CA1 (gene) explained

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.

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:

+ H2O ->[{}\atop\ce{Carbonic~anhydrase}] H2CO3

(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, and catalytic efficiency (Kcat/Km) of 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:, Kcat/Km:).^[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. Transmembrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation.^[8]

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.^[9]

Clinical significance

CA1 activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy.^[10] 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.

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.

Interactions

CA1 has been shown to interact with:

• TFCP2^[13]
• HSD17B7^[14]
• MAPK6^[15]

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

Further reading

• Book: Tashian RE, Carter ND . Advances in Human Genetics . Biochemical Genetics of Carbonic Anhydrase . 1976 . 7 . 1–56 . 827930 . 10.1007/978-1-4757-0659-8_1. 978-1-4757-0661-1 .
• Sly WS, Hu PY . Human carbonic anhydrases and carbonic anhydrase deficiencies . Annual Review of Biochemistry . 64 . 1 . 375–401 . 1995 . 7574487 . 10.1146/annurev.bi.64.070195.002111 .
• Kendall AG, Tashian RE . Erythrocyte carbonic anhydrase I: inherited deficiency in humans . Science . 197 . 4302 . 471–2 . Jul 1977 . 406674 . 10.1126/science.406674 . 1977Sci...197..471K .
• Kannan KK, Notstrand B, Fridborg K, Lövgren S, Ohlsson A, Petef M . Crystal structure of human erythrocyte carbonic anhydrase B. Three-dimensional structure at a nominal 2.2-A resolution . Proceedings of the National Academy of Sciences of the United States of America . 72 . 1 . 51–5 . Jan 1975 . 804171 . 432238 . 10.1073/pnas.72.1.51 . free .
• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin . The Journal of Infection . 24 . 3 . 317–20 . May 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• Lowe N, Brady HJ, Barlow JH, Sowden JC, Edwards M, Butterworth PH . Structure and methylation patterns of the gene encoding human carbonic anhydrase I . Gene . 93 . 2 . 277–83 . Sep 1990 . 2121614 . 10.1016/0378-1119(90)90236-K .
• Noda Y, Sumitomo S, Hikosaka N, Mori M . Immunohistochemical observations on carbonic anhydrase I and II in human salivary glands and submandibular obstructive adenitis . Journal of Oral Pathology . 15 . 4 . 187–90 . Apr 1986 . 3088232 . 10.1111/j.1600-0714.1986.tb00604.x .
• Barlow JH, Lowe N, Edwards YH, Butterworth PH . Human carbonic anhydrase I cDNA . Nucleic Acids Research . 15 . 5 . 2386 . Mar 1987 . 3104879 . 340641 . 10.1093/nar/15.5.2386 .
• Edwards YH, Barlow JH, Konialis CP, Povey S, Butterworth PH . Assignment of the gene determining human carbonic anhydrase, CAI, to chromosome 8 . Annals of Human Genetics . 50 . Pt 2 . 123–9 . May 1986 . 3124707 . 10.1111/j.1469-1809.1986.tb01030.x . 44919686 .
• Lin KT, Deutsch HF . Human carbonic anhydrases. XII. The complete primary structure of the C isozyme . The Journal of Biological Chemistry . 249 . 8 . 2329–37 . Apr 1974 . 10.1016/S0021-9258(19)42734-8 . 4207120 . free .
• Giraud N, Marriq C, Laurent-Tabusse G . [Primary structure of human B erythrocyte carbonic anhydrase. 3. Sequence of CNBr fragment I and III (residues 149-260)] . Biochimie . 56 . 8 . 1031–43 . 1975 . 4217196 . 10.1016/S0300-9084(74)80093-3 .
• Andersson B, Nyman PO, Strid L . Amino acid sequence of human erythrocyte carbonic anhydrase B . Biochemical and Biophysical Research Communications . 48 . 3 . 670–7 . Aug 1972 . 4625868 . 10.1016/0006-291X(72)90400-7 .
• Lin KT, Deutsch HF . Human carbonic anhydrases. XI. The complete primary structure of carbonic anhydrase B . The Journal of Biological Chemistry . 248 . 6 . 1885–93 . Mar 1973 . 10.1016/S0021-9258(19)44161-6 . 4632246 . free .
• Omoto K, Ueda S, Goriki K, Takahashi N, Misawa S, Pagaran IG . Population genetic studies of the Philippine Negritos. III. Identification of the carbonic anhydrase-1 variant with CA1 Guam . American Journal of Human Genetics . 33 . 1 . 105–11 . Jan 1981 . 6781336 . 1684865 .
• Chegwidden WR, Wagner LE, Venta PJ, Bergenhem NC, Yu YS, Tashian RE . Marked zinc activation of ester hydrolysis by a mutation, 67-His (CAT) to Arg (CGT), in the active site of human carbonic anhydrase I . Human Mutation . 4 . 4 . 294–6 . 1995 . 7866410 . 10.1002/humu.1380040411 . 21458184 .
• Bekku S, Mochizuki H, Takayama E, Shinomiya N, Fukamachi H, Ichinose M, Tadakuma T, Yamamoto T . Carbonic anhydrase I and II as a differentiation marker of human and rat colonic enterocytes . Research in Experimental Medicine. Zeitschrift für die Gesamte Experimentelle Medizin Einschliesslich Experimenteller Chirurgie . 198 . 4 . 175–85 . Dec 1998 . 9879596 . 10.1007/s004330050101. 11297322 .
• Puscas I, Coltau M, Baican M, Pasca R, Domuta G, Hecht A . 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 . Drugs Under Experimental and Clinical Research . 27 . 2 . 53–60 . 2001 . 11392054 .

Notes and References

1. Lowe N, Edwards YH, Edwards M, Butterworth PH . Physical mapping of the human carbonic anhydrase gene cluster on chromosome 8 . Genomics . 10 . 4 . 882–8 . Aug 1991 . 1916821 . 10.1016/0888-7543(91)90176-F .
2. Web site: Entrez Gene: CA1 carbonic anhydrase I.
3. Web site: CA1 - Carbonic anhydrase 1 - Homo sapiens (Human) - CA1 gene & protein. www.uniprot.org. 2016-03-23.
4. Kumar V, Kannan KK . Enzyme-substrate interactions. Structure of human carbonic anhydrase I complexed with bicarbonate . Journal of Molecular Biology . 241 . 2 . 226–32 . Aug 1994 . 8057362 . 10.1006/jmbi.1994.1491 .
5. Carbonic acid has a pK_a 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 + H⁺ H₂CO₃ and H₂CO₃ CO₂ + H₂O
6. Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT . Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction? . Journal of Biological Inorganic Chemistry . 4 . 5 . 528–36 . Oct 1999 . 10550681 . 10.1007/s007750050375. 25890428 .
7. Silverman. David N.. Lindskog. Sven . vanc . 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. 10.1021/ar00145a005.
8. Alvarez BV, Quon AL, Mullen J, Casey JR . Quantification of carbonic anhydrase gene expression in ventricle of hypertrophic and failing human heart . BMC Cardiovascular Disorders . 13 . 2 . 2013-01-01 . 23297731 . 3570296 . 10.1186/1471-2261-13-2 . free .
9. Ferraroni M, Tilli S, Briganti F, Chegwidden WR, Supuran CT, Wiebauer KE, Tashian RE, Scozzafava A . 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 . May 2002 . 12009884 . 10.1021/bi0120446.
10. 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 . Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy . Journal of the American Heart Association . 3 . 2 . e000434 . 2014-01-01 . 24670789 . 4187518 . 10.1161/JAHA.113.000434 .
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 . Maciej Wojtkowski . Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation . Nature Medicine . 13 . 2 . 181–8 . Feb 2007 . 17259996 . 10.1038/nm1534 . 14404913 .
12. Supuran CT . Carbonic anhydrases: novel therapeutic applications for inhibitors and activators . Nature Reviews. Drug Discovery . 7 . 2 . 168–81 . Feb 2008 . 10.1038/nrd2467 . 18167490 . 3833178 .
13. 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 . 6 . A proteome-scale map of the human interactome network . Cell . 159 . 5 . 1212–26 . Nov 2014 . 25416956 . 4266588 . 10.1016/j.cell.2014.10.050 .
14. 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 . 6 . Toward an understanding of the protein interaction network of the human liver . Molecular Systems Biology . 7 . 536 . 2011-01-01 . 21988832 . 3261708 . 10.1038/msb.2011.67 .
15. Vinayagam A, Stelzl U, Foulle R, Plassmann S, Zenkner M, Timm J, Assmus HE, Andrade-Navarro MA, Wanker EE . A directed protein interaction network for investigating intracellular signal transduction . Science Signaling . 4 . 189 . rs8 . Sep 2011 . 21900206 . 10.1126/scisignal.2001699 . 7418133 .