Carbonic anhydrases (EC 4.2.1.1) (CA) [1,2,3,4] are zinc metalloenzymes which catalyze the reversible hydration of carbon dioxide, a reaction underlying many diverse physiological processes in animals, plants, archaebacteria, and eubacteria. Currently there are five evolutionarily distinct CA families (α, β, γ, delta and epsilon) that have no significant sequence identity and were invented independently. The α-CAs are found predominantly in animals but also in bacteria and green algae [5,6,7].

To date 15 α-CA or α-CA-like proteins have been identified in mammals. These can be divided into five broad subgroups: the cytosolic CAs (CA-I, CA-II, CA-III, CA-VII and CA XIII), mitochondrial CAs (CA-VA and CA-VB), secreted CAs (CA-VI), membrane-associated (CA-IV, CA-IX, CA-XII and CA-XIV) and those without CA activity, the CA-related proteins (CA-RP VIII, X and XI) [6].

In the alga Chlamydomonas reinhardtii, two CA isozymes have been sequenced [8]. They are periplasmic glycoproteins evolutionary related to mammalian CAs. Some bacteria, such as Neisseria gonorrhoeae [9] also have an α-type CA.

The dominating secondary structure is a 10-stranded, twisted β-sheet, which divides the molecules into two halves (see <PDB:1RAZ>). Except for two pairs of parallel strands, the β sheet is antiparallel. A few relatively short helices are located on the surface of the molecule [10]. α-CAs contain a single zinc atom bound to three conserved histidine residues. The catalytically active group is the zinc-bound water which ionizes to a hydroxide group. In the mechanism of catalysis, nucleophilic attack of CO2 by a zinc-bound hydroxide ion is followed by displacement of the resulting zinc-bound bicarbonate ion by water; subsequent deprotonation regenerates the nucleophilic zinc-bound hydroxide ion [5,11].

Protein D8 from Vaccinia and other poxviruses is related to CAs but has lost two of the zinc-binding histidines as well as many otherwise conserved residues. This is also true of the N-terminal extracellular domain of some receptor-type tyrosine-protein phosphatases (see <PDOC00323>).

We derived a signature pattern for the α-CAs which includes one of the zinc-binding histidines. We also developed a profile that covers the entire α-CA catalytic domain.