 (2010)
  6. Catalysis and pH control by membrane-associated carbonic anhydrase IX in MDA-MB-231 breast cancer cells. Li Y, Tu C, Wang H, Silverman DN, Frost SC. J Biol Chem 286 15789-15796 (2011)
  7. Proton transfer in catalysis and the role of proton shuttles in carbonic anhydrase. Mikulski RL, Silverman DN. Biochim Biophys Acta 1804 422-426 (2010)
  8. The Structure of Carbonic Anhydrase IX Is Adapted for Low-pH Catalysis. Mahon BP, Bhatt A, Socorro L, Driscoll JM, Okoh C, Lomelino CL, Mboge MY, Kurian JJ, Tu C, Agbandje-McKenna M, Frost SC, McKenna R. Biochemistry 55 4642-4653 (2016)
  9. A surface proton antenna in carbonic anhydrase II supports lactate transport in cancer cells. Noor SI, Jamali S, Ames S, Langer S, Deitmer JW, Becker HM. Elife 7 e35176 (2018)
  10. Transport activity of the sodium bicarbonate cotransporter NBCe1 is enhanced by different isoforms of carbonic anhydrase. Schueler C, Becker HM, McKenna R, Deitmer JW. PLoS One 6 e27167 (2011)
  11. Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network. Avvaru BS, Busby SA, Chalmers MJ, Griffin PR, Venkatakrishnan B, Agbandje-McKenna M, Silverman DN, McKenna R. Biochemistry 48 7365-7372 (2009)
  12. Role of hydrophilic residues in proton transfer during catalysis by human carbonic anhydrase II. Zheng J, Avvaru BS, Tu C, McKenna R, Silverman DN. Biochemistry 47 12028-12036 (2008)
  13. Water networks in fast proton transfer during catalysis by human carbonic anhydrase II. Mikulski R, West D, Sippel KH, Avvaru BS, Aggarwal M, Tu C, McKenna R, Silverman DN. Biochemistry 52 125-131 (2013)
  14. Neutron structure of human carbonic anhydrase II: a hydrogen-bonded water network "switch" is observed between pH 7.8 and 10.0. Fisher Z, Kovalevsky AY, Mustyakimov M, Silverman DN, McKenna R, Langan P. Biochemistry 50 9421-9423 (2011)
  15. Kinetic and structural characterization of thermostabilized mutants of human carbonic anhydrase II. Fisher Z, Boone CD, Biswas SM, Venkatakrishnan B, Aggarwal M, Tu C, Agbandje-McKenna M, Silverman D, McKenna R. Protein Eng Des Sel 25 347-355 (2012)
  16. Origins of enhanced proton transport in the Y7F mutant of human carbonic anhydrase II. Maupin CM, Saunders MG, Thorpe IF, McKenna R, Silverman DN, Voth GA. J Am Chem Soc 130 11399-11408 (2008)
  17. Structural and kinetic study of the extended active site for proton transfer in human carbonic anhydrase II. Domsic JF, Williams W, Fisher SZ, Tu C, Agbandje-McKenna M, Silverman DN, McKenna R. Biochemistry 49 6394-6399 (2010)
  18. Carbonic anhydrases and their biotechnological applications. Boone CD, Habibzadegan A, Gill S, McKenna R. Biomolecules 3 553-562 (2013)
  19. Joint neutron crystallographic and NMR solution studies of Tyr residue ionization and hydrogen bonding: Implications for enzyme-mediated proton transfer. Michalczyk R, Unkefer CJ, Bacik JP, Schrader TE, Ostermann A, Kovalevsky AY, McKenna R, Fisher SZ. Proc Natl Acad Sci U S A 112 5673-5678 (2015)
  20. Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency. Sanyanga TA, Nizami B, Bishop ÖT. Molecules 24 E3987 (2019)
  21. Tracking solvent and protein movement during CO2 release in carbonic anhydrase II crystals. Kim CU, Song H, Avvaru BS, Gruner SM, Park S, McKenna R. Proc Natl Acad Sci U S A 113 5257-5262 (2016)
  22. Slow proton transfer from the hydrogen-labelled carboxylic acid side chain (Glu-165) of triosephosphate isomerase to imidazole buffer in D2O. O'Donoghue AC, Amyes TL, Richard JP. Org Biomol Chem 6 391-396 (2008)
  23. The Crystal Structure of a hCA VII Variant Provides Insights into the Molecular Determinants Responsible for Its Catalytic Behavior. Buonanno M, Di Fiore A, Langella E, D'Ambrosio K, Supuran CT, Monti SM, De Simone G. Int J Mol Sci 19 E1571 (2018)
  24. Kinetic and crystallographic studies of the role of tyrosine 7 in the active site of human carbonic anhydrase II. Mikulski R, Avvaru BS, Tu C, Case N, McKenna R, Silverman DN. Arch Biochem Biophys 506 181-187 (2011)
  25. Membrane inlet for mass spectrometric measurement of catalysis by enzymatic decarboxylases. Moral ME, Tu C, Richards NG, Silverman DN. Anal Biochem 418 73-77 (2011)
  26. Structural and kinetic effects on changes in the CO(2) binding pocket of human carbonic anhydrase II. West D, Kim CU, Tu C, Robbins AH, Gruner SM, Silverman DN, McKenna R. Biochemistry 51 9156-9163 (2012)
  27. Multicomponent self-assembly of a pentanuclear Ir-Zn heterometal-organic polyhedron for carbon dioxide fixation and sulfite sequestration. Li X, Wu J, He C, Zhang R, Duan C. Chem Commun (Camb) 52 5104-5107 (2016)
  28. Role of Trp19 and Tyr200 in catalysis by the γ-class carbonic anhydrase from Methanosarcina thermophila. Zimmerman S, Domsic JF, Tu C, Robbins AH, McKenna R, Silverman DN, Ferry JG. Arch Biochem Biophys 529 11-17 (2013)
  29. Comparison of solution and crystal properties of Co(II)-substituted human carbonic anhydrase II. Avvaru BS, Arenas DJ, Tu C, Tanner DB, McKenna R, Silverman DN. Arch Biochem Biophys 502 53-59 (2010)
  30. Structure and catalysis by carbonic anhydrase II: role of active-site tryptophan 5. Mikulski R, Domsic JF, Ling G, Tu C, Robbins AH, Silverman DN, McKenna R. Arch Biochem Biophys 516 97-102 (2011)
  31. Exploration of the residues modulating the catalytic features of human carbonic anhydrase XIII by a site-specific mutagenesis approach. De Simone G, Di Fiore A, Truppo E, Langella E, Vullo D, Supuran CT, Monti SM. J Enzyme Inhib Med Chem 34 1506-1510 (2019)
  32. Structural, catalytic and stabilizing consequences of aromatic cluster variants in human carbonic anhydrase II. Boone CD, Gill S, Tu C, Silverman DN, McKenna R. Arch Biochem Biophys 539 31-37 (2013)
  33. Mutation of Phe91 to Asn in human carbonic anhydrase I unexpectedly enhanced both catalytic activity and affinity for sulfonamide inhibitors. Kockar F, Maresca A, Aydin M, Işik S, Turkoglu S, Sinan S, Arslan O, Güler OO, Turan Y, Supuran CT. Bioorg Med Chem 18 5498-5503 (2010)
  34. Intact carbonic acid is a viable protonating agent for biological bases. Aminov D, Pines D, Kiefer PM, Daschakraborty S, Hynes JT, Pines E. Proc Natl Acad Sci U S A 116 20837-20843 (2019)
  35. Mutation of active site residues Asn67 to Ile, Gln92 to Val and Leu204 to Ser in human carbonic anhydrase II: influences on the catalytic activity and affinity for inhibitors. Turkoglu S, Maresca A, Alper M, Kockar F, Işık S, Sinan S, Ozensoy O, Arslan O, Supuran CT. Bioorg Med Chem 20 2208-2213 (2012)
  36. Structural insights into the effect of active-site mutation on the catalytic mechanism of carbonic anhydrase. Kim JK, Lee C, Lim SW, Andring JT, Adhikari A, McKenna R, Kim CU. IUCrJ 7 985-994 (2020)
  37. Energetics and dynamics of the proton shuttle of carbonic anhydrase II. Raum HN, Fisher SZ, Weininger U. Cell Mol Life Sci 80 286 (2023)


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