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{{Infobox_gene}}
{{PBB_Controls
'''Carbonic anhydrase 1''' is an [[enzyme]] that in humans is encoded by the ''CA1'' [[gene]].<ref name="pmid1916821">{{cite journal | vauthors = Lowe N, Edwards YH, Edwards M, Butterworth PH | title = Physical mapping of the human carbonic anhydrase gene cluster on chromosome 8 | journal = Genomics | volume = 10 | issue = 4 | pages = 882–8 | date = Aug 1991 | pmid = 1916821 | pmc =  | doi = 10.1016/0888-7543(91)90176-F }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CA1 carbonic anhydrase I| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=759| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
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| update_citations = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
[[Carbonic anhydrase]]s (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of [[carbon dioxide]].  They participate in a variety of biological processes, including [[cellular respiration]], [[calcification]], acid-base balance, bone resorption, and the formation of aqueous humor, [[cerebrospinal fluid]], [[saliva]], and [[gastric acid]].
{{GNF_Protein_box
| image = PBB_Protein_CA1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1azm.
  | PDB = {{PDB2|1azm}}, {{PDB2|1bzm}}, {{PDB2|1crm}}, {{PDB2|1czm}}, {{PDB2|1hcb}}, {{PDB2|1hug}}, {{PDB2|1huh}}, {{PDB2|1j9w}}, {{PDB2|1jv0}}, {{PDB2|2cab}}, {{PDB2|2foy}}, {{PDB2|2fw4}}, {{PDB2|2nmx}}, {{PDB2|2nn1}}, {{PDB2|2nn7}}
| Name = Carbonic anhydrase I
| HGNCid = 1368
| Symbol = CA1
| AltSymbols =; Car1
| OMIM = 114800
| ECnumber = 
| Homologene = 20414
| MGIid = 88268
| GeneAtlas_image1 = PBB_GE_CA1_205949_at_tn.png
| GeneAtlas_image2 = PBB_GE_CA1_205950_s_at_tn.png
| Function = {{GNF_GO|id=GO:0004089 |text = carbonate dehydratase activity}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0016829 |text = lyase activity}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0006730 |text = one-carbon compound metabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 759
    | Hs_Ensembl = ENSG00000133742
    | Hs_RefseqProtein = NP_001729
    | Hs_RefseqmRNA = NM_001738
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 8
    | Hs_GenLoc_start = 86427089
    | Hs_GenLoc_end = 86478495
    | Hs_Uniprot = P00915
    | Mm_EntrezGene = 12346
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = XM_978562
    | Mm_RefseqProtein = XP_983656
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
'''Carbonic anhydrase I''', also known as '''CA1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CA1 carbonic anhydrase I| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=759| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
They show extensive diversity in tissue distribution and in their subcellular localization.  CA1 is closely linked to CA2 and CA3 genes on [[chromosome 8]], and it encodes a cytosolic protein which is found at the highest level in [[erythrocyte]]s.  Transcript variants of CA1 utilizing alternative polyA_sites have been described in literature.<ref name="entrez" />
{{PBB_Summary
| section_title =
| summary_text = Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide.  They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid.  They show extensive diversity in tissue distribution and in their subcellular localization.  CA1 is closely linked to CA2 and CA3 genes on chromosome 8, and it encodes a cytosolic protein which is found at the highest level in erythrocytes.  Transcript variants of CA1 utilizing alternative polyA_sites have been described in literature.<ref name="entrez">{{cite web | title = Entrez Gene: CA1 carbonic anhydrase I| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=759| accessdate = }}</ref>
}}


==References==
== Structure ==
{{reflist|2}}
The human CA1 protein contains an N-terminus [[active site]], [[Zinc binding protein|zinc binding site]], and substrate-binding site.<ref name="uniprot.org">{{Cite web|url=http://www.uniprot.org/uniprot/P00915|title=CA1 - Carbonic anhydrase 1 - Homo sapiens (Human) - CA1 gene & protein|website=www.uniprot.org|access-date=2016-03-23}}</ref> The [[crystal structure]] of the human CA1-[[bicarbonate]] anion complex reveals the geometry of two [[Hydrogen bond|H-bonds]] between the [[Glutamic acid|Glu]]106-[[Threonine|Thr]]199 pair and the Glu117-[[Histidine|His]]119 pair, and one pi H-bond between a water molecule and the [[Phenyl group|phenyl ring]] of the [[Tyrosine|Tyr]]114 residue. The [[product inhibition]] of CA1 via bicarbonate [[anions]] is correlated to the proton localization change on His119. So the Glu117-His119 H-bond is considered to regulate the ionicity of the zinc ion and the binding strength of the bicarbonate anion.<ref>{{cite journal | vauthors = Kumar V, Kannan KK | title = Enzyme-substrate interactions. Structure of human carbonic anhydrase I complexed with bicarbonate | journal = Journal of Molecular Biology | volume = 241 | issue = 2 | pages = 226–32 | date = Aug 1994 | pmid = 8057362 | doi = 10.1006/jmbi.1994.1491 }}</ref>
==Further reading==
 
{{refbegin | 2}}
== Mechanism ==
{{PBB_Further_reading
The reaction catalyzed by CA1 is the same as other carbonic anhydrase family proteins:
| citations =
 
*{{cite journal  | author=Tashian RE, Carter ND |title=Biochemical genetics of carbonic anhydrase. |journal=Adv. Hum. Genet. |volume=7 |issue=  |pages= 1-56 |year= 1977 |pmid= 827930 |doi=  }}
<math>\rm CO_2 + H_2O \xrightarrow{Carbonic\ anhydrase} H_2CO_3</math>
*{{cite journal  | author=Sly WS, Hu PY |title=Human carbonic anhydrases and carbonic anhydrase deficiencies. |journal=Annu. Rev. Biochem. |volume=64 |issue= |pages= 375-401 |year= 1995 |pmid= 7574487 |doi= 10.1146/annurev.bi.64.070195.002111 }}
 
*{{cite journal  | author=Kendall AG, Tashian RE |title=Erythrocyte carbonic anhydrase I: inherited deficiency in humans. |journal=Science |volume=197 |issue= 4302 |pages= 471-2 |year= 1977 |pmid= 406674 |doi= }}
(in [[Biological tissue|tissues]] - 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{{su|b=3|p=−}} + 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>
*{{cite journal | author=Kannan KK, Notstrand B, Fridborg K, ''et al.'' |title=Crystal structure of human erythrocyte carbonic anhydrase B. Three-dimensional structure at a nominal 2.2-A resolution. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=72 |issue= 1 |pages= 51-5 |year= 1975 |pmid= 804171 |doi= }}
 
*{{cite journal  | author=Dawson SJ, White LA |title=Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin. |journal=J. Infect. |volume=24 |issue= 3 |pages= 317-20 |year= 1992 |pmid= 1602151 |doi= }}
The CA1-catalyzed reaction has a relatively low [[Michaelis constant|reaction affinity (Km)]] of 4.0 mM for CO<sub>2</sub>,<ref name="uniprot.org"/><ref>{{cite journal | vauthors = Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT | title = Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction? | journal = Journal of Biological Inorganic Chemistry | volume = 4 | issue = 5 | pages = 528–36 | date = Oct 1999 | pmid = 10550681 | doi=10.1007/s007750050375}}</ref> [[Turnover number|turnover number (Kcat)]] of 2x10^<sup>5</sup> s<sup>−1</sup>, and [[Catalytic efficiency|catalytic efficiency (Kcat/Km)]] of 5x10^<sup>7</sup> M<sup>−1</sup>s<sup>−1</sup> comparing to other [[isozyme]]s of the α-CA family of carbonic anhydrases. The turnover rate and catalytic rate of CA1 are only about 10% that of CA2 (Kcat: 1.4x10^<sup>6</sup> s<sup>−1</sup>, Kcat/Km: 1.5x10^<sup>8</sup> M<sup>−1</sup>s<sup>−1</sup>).<ref>{{Cite journal|last=Silverman|first=David N.|last2=Lindskog|first2=Sven | name-list-format = vanc |date=2002-05-01|title=The catalytic mechanism of carbonic anhydrase: implications of a rate-limiting protolysis of water|url=http://pubs.acs.org/doi/abs/10.1021/ar00145a005|journal=Accounts of Chemical Research|volume=21|issue=1|pages=30–36|doi=10.1021/ar00145a005}}</ref>
*{{cite journal  | author=Lowe N, Edwards YH, Edwards M, Butterworth PH |title=Physical mapping of the human carbonic anhydrase gene cluster on chromosome 8. |journal=Genomics |volume=10 |issue= 4 |pages= 882-8 |year= 1991 |pmid= 1916821 |doi= }}
 
*{{cite journal  | author=Lowe N, Brady HJ, Barlow JH, ''et al.'' |title=Structure and methylation patterns of the gene encoding human carbonic anhydrase I. |journal=Gene |volume=93 |issue= 2 |pages= 277-83 |year= 1990 |pmid= 2121614 |doi= }}
== Function ==
*{{cite journal  | author=Noda Y, Sumitomo S, Hikosaka N, Mori M |title=Immunohistochemical observations on carbonic anhydrase I and II in human salivary glands and submandibular obstructive adenitis. |journal=J. Oral Pathol. |volume=15 |issue= 4 |pages= 187-90 |year= 1986 |pmid= 3088232 |doi= }}
Carbonic anhydrase 1 belongs to α-CA sub-family and is localized in the [[cytosol]] of [[red blood cell]], [[GI tract]], [[Cardiac|cardiac tissues]] and other organs or tissues.<ref name=":0"/> Transmembrane transport of CA-produced bicarbonate contributes significantly to cellular [[pH]] regulation.<ref>{{cite journal | vauthors = Alvarez BV, Quon AL, Mullen J, Casey JR | title = Quantification of carbonic anhydrase gene expression in ventricle of hypertrophic and failing human heart | journal = BMC Cardiovascular Disorders | volume = 13 | pages = 2 | date = 2013-01-01 | pmid = 23297731 | pmc = 3570296 | doi = 10.1186/1471-2261-13-2 }}</ref>
*{{cite journal  | author=Barlow JH, Lowe N, Edwards YH, Butterworth PH |title=Human carbonic anhydrase I cDNA. |journal=Nucleic Acids Res. |volume=15 |issue= 5 |pages= 2386 |year= 1987 |pmid= 3104879 |doi= }}
 
*{{cite journal  | author=Edwards YH, Barlow JH, Konialis CP, ''et al.'' |title=Assignment of the gene determining human carbonic anhydrase, CAI, to chromosome 8. |journal=Ann. Hum. Genet. |volume=50 |issue= Pt 2 |pages= 123-9 |year= 1988 |pmid= 3124707 |doi=  }}
In a human zinc-activated [[Human genetic variation|variant]] of CA1, the Michigan Variant, a single [[point mutation]] changes [[Histidine|His]] 67 to [[Arginine|Arg]] in a critical region of the active site. This variant of the zinc [[Metalloprotein|metalloenzyme]] appears to be unique in that it possesses esterase activity that is specifically enhanced by added free zinc ions.<ref>{{cite journal | vauthors = Ferraroni M, Tilli S, Briganti F, Chegwidden WR, Supuran CT, Wiebauer KE, Tashian RE, Scozzafava A | title = Crystal structure of a zinc-activated variant of human carbonic anhydrase I, CA I Michigan 1: evidence for a second zinc binding site involving arginine coordination | journal = Biochemistry | volume = 41 | issue = 20 | pages = 6237–44 | date = May 2002 | pmid = 12009884 | doi=10.1021/bi0120446}}</ref>
*{{cite journal | author=Lin KT, Deutsch HF |title=Human carbonic anhydrases. XII. The complete primary structure of the C isozyme. |journal=J. Biol. Chem. |volume=249 |issue= 8 |pages= 2329-37 |year= 1974 |pmid= 4207120 |doi= }}
 
*{{cite journal | author=Giraud N, Marriq C, Laurent-Tabusse G |title=[Primary structure of human B erythrocyte carbonic anhydrase. 3. Sequence of CNBr fragment I and III (residues 149-260)] |journal=Biochimie |volume=56 |issue= 8 |pages= 1031-43 |year= 1975 |pmid= 4217196 |doi= }}
== Clinical significance ==
*{{cite journal  | author=Andersson B, Nyman PO, Strid L |title=Amino acid sequence of human erythrocyte carbonic anhydrase B. |journal=Biochem. Biophys. Res. Commun. |volume=48 |issue= 3 |pages= 670-7 |year= 1972 |pmid= 4625868 |doi= }}
CA1 activation is associated with worsened pathological remodeling in human [[Ischemic cardiomyopathy|ischemic]] [[Diabetes mellitus|diabetic]] [[cardiomyopathy]].<ref name=":0">{{cite journal | vauthors = Torella D, Ellison GM, Torella M, Vicinanza C, Aquila I, Iaconetti C, Scalise M, Marino F, Henning BJ, Lewis FC, Gareri C, Lascar N, Cuda G, Salvatore T, Nappi G, Indolfi C, Torella R, Cozzolino D, Sasso FC | title = Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy | journal = Journal of the American Heart Association | volume = 3 | issue = 2 | pages = e000434 | date = 2014-01-01 | pmid = 24670789 | pmc = 4187518 | doi = 10.1161/JAHA.113.000434 }}</ref> In [[Diabetes mellitus type 2|diabetic mellitus type 2]] patients with [[Dressler syndrome|postinfarct heart failure]] who were undergoing surgical coronary [[revascularization]], myocardial levels of CA1 were sixfold higher than nondiabetic patients. Elevated CA1 expression was mainly localized in the [[Interstitium|cardiac interstitium]] and [[Endothelium|endothelial]] cells. Furthermore, high glucose-induced elevation of CA1 hampers endothelial cell [[Cell permeability|permeability]] and determines endothelial cell [[apoptosis]] ''[[in vitro]]''.<ref name=":0" />
*{{cite journal  | author=Lin KT, Deutsch HF |title=Human carbonic anhydrases. XI. The complete primary structure of carbonic anhydrase B. |journal=J. Biol. Chem. |volume=248 |issue= 6 |pages= 1885-93 |year= 1973 |pmid= 4632246 |doi=  }}
 
*{{cite journal  | author=Omoto K, Ueda S, Goriki K, ''et al.'' |title=Population genetic studies of the Philippine Negritos. III. Identification of the carbonic anhydrase-1 variant with CA1 Guam. |journal=Am. J. Hum. Genet. |volume=33 |issue= 1 |pages= 105-11 |year= 1981 |pmid= 6781336 |doi=  }}
CA1 also mediates [[hemorrhagic]] [[retina]]l and [[Cerebral circulation|cerebral vascular]] permeability through [[prekallikrein]] activation and [[Serine protease|serine protease factor XIIa]] generation. These phenomena induce proliferative diabetic [[retinopathy]] and [[Diabetic macular edema|diabetic macular edema disease]] progression, which represent leading causes of vision loss.<ref>{{cite journal | vauthors = Gao BB, Clermont A, Rook S, Fonda SJ, Srinivasan VJ, Wojtkowski M, Fujimoto JG, Avery RL, Arrigg PG, Bursell SE, Aiello LP, Feener EP | title = Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation | journal = Nature Medicine | volume = 13 | issue = 2 | pages = 181–8 | date = Feb 2007 | pmid = 17259996 | doi = 10.1038/nm1534 }}</ref>
*{{cite journal  | author=Chegwidden WR, Wagner LE, Venta PJ, ''et al.'' |title=Marked zinc activation of ester hydrolysis by a mutation, 67-His (CAT) to Arg (CGT), in the active site of human carbonic anhydrase I. |journal=Hum. Mutat. |volume=4 |issue= 4 |pages= 294-6 |year= 1995 |pmid= 7866410 |doi= 10.1002/humu.1380040411 }}
 
*{{cite journal | author=Bekku S, Mochizuki H, Takayama E, ''et al.'' |title=Carbonic anhydrase I and II as a differentiation marker of human and rat colonic enterocytes. |journal=Research in experimental medicine. Zeitschrift für die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie |volume=198 |issue= 4 |pages= 175-85 |year= 1999 |pmid= 9879596 |doi= }}
As CA1 is an important therapeutic target, development of its inhibitors will contribute to disease treatment. Compared to other CA family members, CA1 has relatively low affinity to common CA inhibitors.<ref>{{cite journal | vauthors = Supuran CT | title = Carbonic anhydrases: novel therapeutic applications for inhibitors and activators | journal = Nature Reviews. Drug Discovery | volume = 7 | issue = 2 | pages = 168–81 | date = Feb 2008 | doi = 10.1038/nrd2467 | pmid = 18167490 }}</ref> Nonetheless, it has medium affinity for CA inhibitor [[Sulfonamide (medicine)|sulfonamides]].<ref>{{cite web|url=http://cdn.intechopen.com/pdfs/36516.pdf|title=Carbonic Anhydrase Inhibitors and Activators: Small Organic Molecules as Drugs and Prodrugs|last=Şentürk|first=Murat|name-list-format = vanc |website=|publisher=|access-date=}}</ref>
*{{cite journal | author=Puscas I, Coltau M, Baican M, ''et al.'' |title=Vasoconstrictive drugs increase carbonic anhydrase I in vascular smooth muscle while vasodilating drugs reduce the activity of this isozyme by a direct mechanism of action. |journal=Drugs under experimental and clinical research |volume=27 |issue= 2 |pages= 53-60 |year= 2001 |pmid= 11392054 |doi=  }}
 
}}
== Interactions ==
CA1 has been shown to interact with:
 
* [[TFCP2]]<ref>{{cite journal | vauthors = Rolland T, Taşan M, Charloteaux B, Pevzner SJ, Zhong Q, Sahni N, Yi S, Lemmens I, Fontanillo C, Mosca R, Kamburov A, Ghiassian SD, Yang X, Ghamsari L, Balcha D, Begg BE, Braun P, Brehme M, Broly MP, Carvunis AR, Convery-Zupan D, Corominas R, Coulombe-Huntington J, Dann E, Dreze M, Dricot A, Fan C, Franzosa E, Gebreab F, Gutierrez BJ, Hardy MF, Jin M, Kang S, Kiros R, Lin GN, Luck K, MacWilliams A, Menche J, Murray RR, Palagi A, Poulin MM, Rambout X, Rasla J, Reichert P, Romero V, Ruyssinck E, Sahalie JM, Scholz A, Shah AA, Sharma A, Shen Y, Spirohn K, Tam S, Tejeda AO, Trigg SA, Twizere JC, Vega K, Walsh J, Cusick ME, Xia Y, Barabási AL, Iakoucheva LM, Aloy P, De Las Rivas J, Tavernier J, Calderwood MA, Hill DE, Hao T, Roth FP, Vidal M | display-authors = 6 | title = A proteome-scale map of the human interactome network | journal = Cell | volume = 159 | issue = 5 | pages = 1212–26 | date = Nov 2014 | pmid = 25416956 | pmc = 4266588 | doi = 10.1016/j.cell.2014.10.050 }}</ref>
* [[HSD17B7]]<ref>{{cite journal | vauthors = Wang J, Huo K, Ma L, Tang L, Li D, Huang X, Yuan Y, Li C, Wang W, Guan W, Chen H, Jin C, Wei J, Zhang W, Yang Y, Liu Q, Zhou Y, Zhang C, Wu Z, Xu W, Zhang Y, Liu T, Yu D, Zhang Y, Chen L, Zhu D, Zhong X, Kang L, Gan X, Yu X, Ma Q, Yan J, Zhou L, Liu Z, Zhu Y, Zhou T, He F, Yang X | display-authors = 6 | title = Toward an understanding of the protein interaction network of the human liver | journal = Molecular Systems Biology | volume = 7 | pages = 536 | date = 2011-01-01 | pmid = 21988832 | pmc = 3261708 | doi = 10.1038/msb.2011.67 }}</ref>
* [[MAPK6]]<ref>{{cite journal | vauthors = Vinayagam A, Stelzl U, Foulle R, Plassmann S, Zenkner M, Timm J, Assmus HE, Andrade-Navarro MA, Wanker EE | title = A directed protein interaction network for investigating intracellular signal transduction | journal = Science Signaling | volume = 4 | issue = 189 | pages = rs8 | date = Sep 2011 | pmid = 21900206 | doi = 10.1126/scisignal.2001699 }}</ref>
 
These interactions have been confirmed using the [[High throughput biology|high throughput method]] (one hit)
 
== References ==
{{reflist|33em}}
 
==External links==
* {{UCSC gene info|CA1}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Tashian RE, Carter ND | title = Biochemical genetics of carbonic anhydrase | journal = Advances in Human Genetics | volume = 7 | issue =  | pages = 1–56 | year = 1977 | pmid = 827930 | doi =  }}
* {{cite journal | vauthors = Sly WS, Hu PY | title = Human carbonic anhydrases and carbonic anhydrase deficiencies | journal = Annual Review of Biochemistry | volume = 64 | issue = 1 | pages = 375–401 | year = 1995 | pmid = 7574487 | doi = 10.1146/annurev.bi.64.070195.002111 }}
* {{cite journal | vauthors = Kendall AG, Tashian RE | title = Erythrocyte carbonic anhydrase I: inherited deficiency in humans | journal = Science | volume = 197 | issue = 4302 | pages = 471–2 | date = Jul 1977 | pmid = 406674 | doi = 10.1126/science.406674 }}
* {{cite journal | vauthors = Kannan KK, Notstrand B, Fridborg K, Lövgren S, Ohlsson A, Petef M | title = Crystal structure of human erythrocyte carbonic anhydrase B. Three-dimensional structure at a nominal 2.2-A resolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 72 | issue = 1 | pages = 51–5 | date = Jan 1975 | pmid = 804171 | pmc = 432238 | doi = 10.1073/pnas.72.1.51 }}
* {{cite journal | vauthors = Dawson SJ, White LA | title = Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin | journal = The Journal of Infection | volume = 24 | issue = 3 | pages = 317–20 | date = May 1992 | pmid = 1602151 | doi = 10.1016/S0163-4453(05)80037-4 }}
* {{cite journal | vauthors = Lowe N, Brady HJ, Barlow JH, Sowden JC, Edwards M, Butterworth PH | title = Structure and methylation patterns of the gene encoding human carbonic anhydrase I | journal = Gene | volume = 93 | issue = 2 | pages = 277–83 | date = Sep 1990 | pmid = 2121614 | doi = 10.1016/0378-1119(90)90236-K }}
* {{cite journal | vauthors = Noda Y, Sumitomo S, Hikosaka N, Mori M | title = Immunohistochemical observations on carbonic anhydrase I and II in human salivary glands and submandibular obstructive adenitis | journal = Journal of Oral Pathology | volume = 15 | issue = 4 | pages = 187–90 | date = Apr 1986 | pmid = 3088232 | doi = 10.1111/j.1600-0714.1986.tb00604.x }}
* {{cite journal | vauthors = Barlow JH, Lowe N, Edwards YH, Butterworth PH | title = Human carbonic anhydrase I cDNA | journal = Nucleic Acids Research | volume = 15 | issue = 5 | pages = 2386 | date = Mar 1987 | pmid = 3104879 | pmc = 340641 | doi = 10.1093/nar/15.5.2386 }}
* {{cite journal | vauthors = Edwards YH, Barlow JH, Konialis CP, Povey S, Butterworth PH | title = Assignment of the gene determining human carbonic anhydrase, CAI, to chromosome 8 | journal = Annals of Human Genetics | volume = 50 | issue = Pt 2 | pages = 123–9 | date = May 1986 | pmid = 3124707 | doi = 10.1111/j.1469-1809.1986.tb01030.x }}
* {{cite journal | vauthors = Lin KT, Deutsch HF | title = Human carbonic anhydrases. XII. The complete primary structure of the C isozyme | journal = The Journal of Biological Chemistry | volume = 249 | issue = 8 | pages = 2329–37 | date = Apr 1974 | pmid = 4207120 | doi =  }}
* {{cite journal | vauthors = Giraud N, Marriq C, Laurent-Tabusse G | title = [Primary structure of human B erythrocyte carbonic anhydrase. 3. Sequence of CNBr fragment I and III (residues 149-260)] | journal = Biochimie | volume = 56 | issue = 8 | pages = 1031–43 | year = 1975 | pmid = 4217196 | doi = 10.1016/S0300-9084(74)80093-3 }}
* {{cite journal | vauthors = Andersson B, Nyman PO, Strid L | title = Amino acid sequence of human erythrocyte carbonic anhydrase B | journal = Biochemical and Biophysical Research Communications | volume = 48 | issue = 3 | pages = 670–7 | date = Aug 1972 | pmid = 4625868 | doi = 10.1016/0006-291X(72)90400-7 }}
* {{cite journal | vauthors = Lin KT, Deutsch HF | title = Human carbonic anhydrases. XI. The complete primary structure of carbonic anhydrase B | journal = The Journal of Biological Chemistry | volume = 248 | issue = 6 | pages = 1885–93 | date = Mar 1973 | pmid = 4632246 | doi =  }}
* {{cite journal | vauthors = Omoto K, Ueda S, Goriki K, Takahashi N, Misawa S, Pagaran IG | title = Population genetic studies of the Philippine Negritos. III. Identification of the carbonic anhydrase-1 variant with CA1 Guam | journal = American Journal of Human Genetics | volume = 33 | issue = 1 | pages = 105–11 | date = Jan 1981 | pmid = 6781336 | pmc = 1684865 | doi =  }}
* {{cite journal | vauthors = Chegwidden WR, Wagner LE, Venta PJ, Bergenhem NC, Yu YS, Tashian RE | title = Marked zinc activation of ester hydrolysis by a mutation, 67-His (CAT) to Arg (CGT), in the active site of human carbonic anhydrase I | journal = Human Mutation | volume = 4 | issue = 4 | pages = 294–6 | year = 1995 | pmid = 7866410 | doi = 10.1002/humu.1380040411 }}
* {{cite journal | vauthors = Bekku S, Mochizuki H, Takayama E, Shinomiya N, Fukamachi H, Ichinose M, Tadakuma T, Yamamoto T | title = Carbonic anhydrase I and II as a differentiation marker of human and rat colonic enterocytes | journal = Research in Experimental Medicine. Zeitschrift Für Die Gesamte Experimentelle Medizin Einschliesslich Experimenteller Chirurgie | volume = 198 | issue = 4 | pages = 175–85 | date = Dec 1998 | pmid = 9879596 | doi =  }}
* {{cite journal | vauthors = Puscas I, Coltau M, Baican M, Pasca R, Domuta G, Hecht A | title = Vasoconstrictive drugs increase carbonic anhydrase I in vascular smooth muscle while vasodilating drugs reduce the activity of this isozyme by a direct mechanism of action | journal = Drugs Under Experimental and Clinical Research | volume = 27 | issue = 2 | pages = 53–60 | year = 2001 | pmid = 11392054 | doi =  }}
{{refend}}
{{refend}}
{{PDB Gallery|geneid=759}}
{{Carbonic anhydrases}}


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[[Category:Enzymes]]
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Revision as of 01:57, 27 October 2017

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Carbonic anhydrase 1 is an enzyme that in humans is encoded by the CA1 gene.[1][2]

Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including cellular respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid.

They show extensive diversity in tissue distribution and in their subcellular localization. CA1 is closely linked to CA2 and CA3 genes on chromosome 8, and it encodes a cytosolic protein which is found at the highest level in erythrocytes. Transcript variants of CA1 utilizing alternative polyA_sites have been described in literature.[2]

Structure

The human CA1 protein contains an N-terminus active site, zinc binding site, and substrate-binding site.[3] The crystal structure of the human CA1-bicarbonate anion complex reveals the geometry of two H-bonds between the Glu106-Thr199 pair and the Glu117-His119 pair, and one pi H-bond between a water molecule and the phenyl ring of the Tyr114 residue. The product inhibition of CA1 via bicarbonate anions is correlated to the proton localization change on His119. So the Glu117-His119 H-bond is considered to regulate the ionicity of the zinc ion and the binding strength of the bicarbonate anion.[4]

Mechanism

The reaction catalyzed by CA1 is the same as other carbonic anhydrase family proteins:

<math>\rm CO_2 + H_2O \xrightarrow{Carbonic\ anhydrase} H_2CO_3</math>

(in tissues - high CO2 concentration)[5]

The CA1-catalyzed reaction has a relatively low reaction affinity (Km) of 4.0 mM for CO2,[3][6] turnover number (Kcat) of 2x10^5 s−1, and catalytic efficiency (Kcat/Km) of 5x10^7 M−1s−1 comparing to other isozymes of the α-CA family of carbonic anhydrases. The turnover rate and catalytic rate of CA1 are only about 10% that of CA2 (Kcat: 1.4x10^6 s−1, Kcat/Km: 1.5x10^8 M−1s−1).[7]

Function

Carbonic anhydrase 1 belongs to α-CA sub-family and is localized in the cytosol of red blood cell, GI tract, cardiac tissues and other organs or tissues.[8] Transmembrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation.[9]

In a human zinc-activated variant of CA1, the Michigan Variant, a single point mutation changes His 67 to Arg in a critical region of the active site. This variant of the zinc metalloenzyme appears to be unique in that it possesses esterase activity that is specifically enhanced by added free zinc ions.[10]

Clinical significance

CA1 activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy.[8] In diabetic mellitus type 2 patients with postinfarct heart failure who were undergoing surgical coronary revascularization, myocardial levels of CA1 were sixfold higher than nondiabetic patients. Elevated CA1 expression was mainly localized in the cardiac interstitium and endothelial cells. Furthermore, high glucose-induced elevation of CA1 hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro.[8]

CA1 also mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation and serine protease factor XIIa generation. These phenomena induce proliferative diabetic retinopathy and diabetic macular edema disease progression, which represent leading causes of vision loss.[11]

As CA1 is an important therapeutic target, development of its inhibitors will contribute to disease treatment. Compared to other CA family members, CA1 has relatively low affinity to common CA inhibitors.[12] Nonetheless, it has medium affinity for CA inhibitor sulfonamides.[13]

Interactions

CA1 has been shown to interact with:

These interactions have been confirmed using the high throughput method (one hit)

References

  1. ↑ Lowe N, Edwards YH, Edwards M, Butterworth PH (Aug 1991). "Physical mapping of the human carbonic anhydrase gene cluster on chromosome 8". Genomics. 10 (4): 882–8. doi:10.1016/0888-7543(91)90176-F. PMID 1916821.
  2. ↑ 2.0 2.1 "Entrez Gene: CA1 carbonic anhydrase I".
  3. ↑ 3.0 3.1 "CA1 - Carbonic anhydrase 1 - Homo sapiens (Human) - CA1 gene & protein". www.uniprot.org. Retrieved 2016-03-23.
  4. ↑ Kumar V, Kannan KK (Aug 1994). "Enzyme-substrate interactions. Structure of human carbonic anhydrase I complexed with bicarbonate". Journal of Molecular Biology. 241 (2): 226–32. doi:10.1006/jmbi.1994.1491. PMID 8057362.
  5. ↑ Carbonic acid has a pKa 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−
    3     + H+ <math>\rightleftharpoons</math> H2CO3 and H2CO3 <math>\rightleftharpoons</math> CO2 + H2O
  6. ↑ Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT (Oct 1999). "Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction?". Journal of Biological Inorganic Chemistry. 4 (5): 528–36. doi:10.1007/s007750050375. PMID 10550681.
  7. ↑ Silverman DN, Lindskog S (2002-05-01). "The catalytic mechanism of carbonic anhydrase: implications of a rate-limiting protolysis of water". Accounts of Chemical Research. 21 (1): 30–36. doi:10.1021/ar00145a005.
  8. ↑ 8.0 8.1 8.2 Torella D, Ellison GM, Torella M, Vicinanza C, Aquila I, Iaconetti C, Scalise M, Marino F, Henning BJ, Lewis FC, Gareri C, Lascar N, Cuda G, Salvatore T, Nappi G, Indolfi C, Torella R, Cozzolino D, Sasso FC (2014-01-01). "Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy". Journal of the American Heart Association. 3 (2): e000434. doi:10.1161/JAHA.113.000434. PMC 4187518. PMID 24670789.
  9. ↑ Alvarez BV, Quon AL, Mullen J, Casey JR (2013-01-01). "Quantification of carbonic anhydrase gene expression in ventricle of hypertrophic and failing human heart". BMC Cardiovascular Disorders. 13: 2. doi:10.1186/1471-2261-13-2. PMC 3570296. PMID 23297731.
  10. ↑ Ferraroni M, Tilli S, Briganti F, Chegwidden WR, Supuran CT, Wiebauer KE, Tashian RE, Scozzafava A (May 2002). "Crystal structure of a zinc-activated variant of human carbonic anhydrase I, CA I Michigan 1: evidence for a second zinc binding site involving arginine coordination". Biochemistry. 41 (20): 6237–44. doi:10.1021/bi0120446. PMID 12009884.
  11. ↑ Gao BB, Clermont A, Rook S, Fonda SJ, Srinivasan VJ, Wojtkowski M, Fujimoto JG, Avery RL, Arrigg PG, Bursell SE, Aiello LP, Feener EP (Feb 2007). "Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation". Nature Medicine. 13 (2): 181–8. doi:10.1038/nm1534. PMID 17259996.
  12. ↑ Supuran CT (Feb 2008). "Carbonic anhydrases: novel therapeutic applications for inhibitors and activators". Nature Reviews. Drug Discovery. 7 (2): 168–81. doi:10.1038/nrd2467. PMID 18167490.
  13. ↑ Şentürk M. "Carbonic Anhydrase Inhibitors and Activators: Small Organic Molecules as Drugs and Prodrugs" (PDF).
  14. ↑ Rolland T, Taşan M, Charloteaux B, Pevzner SJ, Zhong Q, Sahni N, et al. (Nov 2014). "A proteome-scale map of the human interactome network". Cell. 159 (5): 1212–26. doi:10.1016/j.cell.2014.10.050. PMC 4266588. PMID 25416956.
  15. ↑ Wang J, Huo K, Ma L, Tang L, Li D, Huang X, et al. (2011-01-01). "Toward an understanding of the protein interaction network of the human liver". Molecular Systems Biology. 7: 536. doi:10.1038/msb.2011.67. PMC 3261708. PMID 21988832.
  16. ↑ Vinayagam A, Stelzl U, Foulle R, Plassmann S, Zenkner M, Timm J, Assmus HE, Andrade-Navarro MA, Wanker EE (Sep 2011). "A directed protein interaction network for investigating intracellular signal transduction". Science Signaling. 4 (189): rs8. doi:10.1126/scisignal.2001699. PMID 21900206.

External links

Further reading

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