Theoretical Chemistry Accounts

, Volume 118, Issue 1, pp 193–201

New computational evidence for the catalytic mechanism of carbonic anhydrase


  • Gian Pietro Miscione
    • Dipartimento di Chimica “G.Ciamician”Università di Bologna
  • Marco Stenta
    • Dipartimento di Chimica Organica “A.Mangini”Università di Bologna
  • Domenico Spinelli
    • Dipartimento di Chimica Organica “A.Mangini”Università di Bologna
  • Ernst Anders
    • Institut für Organische Chemie und Makromolekulare ChemieFriedrich-Schiller-Universität Jena
    • Dipartimento di Chimica “G.Ciamician”Università di Bologna
Regular Article

DOI: 10.1007/s00214-007-0274-x

Cite this article as:
Miscione, G.P., Stenta, M., Spinelli, D. et al. Theor Chem Account (2007) 118: 193. doi:10.1007/s00214-007-0274-x


Some aspects of the catalytic mechanism of HCA have been investigated. Either a zinc-bound water or a zinc-bound hydroxide has been considered as a nucleophile attacking CO2. No reaction path exists in the former case, while a transition state for the nucleophilic attack has been located in the latter (barrier of 7.6  kcal  mol−1). This activation energy is determined by the breaking of the hydrogen-bond network that shields the zinc-bound hydroxide when the CO2 molecule approaches the reaction center. No ambiguity exists about the mechanism for the internal rearrangement of the zinc–bicarbonate complex. The rotation pathway (Lindskog mechanism) proposed by many authors is too energy demanding since it causes the breaking of the hydrogen-bond network around the bicarbonate. The only possible rearrangement mechanism is a proton transfer (Lipscomb) that occurs in two steps (each step corresponding to a double proton transfer) and involves the Thr199 residue as a proton shuttle.


Carbonic anhydraseCatalytic mechanismTheoretical studyDFT computations
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© Springer-Verlag 2007