{ "id": "epyhy2qq6e", "slug": "ca2", "title": "CA2", "updated": "2026-10-21", "topic_path": [ { "id": "life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/topics/life" }, { "id": "life.biology", "label": "Biological foundations", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology" }, { "id": "life.biology.genetics", "label": "Genetics and genomic reference", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics" }, { "id": "life.biology.genetics.gene_record_human", "label": "Human gene and locus records", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics.gene_record_human" }, { "id": "life.biology.genetics.gene_record_human.metabolic-and-enzyme-genes", "label": "Metabolic and enzyme genes", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics.gene_record_human.metabolic-and-enzyme-genes" } ], "geo": [ { "id": "geo.us.t1946.life.biology.genetics.gene_record_human.metabolic-and-enzyme-genes", "label": "United States · 1946 to 2000: Metabolic and enzyme genes", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.biology.genetics.gene_record_human.metabolic-and-enzyme-genes", "path": [ { "id": "geo.us", "label": "United States", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us" }, { "id": "geo.us.t1946", "label": "United States · 1946 to 2000", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946" }, { "id": "geo.us.t1946.life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life" }, { "id": "geo.us.t1946.life.biology", "label": "Biological foundations", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.biology" }, { "id": "geo.us.t1946.life.biology.genetics", "label": "Genetics and genomic reference", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.biology.genetics" }, { "id": "geo.us.t1946.life.biology.genetics.gene_record_human", "label": "Human gene and locus records", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.biology.genetics.gene_record_human" }, { "id": "geo.us.t1946.life.biology.genetics.gene_record_human.metabolic-and-enzyme-genes", "label": "Metabolic and enzyme genes", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t1946.life.biology.genetics.gene_record_human.metabolic-and-enzyme-genes" } ] } ], "excerpt": "CA2 is the human gene encoding carbonic anhydrase II, a zinc enzyme abundant in red blood cells that converts carbon dioxide to bicarbonate and regulates acid-base balance.", "snippet": "CA2 is the human gene encoding carbonic anhydrase II, a zinc enzyme abundant in red blood cells that converts carbon dioxide to bicarbonate and regulates acid-base balance.", "node": "life.biology.genetics.gene_record_human.metabolic-and-enzyme-genes", "markdown": "# CA2\n\n**CA2** is the human gene encoding carbonic anhydrase II (CA II), a cytosolic zinc metalloenzyme of the α-carbonic anhydrase family (carbonate hydro-lyase, EC 4.2.1.1) that catalyzes the reversible hydration of carbon dioxide, CO₂ + H₂O ↔ HCO₃⁻ + H⁺.[1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) • [2](https://www.ncbi.nlm.nih.gov/gene/%20760) CA II is described as the physiologically dominant carbonic anhydrase isoform in humans, abundant in red blood cells and active in pH regulation, CO₂/bicarbonate homeostasis, respiration, and electrolyte secretion, and its deficiency causes osteopetrosis with renal tubular acidosis.[3](https://pubmed.ncbi.nlm.nih.gov/42486551/) • [2](https://www.ncbi.nlm.nih.gov/gene/%20760)\n\n| Key fact | Detail |\n|---|---|\n| Reaction | Reversible hydration of CO₂ to bicarbonate and a proton, EC 4.2.1.1[1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) |\n| Gene | CA2, Gene ID 760, protein-coding, chromosome 8q21.2, 7 exons, two transcript variants[2](https://www.ncbi.nlm.nih.gov/gene/%20760) |\n| Protein | 259-residue, high-activity cytosolic isoform first sequenced from human erythrocytes[4](https://academic.oup.com/femsre/article/24/4/335/509557) |\n| Active site | Tetrahedral zinc coordinated by three histidines (positions 94, 96, 119 in human CA II) and a water molecule[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6158936/) • [1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) |\n| Rate-limiting step | Intramolecular proton transfer from zinc-bound water to His-64, the proton shuttle[1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) |\n| Deficiency disease | Osteopetrosis, autosomal recessive 3, with renal tubular acidosis (MIM 259730); ClinGen classification Definitive[6](https://search.clinicalgenome.org/kb/genes/HGNC%3A1373) • [7](https://www.ncbi.nlm.nih.gov/clinvar/RCV000373455/?cmd=ClearHT) |\n| Drug target | Inhibited by sulfonamides such as acetazolamide, methazolamide, and dichlorphenamide; systemic CA II inhibition lowers intraocular pressure by 25–30% in glaucoma therapy[1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) • [8](https://applications.emro.who.int/imemrf/Pak_J_Pharm_Sci/Pak_J_Pharm_Sci_2019_32_2_709_720.pdf) |\n\n## Structure and catalytic mechanism\n\n[Carbonic anhydrase](https://www.edgepedia.org/carbonic-anhydrase) was isolated from ox blood in 1932, found to be distinct from hemoglobin, and named for its catalysis of CO₂ hydration; Keilin and Martin later showed that activity was directly proportional to zinc content, making carbonic anhydrase the first zinc metalloenzyme identified.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6158936/) • [4](https://academic.oup.com/femsre/article/24/4/335/509557) The first CA sequences came from human erythrocytes: the 260-residue, low-activity CA I and the 259-residue, high-activity CA II.[4](https://academic.oup.com/femsre/article/24/4/335/509557)\n\nThe crystal structure of human CA II has been refined at 2.0 Å resolution. All structurally characterized α-carbonic anhydrases share the same tertiary fold, dominated by a central 10-stranded β-sheet, with the zinc ion in a cone-shaped cavity coordinated to three histidyl residues and a solvent molecule.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6158936/) • [1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) In human CA II the three zinc-ligating histidines occupy positions x, x+2, and x+25 with x = 94.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6158936/)\n\nThe catalytic mechanism of CA II has been studied in particular detail. The bound metal ion lowers the pKa of a water molecule so that it becomes a zinc-bound hydroxide, which attacks a CO₂ molecule loosely bound in a hydrophobic pocket of the active site, defined in hCA II by residues including Val121, Val143, and Leu198.[9](https://www.tandfonline.com/doi/pdf/10.3109/14756366.2012.672983?download=true) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC7567974/) The resulting zinc-coordinated bicarbonate is displaced from the metal by water. The rate-limiting step is an intramolecular proton transfer from the zinc-bound water to His-64, which shuttles protons between the metal center and buffer molecules in the medium, assisted by an ordered water wire in the active site.[1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) • [11](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964523/) Second-shell residues tune the metal center: the Glu106 carboxylate hydrogen-bonds to the hydroxyl group of Thr199, and this hydrogen-bonded system guides inhibitors binding at or near the metal.[12](https://www.sciencedirect.com/science/article/abs/pii/S0045206819318255) • [1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) Reversing the polarity of the residue 117–His119 hydrogen bond (the E117Q variant) stabilizes H119 as a histidinate anion and causes an enormously diminished catalytic activity and sulfonamide affinity, showing how sensitive catalysis is to the second coordination sphere.[13](https://pubmed.ncbi.nlm.nih.gov/8639494/)\n\n## Gene and expression\n\nCA2 (official symbol CA2, HGNC:1373; aliases CAC, CAII, Car2, CA-II, HEL-76, HEL-S-282) sits on chromosome 8q21.2, spans 7 exons, and encodes a protein-coding transcript with two variants encoding different isoforms.[2](https://www.ncbi.nlm.nih.gov/gene/%20760) On GRCh38 the gene occupies chr8:85464007–85481493.[2](https://www.ncbi.nlm.nih.gov/gene/%20760) Expression is biased toward the stomach (RPKM 493.8) and colon (RPKM 349.1), with expression in eight other tissues.[2](https://www.ncbi.nlm.nih.gov/gene/%20760) The protein is also located in the brain, kidney, gastric mucosa, osteoclasts, red blood cells, skeletal muscle, testes, pancreas, and lungs.[12](https://www.sciencedirect.com/science/article/abs/pii/S0045206819318255)\n\n## Physiological role\n\nThe only known physiological function of carbonic anhydrase is to catalyze the reversible hydration of CO₂.[14](https://shura.shu.ac.uk/20356/1/10701002.pdf) CA II, a cytosolic protein found throughout most vertebrates and especially plentiful in erythrocytes and various other tissues, contributes to acid-base balance, CO₂/bicarbonate equilibrium, breathing, and the discharge of acid- or bicarbonate-rich electrolytes in organs including the stomach, kidneys, cerebrospinal fluid, eyes, and bones.[3](https://pubmed.ncbi.nlm.nih.gov/42486551/) In the kidney, the combined action of cytosolic CA II and membrane-bound CA IV maintains acid-base status by reclaiming bicarbonate in the proximal tubule and secreting Na⁺ in exchange for H⁺.[14](https://shura.shu.ac.uk/20356/1/10701002.pdf) Among the sixteen reported human CA isoforms, hCA II is described as the most dominant physiologic isoform, and because of its high availability in the retina and lens it plays a prominent role in regulating intraocular pressure.[12](https://www.sciencedirect.com/science/article/abs/pii/S0045206819318255)\n\n## CA II deficiency\n\nDefects in the CA2 enzyme are associated with osteopetrosis and renal tubular acidosis.[2](https://www.ncbi.nlm.nih.gov/gene/%20760) The disorder, osteopetrosis with renal tubular acidosis (autosomal recessive 3, MIM 259730), is classified by ClinGen's Skeletal Disorders Gene Curation Expert Panel as a Definitive gene-disease validity pairing, inherited autosomal recessively.[6](https://search.clinicalgenome.org/kb/genes/HGNC%3A1373) A splice junction mutation in intron 2 of the CA2 gene underlies the deficiency syndrome in patients of Arab descent, and the variant NM_000067.3(CA2):c.232+1G>A is classified as pathogenic by eight submissions in ClinVar.[7](https://www.ncbi.nlm.nih.gov/clinvar/RCV000373455/?cmd=ClearHT)\n\n## Pharmacology\n\nCA II is a drug target. Classical inhibitors are sulfonamides, including acetazolamide, [methazolamide](https://www.edgepedia.org/methazolamide), [dichlorphenamide](https://www.edgepedia.org/dichlorphenamide), and ethoxzolamide, used systemically in antiglaucoma therapy; by inhibiting the sulfonamide-sensitive CA II in the ciliary processes they reduce bicarbonate and aqueous humor formation, lowering intraocular pressure by 25–30%.[1](https://www.sciencedirect.com/science/article/pii/S0163725896001982) • [8](https://applications.emro.who.int/imemrf/Pak_J_Pharm_Sci/Pak_J_Pharm_Sci_2019_32_2_709_720.pdf) Inhibitors of CA I and CA II are also used or investigated for edema, epilepsy, obesity, acute mountain sickness, and idiopathic intracranial hypertension, with drugs in clinical use including acetazolamide, dorzolamide, [brinzolamide](https://www.edgepedia.org/brinzolamide), topiramate, and zonisamide, and SLC-0111 in clinical development as an antitumor agent.[3](https://pubmed.ncbi.nlm.nih.gov/42486551/)\n\nInhibition selectivity is a recurring problem. The catalytic zinc-binding region is highly conserved across the catalytically active human isoforms, so classical sulfonamides often inhibit CA I, CA II, and other isoforms simultaneously; because CA II is the most physiologically abundant isoform, it is often regarded as the predominant off-target isozyme, sequestering free inhibitor and contributing to systemic side effects such as fatigue and nausea.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964523/) • [15](https://www.mdpi.com/1422-0067/27/14/6375) At least five different inhibition mechanisms have been described for CA I and CA II, with more than 50 chemotypes acting as inhibitors, and structure-based design has produced highly isoform-selective inhibitors for human CA isoforms.[3](https://pubmed.ncbi.nlm.nih.gov/42486551/) • [16](https://pmc.ncbi.nlm.nih.gov/articles/PMC7901698/)\n\n## References\n\n1. [Sven Lindskog (1997). Structure and mechanism of carbonic anhydrase. Pharmacology & Therapeutics 74(1).](https://www.sciencedirect.com/science/article/pii/S0163725896001982)\n2. [CA2 carbonic anhydrase 2 [Homo sapiens], Gene ID 760, NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/%20760)\n3. [Carbonic anhydrases I and II, PubMed](https://pubmed.ncbi.nlm.nih.gov/42486551/)\n4. [Prokaryotic carbonic anhydrases, FEMS Microbiology Reviews](https://academic.oup.com/femsre/article/24/4/335/509557)\n5. [Crystallography and Its Impact on Carbonic Anhydrase Research, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6158936/)\n6. [CA2 curation results, ClinGen](https://search.clinicalgenome.org/kb/genes/HGNC%3A1373)\n7. [NM_000067.3(CA2):c.232+1G>A and Osteopetrosis with renal tubular acidosis, ClinVar](https://www.ncbi.nlm.nih.gov/clinvar/RCV000373455/?cmd=ClearHT)\n8. [Therapeutic potential of carbonic anhydrase inhibitors: An overview, Pak J Pharm Sci](https://applications.emro.who.int/imemrf/Pak_J_Pharm_Sci/Pak_J_Pharm_Sci_2019_32_2_709_720.pdf)\n9. [Structure-based drug discovery of carbonic anhydrase inhibitors, J Enzyme Inhib Med Chem](https://www.tandfonline.com/doi/pdf/10.3109/14756366.2012.672983?download=true)\n10. [Perspectives on the Classical Enzyme Carbonic Anhydrase and the Search for Inhibitors, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7567974/)\n11. [Non-Classical Inhibition of Carbonic Anhydrase, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964523/)\n12. [Structure-activity relationship of human carbonic anhydrase-II inhibitors, Bioorganic Chemistry](https://www.sciencedirect.com/science/article/abs/pii/S0045206819318255)\n13. [Reversal of the hydrogen bond to zinc ligand histidine-119..., PubMed](https://pubmed.ncbi.nlm.nih.gov/8639494/)\n14. [Physiological roles of the carbonic anhydrases, Sheffield Hallam University](https://shura.shu.ac.uk/20356/1/10701002.pdf)\n15. [Carbonic Anhydrase I and II as Biomarkers and Therapeutic Targets in Human Disease, IJMS](https://www.mdpi.com/1422-0067/27/14/6375)\n16. [Reconsidering anion inhibitors in the general context of drug design studies of carbonic anhydrase, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7901698/)\n\n---\n*Topic: Encyclopedia › Life and health › Biological foundations › Genetics and genomic reference › Human gene and locus records › Metabolic and enzyme genes*\n\n*Initially written Oct 21, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/ca2", "markdown_url": "https://www.edgepedia.org/ca2.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"CA2\", Edgepedia (EdgeChat), https://www.edgepedia.org/ca2. Edgepedia Community License 1.0.", "credit_md": "\"[CA2](https://www.edgepedia.org/ca2)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/ca2](https://www.edgepedia.org/ca2). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"CA2\", Edgepedia (EdgeChat), https://www.edgepedia.org/ca2. Edgepedia Community License 1.0.", "speakable": "CA2 is the human gene encoding carbonic anhydrase II, a zinc enzyme abundant in red blood cells that converts carbon dioxide to bicarbonate and regulates acid-base balance." }