Carbonic anhydrase 4

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. CA IV is a glycosylphosphatidyl-inositol-anchored membrane isozyme expressed on the luminal surfaces of pulmonary (and certain other) capillaries and of proximal renal tubules. Its exact function is not known, however, it may have a role in inherited renal abnormalities of bicarbonate transport.

CA IV has been identified in pulmonary epithelium of many mammalian species and may be uniquely adaptive for gas exchange necessary for the high metabolic requirements of mammals. A majority of the {{CO2}} produced by metabolism is transported as bicarbonate ({{chem|HCO|3|-}}). At the tissue capillary, {{CO2}} diffuses from tissue to plasma. Other forms of carbonic anhydrase enzyme are not present in the plasma, restricting the equilibrium reaction of {{CO2}}+{{H2O-nl}} = {{chem|H|2|CO|3}} = H+ {{chem|HCO|3|-}}. {{CO2}} in the plasma diffuses into the Red Blood Cell. CA is present within the Red Blood Cell, facilitating the conversion of {{CO2}} to {{chem|HCO|3|-}}. {{chem|HCO|3|-}} so produced is transferred by the {{chem|HCO|3|-}}/Cl- "shuttle" from the interior of the Red Blood Cell to the plasma. {{chem|HCO|3|-}} does not diffuse across cell membranes and, in the absence of CA, stays as {{chem|HCO|3|-}} and concentrates in plasma. Up to 80% of metabolically produced {{CO2}} is transported in plasma in the form of {{chem|HCO|3|-}}. Blood moves from the tissue capillary to the pulmonary capillary where {{CO2}} is exchanged at the lung. In the pulmonary capillary, bicarbonate can not simply diffuse either into the Red Blood Cell or the alveoli. It is traditionally thought that {{chem|HCO|3|-}} is returned to the interior of the Red Blood Cell by a reversal of the {{chem|HCO|3|-}}/Cl- shuttle, where, in the presence of CA, it is returned to a {{CO2}} form to diffuse from the interior of the Red Blood Cell, to the plasma and then into the alveoli. Membrane bound CA (CA IV) on the luminal side of the pulmonary membrane would have direct contact with plasma {{chem|HCO|3|-}} and would enzymatically convert {{chem|HCO|3|-}} to {{CO2}} in the area immediately proximal to the exchange membrane, greatly increasing the concentration gradient for exchange. In this way, plasma {{chem|HCO|3|-}} can be converted to {{CO2}} within the plasma compartment and exchanged with the alveoli without the requirement of returning the {{chem|HCO|3|-}} to the interior of the Red Blood Cell.

CA4 has been shown to interact with Band 3.{{cite journal | vauthors = Sterling D, Alvarez BV, Casey JR | title = The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV | journal = J. Biol. Chem. | volume = 277 | issue = 28 | pages = 25239–46 | date = Jul 2002 | pmid = 11994299 | doi = 10.1074/jbc.M202562200 | doi-access = free }}

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• {{cite journal | vauthors = Okuyama T, Sato S, Zhu XL, Waheed A, Sly WS | title = Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression in COS cell membranes. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 4 | pages = 1315–9 | year = 1992 | pmid = 1311094 | pmc = 48440 | doi = 10.1073/pnas.89.4.1315 | bibcode = 1992PNAS...89.1315O | doi-access = free }}
• {{cite journal | vauthors = Hageman GS, Zhu XL, Waheed A, Sly WS | title = Localization of carbonic anhydrase IV in a specific capillary bed of the human eye. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 7 | pages = 2716–20 | year = 1991 | pmid = 1901414 | pmc = 51309 | doi = 10.1073/pnas.88.7.2716 | bibcode = 1991PNAS...88.2716H | doi-access = free }}
• {{cite journal | vauthors = Zhu XL, Sly WS | title = Carbonic anhydrase IV from human lung. Purification, characterization, and comparison with membrane carbonic anhydrase from human kidney. | journal = J. Biol. Chem. | volume = 265 | issue = 15 | pages = 8795–801 | year = 1990 | doi = 10.1016/S0021-9258(19)38958-6 | pmid = 2111324 | doi-access = free }}
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• {{cite journal | vauthors = Okuyama T, Waheed A, Kusumoto W, Zhu XL, Sly WS | title = Carbonic anhydrase IV: role of removal of C-terminal domain in glycosylphosphatidylinositol anchoring and realization of enzyme activity. | journal = Arch. Biochem. Biophys. | volume = 320 | issue = 2 | pages = 315–22 | year = 1995 | pmid = 7625839 | doi = 10.1016/0003-9861(95)90015-2 }}
• {{cite journal | vauthors = Mahieu I, Benjamin A, Stephens R, Walters D, Carter N | title = Characterization of membrane bound carbonic anhydrase IV (CA IV) located on the external surface of lung pulmonary endothelial cells. | journal = Biochem. Soc. Trans. | volume = 23 | issue = 2 | pages = 320S | year = 1995 | pmid = 7672351 | doi = 10.1042/bst023320s}}
• {{cite journal | vauthors = Sender S, Gros G, Waheed A, Hageman GS, Sly WS | title = Immunohistochemical localization of carbonic anhydrase IV in capillaries of rat and human skeletal muscle. | journal = J. Histochem. Cytochem. | volume = 42 | issue = 9 | pages = 1229–36 | year = 1994 | pmid = 8064130 | doi = 10.1177/42.9.8064130 | doi-access = free }}
• {{cite journal | vauthors = Fleming RE, Parkkila S, Parkkila AK, Rajaniemi H, Waheed A, Sly WS | title = Carbonic anhydrase IV expression in rat and human gastrointestinal tract regional, cellular, and subcellular localization. | journal = J. Clin. Invest. | volume = 96 | issue = 6 | pages = 2907–13 | year = 1996 | pmid = 8675662 | pmc = 186002 | doi = 10.1172/JCI118362 }}
• {{cite journal | vauthors = Waheed A, Okuyama T, Heyduk T, Sly WS | title = Carbonic anhydrase IV: purification of a secretory form of the recombinant human enzyme and identification of the positions and importance of its disulfide bonds. | journal = Arch. Biochem. Biophys. | volume = 333 | issue = 2 | pages = 432–8 | year = 1996 | pmid = 8809084 | doi = 10.1006/abbi.1996.0412 }}
• {{cite journal | vauthors = Parkkila S, Parkkila AK, Juvonen T, Waheed A, Sly WS, Saarnio J, Kaunisto K, Kellokumpu S, Rajaniemi H | title = Membrane-bound carbonic anhydrase IV is expressed in the luminal plasma membrane of the human gallbladder epithelium. | journal = Hepatology | volume = 24 | issue = 5 | pages = 1104–8 | year = 1996 | pmid = 8903383 | doi = 10.1002/hep.510240521 | s2cid = 11461543 }}
• {{cite journal |author6-link=David W. Christianson| vauthors = Stams T, Nair SK, Okuyama T, Waheed A, Sly WS, Christianson DW | title = Crystal structure of the secretory form of membrane-associated human carbonic anhydrase IV at 2.8-A resolution. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 24 | pages = 13589–94 | year = 1997 | pmid = 8942978 | pmc = 19359 | doi = 10.1073/pnas.93.24.13589 | doi-access = free }}
• {{cite journal | vauthors = Bardien S, Ramesar R, Bhattacharya S, Greenberg J | title = Retinitis pigmentosa locus on 17q (RP17): fine localization to 17q22 and exclusion of the PDEG and TIMP2 genes. | journal = Hum. Genet. | volume = 101 | issue = 1 | pages = 13–7 | year = 1997 | pmid = 9385361 | doi = 10.1007/s004390050577 | s2cid = 26680917 }}
• {{cite journal | vauthors = Sender S, Decker B, Fenske CD, Sly WS, Carter ND, Gros G | title = Localization of carbonic anhydrase IV in rat and human heart muscle. | journal = J. Histochem. Cytochem. | volume = 46 | issue = 7 | pages = 855–61 | year = 1998 | pmid = 9632745 | doi = 10.1177/002215549804600709 | doi-access = free }}
• {{cite journal | vauthors = Wistrand PJ, Carter ND, Conroy CW, Mahieu I | title = Carbonic anhydrase IV activity is localized on the exterior surface of human erythrocytes. | journal = Acta Physiol. Scand. | volume = 165 | issue = 2 | pages = 211–8 | year = 1999 | pmid = 10090333 | doi = 10.1046/j.1365-201x.1999.00478.x }}
• {{cite journal | vauthors = Fujikawa-Adachi K, Nishimori I, Sakamoto S, Morita M, Onishi S, Yonezawa S, Hollingsworth MA | title = Identification of carbonic anhydrase IV and VI mRNA expression in human pancreas and salivary glands. | journal = Pancreas | volume = 18 | issue = 4 | pages = 329–35 | year = 1999 | pmid = 10231836 | doi = 10.1097/00006676-199905000-00001 }}
• {{cite journal | vauthors = Sterling D, Alvarez BV, Casey JR | title = The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV. | journal = J. Biol. Chem. | volume = 277 | issue = 28 | pages = 25239–46 | year = 2002 | pmid = 11994299 | doi = 10.1074/jbc.M202562200 | doi-access = free }}

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• [https://www.ncbi.nlm.nih.gov/books/NBK1417/ GeneReviews/NCBI/NIH/UW entry on Retinitis Pigmentosa Overview]
• {{PDBe-KB2|P22748|Carbonic anhydrase 4}}

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