Structure and mechanism of carbonic anhydrase.
Carbonic anhydrase (CA; carbonate hydro-lyase, EC 18.104.22.168) is a zinc-containing enzyme that catalyzes the reversible hydration of carbon dioxide: CO2+ H2O<-->HCO3(-)+H+. The enzyme is the target for drugs, such as acetazolamide, methazolamide, and dichlorphenamide, for the treatment of glaucoma. There are three evolutionarily unrelated CA families, designated alpha, beta, and gamma. All known CAs from the animal kingdom are of the alpha type. There are seven mammalian CA isozymes with different tissue distributions and intracellular locations, CA I-VII. Crystal structures of human CA I and II, bovine CA III, and murine CA V have been determined. All of them have the same tertiary fold, with a central 10-stranded beta-sheet as the dominating secondary structure element. The zinc ion is located in a cone-shaped cavity and coordinated to three histidyl residues and a solvent molecule. Inhibitors bind at or near the metal center guided by a hydrogen-bonded system comprising Glu-106 and Thr-199. The catalytic mechanism of CA II has been studied in particular detail. It involves an attack of zinc-bound OH- on a CO2 molecule loosely bound in a hydrophobic pocket. The resulting zinc-coordinated HCO3- ion is displaced from the metal ion by H2O. The rate-limiting step is an intramolecular proton transfer from the zinc-bound water molecule to His-64, which serves as a proton shuttle between the metal center and buffer molecules in the reaction medium.
Pubmed ID: 9336012
Pharmacology & therapeutics
November 14, 1997
- Carbonic Anhydrases
- Protein Conformation
- Structure-Activity Relationship
- Carbonic Anhydrase II turnover rate in human homo sapiens was ~1e+6 1/sec, see BioNumbers database.
- Half life of the zinc ion association in Carbonic anhydrase II in human homo sapiens was 5 days, see BioNumbers database.
- Concentration of Carbonic Anhydrase I in red blood cell in human homo sapiens was 0.08 ca i molecules/hemoglobin molecule, see BioNumbers database.
- Carbonic Anhydrase I turnover rate in human homo sapiens was <=200000 1/sec, see BioNumbers database.
- Kcat of beta Carbonic Anhydrase in pea pisum sativum was 1e+6 1/sec, see BioNumbers database.
- Carbonic Anhydrase III CO2 hydration turnover rate in human homo sapiens was <=8000 1/sec, see BioNumbers database.
- Number of Carbonic Anhydrase isozymes in human homo sapiens was 7 , see BioNumbers database.
- Dissociation constant of the zinc ion in Carbonic anhydrase II in human homo sapiens was 4 pm, see BioNumbers database.
- Nonfacilitated zinc dissociation rate constant of the zinc ion in Carbonic anhydrase II in human homo sapiens was 1.4E-06 1/sec, see BioNumbers database.
- Ratio between CA I to CA II binding to dansylamide in human homo sapiens was 100 fold, see BioNumbers database.