Carbonic anhydrase 434826 222753511 2008-06-30T23:01:58Z Belg4mit 1796889 /* α-CA */ expand acronym not introduced elsewhere in the page [[Image:Carbonic anhydrase.png|thumb|250px|[[Ribbon diagram]] of human carbonic anydrase II, with zinc atom visible in the center]] The '''carbonic anhydrases''' (or '''carbonate dehydratases''') form a family of [[enzyme]]s that [[catalyst|catalyze]] the rapid conversion of [[carbon dioxide]] to [[bicarbonate]] and [[Hydronium ion|proton]]s, a reaction that occurs rather slowly in the absence of a catalyst.<ref name="pmid9336012">{{cite journal | author = Badger MR, Price GD | title = The role of carbonic anhydrase in photosynthesis | journal = Annu. Rev. Plant Physiol. Plant Mol. Bio. | volume = 45 | issue = | pages = 369–392 | year = 1994| doi = 10.1146/annurev.pp.45.060194.002101 }}</ref> The [[active site]] of most carbonic anhydrases contains a [[zinc]] ion; they are therefore classified as [[metalloprotein|metalloenzymes]]. ==Structure and function of carbonic anhydrase== Several forms of carbonic anhydrase occur in nature. In the best-studied ''α-carbonic anhydrase'' form present in animals, the zinc ion is coordinated by the imidazole rings of 3 [[histidine]] residues, His94, His96 and His119. The primary function of the enzyme in animals is to interconvert carbon dioxide and bicarbonate to maintain acid-base balance in blood and other tissues, and to help transport carbon dioxide out of tissues. There exist at least 14 different isoforms in mammals. [[Plant]]s contain a different form called ''β-carbonic anhydrase'', which, from an evolutionary standpoint, is a distinct enzyme, but participates in the same reaction and also uses a zinc ion in its active site. In plants, carbonic anhydrase helps raise the concentration of CO<sub>2</sub> within the [[chloroplast]] in order to increase the carboxylation rate of the enzyme [[Rubisco]]. This is the reaction that integrates CO<sub>2</sub> into [[organic carbon]] sugars during [[photosynthesis]], and can use only the CO<sub>2</sub> form of carbon, not carbonic acid or bicarbonate. In 2000, a [http://www-ssrl.slac.stanford.edu/research/highlights_archive/cd-ca.html cadmium-containing carbonic anhydrase] was found to be expressed in marine [[diatom]]s during zinc limitation. In the open ocean, zinc is often in such low concentrations that it can limit the growth of [[phytoplankton]] like diatoms; thus a carbonic anhydrase using a different metal ion would be beneficial in these environments. Before this discovery, [[cadmium]] has generally been thought of as a very toxic [[Heavy metals|heavy metal]] without biological function. As of 2005, this peculiar carbonic anhydrase form hosts the only known beneficial cadmium-dependent biological reaction. The reaction catalyzed by carbonic anhydrase is: :<math>\rm CO_2 + H_2O \rightarrow^{Carbonic\ anhydrase} HCO_3^- + H^+</math>(in [[Biological tissue|tissue]]s - high CO<sub>2</sub> concentration)<ref>Carbonic acid has a pK<sub>a</sub> of around 6.36 (the exact value depends on the medium) so at pH 7 a small percentage of the bicarbonate is protonated. See [[carbonic acid]] for details concerning the equilibria HCO<sub>3</sub><sup>-</sup> + H<sup>+</sup><math>\rightleftharpoons</math> H<sub>2</sub>CO<sub>3</sub> and H<sub>2</sub>CO<sub>3</sub><math>\rightleftharpoons</math> CO<sub>2</sub> + H<sub>2</sub>O</ref> The reaction [[rate]] of carbonic anhydrase is one of the fastest of all enzymes, and its rate is typically limited by the [[diffusion]] rate of its [[Substrate (biochemistry)|substrate]]s. Typical catalytic rates of the different forms of this enzyme ranging between 10<sup>4</sup> and 10<sup>6</sup> reactions per second.<ref name="Lindskog_1997">{{cite journal | author = Lindskog S | title = Structure and mechanism of carbonic anhydrase | journal = Pharmacol. Ther. | volume = 74 | issue = 1 | pages = 1–20 | year = 1997 | pmid = 9336012 | doi = 10.1016/S0163-7258(96)00198-2 }}</ref> The reverse reaction is also relatively slow (kinetics in the 15-second range), which is why a carbonated drink does not instantly degas when opening the container, but will rapidly degas in one's mouth when carbonic anhydrase is added with saliva. :<math>\rm HCO_3^- + H^+ \rightarrow H_2CO_3 \rightarrow CO_2 + H_2O</math> (in [[lung]]s and [[nephrons]] of the [[kidney]] - low CO<sub>2</sub> concentration, in plant cells) ==Mechanism== [[Image:Carbonic anhydrase 1CA2 active site.png|thumb|200px|Close-up rendering of active site of human carbonic anhydrase II, showing three [[histidine]] residues (in pink) and a [[hydroxide]] group (red and white) coordinating the [[zinc]] ion (purple). From {{PDB|1CA2}}.]] A [[zinc]] [[prosthetic group]] in the enzyme is coordinated in three positions by histidine [[side chain]]s. The fourth coordination position is occupied by water. This causes polarisation of the hydrogen-oxygen bond, making the oxygen slightly more negative, thereby weakening it. A fourth histidine is placed close to the substrate of water and accepts a [[proton]], in an example of general acid-general base catalysis. This leaves a [[hydroxide]] attached to the zinc. The active site also contains specificity pocket for carbon dioxide, bringing it close to the hydroxide group. This allows the electron rich hydroxide to attack the carbon dioxide, forming bicarbonate. ==CA families== [[Image:Carbonic anhydrase 1CA2.png|thumb|200px|Ribbon diagram of human carbonic anhydrase II. [[Active site]] [[zinc]] ion visible at center. From {{PDB|1CA2}}.]] There are at least five distinct CA families (α, β, γ, δ and ε). These families have no significant [[protein sequence|amino acid sequence]] similarity and in most cases are thought to be an example of [[convergent evolution]]. The α-CAs are found in humans. ===α-CA=== The CA enzymes found in [[mammal]]s are divided into four broad subgroups<ref name="pmid11875253">{{cite journal | author = Breton S | title = The cellular physiology of carbonic anhydrases | journal = JOP | volume = 2 | issue = 4 Suppl | pages = 159–64 | year = 2001 | pmid = 11875253 | doi = | issn = | url = http://www.joplink.net/prev/200107/4.html}}</ref>, which, in turn consist of several isoforms: * the [[cytosol]]ic CAs (CA-I, [[Carbonic anhydrase II|CA-II]], CA-III, CA-VII and CA XIII) ({{gene2|CA1|1368}}, {{gene2|CA2|1373}}, {{gene2|CA3|1374}}, {{gene2|CA7|1381}}, {{gene2|CA13|14914}}) * [[mitochondrion|mitochondrial]] CAs (CA-VA and CA-VB) ({{gene|CA5A}}, {{gene|CA5B}}) * secreted CAs (CA-VI) ({{gene2|CA6|1380}}) * membrane-associated CAs (CA-IV, CA-IX, CA-XII, CA-XIV and CA-XV) ({{gene2|CA4|1375}}, {{gene2|CA9|1383}}, {{gene2|CA12|1371}}, {{gene2|CA14|1372}}) There are three additional "acatalytic" CA isoforms (CA-VIII, CA-X, and CA-XI) ({{gene2|CA8|1382}}, {{gene2|CA10|1369}}, {{gene2|CA11|1370}}) whose functions remain unclear.<ref name="pmid9878252">{{cite journal | author = Lovejoy DA, Hewett-Emmett D, Porter CA, Cepoi D, Sheffield A, Vale WW, Tashian RE | title = Evolutionarily conserved, "acatalytic" carbonic anhydrase-related protein XI contains a sequence motif present in the neuropeptide sauvagine: the human CA-RP XI gene (CA11) is embedded between the secretor gene cluster and the DBP gene at 19q13.3 | journal = Genomics | volume = 54 | issue = 3 | pages = 484–93 | year = 1998 | pmid = 9878252 | doi = 10.1006/geno.1998.5585 }}</ref> {| class="wikitable" align="center" |- |+ Comparison of human carbonic anhydrases |- !Isoform !Gene ![[Molecular mass]]<ref name=boron> Unless else specified: {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |location= |year= |pages= |isbn=1-4160-2328-3 |oclc= |doi = }} Page 638</ref> !Location (cell) !Location (tissue)<ref name=boron/> !Relative activity<ref name=boron/> !Sensitivity to [[sulfonamides]]<ref name=boron/> |- | CA-I || {{gene2|CA1|1368}} || 29 kDa || [[cytosol]] || [[red blood cell]] and [[gastrointestinal tract|GI tract]] || 15% || high |- | [[Carbonic anhydrase II|CA-II]] || {{gene2|CA2|1373}} || 29 kDa || [[cytosol]] || almost ubiquitous || 100% || high |- | CA-III || {{gene2|CA3|1374}} || 29 kDa || [[cytosol]] || 8% of soluble protein in Type I [[muscle]] || 1% || low |- | CA-IV || {{gene2|CA4|1375}} || 35 kDa || extracellularily [[glycophosphatidylinositol|GPI]]-linked || Widely distributed, e.g. acid-transporting || ~100% || moderate |- | CA-VA || {{gene|CA5A}} || || [[mitochondria]] || || || |- | CA-VB || {{gene|CA5B}} || || [[mitochondria]] || secreting cells || || |- | CA-VI || {{gene2|CA6|1380}} || || || || || |- | CA-VII || {{gene2|CA7|1381}} || || [[cytosol widely distributed in many cells and tissues]] || || || || |- | CA-IX || {{gene2|CA9|1383}} || || [[cell membrane]]-associated || || |- | CA-XII || {{gene2|CA12|1371}} || 44 kDa || extracellularily located [[active site]] || certain [[cancer]]s || ~30% || |- | CA XIII || {{gene2|CA13|14914}} || || [[cytosol]] || || || || |- | CA-XIV || {{gene2|CA14|1372}} || 54 kDa || extracellularily located [[active site]] || [[kidney]], [[heart]], [[skeletal muscle]], [[brain]] || || |- | and CA-XV || || || || || |} ===β-CA=== Most [[prokaryote|prokaryotic]] and plant [[chloroplast]] CAs belong to the beta family. Two [[sequence motif|signature pattern]]s for this family have been identified: * C-[SA]-D-S-R-[LIVM]-x-[AP] * [EQ]-[YF]-A-[LIVM]-x(2)-[LIVM]-x(4)-[LIVMF](3)-x-G-H-x(2)-C-G ===γ-CA=== The gamma class of CAs come from [[Methanogen|methane-producing bacteria]] that grow in hot springs. ===δ-CA=== The delta class of CAs has been described in [[diatom]]s. The distinction of this class of CA has recently<ref name="Sawaya_2006">{{cite journal | author = Sawaya MR, Cannon GC, Heinhorst S, Tanaka S, Williams EB, Yeates TO, Kerfeld CA | title = The structure of beta-carbonic anhydrase from the carboxysomal shell reveals a distinct subclass with one active site for the price of two | journal = J. Biol. Chem. | volume = 281 | issue = 11 | pages = 7546–55 | year = 2006 | pmid = 16407248 | doi = 10.1074/jbc.M510464200 }}</ref> come into question, however. ===ε-CA=== The epsilon class of CAs occurs exclusively in [[bacteria]] in a few [[chemolithotroph]]s and marine [[cyanobacteria]] that contain cso-[[carboxysome]]s.<ref name="pmid14729686">{{cite journal | author = So AK, Espie GS, Williams EB, Shively JM, Heinhorst S, Cannon GC | title = A novel evolutionary lineage of carbonic anhydrase (epsilon class) is a component of the carboxysome shell | journal = J. Bacteriol. | volume = 186 | issue = 3 | pages = 623–30 | year = 2004 | pmid = 14729686 | doi = 10.1128/JB.186.3.623-630.2004 }}</ref> Recent 3-dimensional analyses<ref name="Sawaya_2006" /> suggest that ε-CA bears some structural resemblance to β-CA, particularly near the metal ion site. Thus, the two forms may be distantly related, even though the underlying [[protein sequence|amino acid sequence]] has since diverged considerably. ==Pharmacological agents affecting CA== :''See [[Carbonic anhydrase inhibitors]]'' ==External links== * {{PDB Molecule of the Month|pdb49_1}} ==References== {{reflist}} {{Carbon-oxygen lyases}} [[Category:EC 4.2.1]] [[Category:Enzymes]] 9. Lyall V, Alam RI, Phan DQ, Ereso GL, Phan TH, Malik SA, Montrose MH, Chu S, Heck GL, Feldman GM, DeSimone JA. Decrease in rat taste receptor cell intracellular pH is the proximate stimulus in sour taste transduction. Am J Physiol Cell Physiol. 2001 Sep;281(3):C1005-13. [[de:Carboanhydrase]] [[es:Anhidrasa carbónica]] [[it:Carbonato deidratasi]] [[he:קרבוניק אנהידראז]] [[ja:炭酸脱水酵素]] [[pl:Anhydraza węglanowa]] [[pt:Anidrase carbónica]] [[fi:Karboanhydraasi]] [[sv:Karboanhydras]]