The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp SLC4A1,2,3 exchanges HCO3- for Cl- SLC4A1,2,3 exchanges HCO3- for Cl- Cl-/HCO3- exchanger transport This event has been computationally inferred from an event that has been demonstrated in another species.

The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 188972 1 extracellular region GO 0005576 chloride [ChEBI:17996] chloride Reactome //www.joaskin.com ChEBI 17996 Reactome DB_ID: 111627 1 cytosol GO 0005829 hydrogencarbonate [ChEBI:17544] hydrogencarbonate ChEBI 17544 Reactome DB_ID: 425425 1 Reactome DB_ID: 352022 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10435967 plasma membrane GO 0005886 SLC4A1,2,3 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity SLC4A2 [plasma membrane] SLC4A3 [plasma membrane] Gallus gallus NCBI Taxonomy 9031 UniProt A0A3Q2U947 UniProt E1C314 GO 0005452 GO molecular function Reactome Database ID Release 77 10435968 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10435968 Reactome Database ID Release 77 10435970 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10435970 Reactome R-GGA-425482 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-425482.1 The proteins responsible for the exchange of Cl- with HCO3- are members of the SLC4 (1-3) and SLC26 (3, 4, 6, 7 and 9) transporter families. The SLC26 members are discussed under the section "Multifunctional anion exchangers".

SLC4A1 (Band 3, AE1, anion exchanger 1) was the first bicarbonate transporter gene to be cloned and sequenced (Lux et al. 1989). It is ubiquitous throughout vertebrates and in humans, is present on erythrocytes and the basolateral surfaces of kidney cells. The erythrocyte and kidney forms are different isoforms of the same protein (Kollert-Jons et al. 1993). Variations in erythroid AE1 determine the Diego blood group system (Bruce et al. 1994). A more serious consequence of mutated erythroid AE1 is Hereditary spherocytosis (a disorder leading to haemolytic anaemia) (Jarolim et al. 1995). Defects in the kidney form of AE1 cause distal (type1) renal tubular acidosis (an inability to acidify urine) (Bruce et al. 1997).

SLC4A2 (Non-erythroid band 3-like protein, AE2, anion exchanger 2) is widely expressed and is considered to be the 'housekeeping' isoform of the bicarbonate transporters (Demuth et al. 1986). SLC4A3 (Cardiac/brain band 3-like protein, AE3) is expressed in heart and brain (Yannoukakos et al. 1994). 2594752 Pubmed 1989 Cloning and characterization of band 3, the human erythrocyte anion-exchange protein (AE1) Lux, SE John, KM Kopito, RR Lodish, HF Proc Natl Acad Sci U S A 86:9089-93 8206915 Pubmed 1994 Band 3 Memphis variant II. Altered stilbene disulfonate binding and the Diego (Dia) blood group antigen are associated with the human erythrocyte band 3 mutation Pro854-->Leu Bruce, LJ Anstee, DJ Spring, FA Tanner, MJ J Biol Chem 269:16155-8 7506871 Pubmed 1993 Anion exchanger 1 in human kidney and oncocytoma differs from erythroid AE1 in its NH2 terminus Kollert-Jöns, A Wagner, S Hübner, S Appelhans, H Drenckhahn, D Am J Physiol 265:F813-21 9312167 Pubmed 1997 Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene Bruce, LJ Cope, DL Jones, GK Schofield, AE Burley, M Povey, S Unwin, RJ Wrong, O Tanner, MJ J Clin Invest 100:1693-707 3015590 Pubmed 1986 Cloning and structural characterization of a human non-erythroid band 3-like protein Demuth, DR Showe, LC Ballantine, M Palumbo, A Fraser, PJ Cioe, L Rovera, G Curtis, PJ EMBO J 5:1205-14 7530501 Pubmed 1995 Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis Jarolim, P Rubin, HL Brabec, V Chrobak, L Zolotarev, AS Alper, SL Brugnara, C Wichterle, H Palek, J 血85:634-40 7923606 Pubmed 1994 Molecular cloning, expression, and chromosomal localization of two isoforms of the AE3 anion exchanger from human heart Yannoukakos, D Stuart-Tilley, A Fernandez, HA Fey, P Duyk, G Alper, SL Circ Res 75:603-14 inferred by electronic annotation IEA GO IEA SLC4A5,7,9 cotransport Na+ with 3HCO3- SLC4A5,7,9 cotransport Na+ with 3HCO3- This event has been computationally inferred from an event that has been demonstrated in another species.

The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 111627 3 Reactome DB_ID: 83910 1 sodium(1+) [ChEBI:29101] sodium(1+) ChEBI 29101 Reactome DB_ID: 425425 3 Reactome DB_ID: 74113 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10435984 SLC4A5,7,9 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity SLC4A9 [plasma membrane] SLC4A5 [plasma membrane] SLC4A7 [plasma membrane] UniProt A0A1L1RK45 UniProt A0A1D5PHQ4 UniProt A0A3Q2UMA3 GO 0008510 GO molecular function Reactome Database ID Release 77 10435985 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10435985 Reactome Database ID Release 77 10435987 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10435987 Reactome R-GGA-425483 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-425483.1 Members of the SLC4A family couple the transport of bicarbonate (HCO3-) with sodium ions (Na+); they being members 4, 5, 7 and 9. SLC4A5 encodes a protein which is expressed in liver, spleen and testes, with lower levels expressed in parts of the brain and kidney (Sassani et al. 2002). It may have a housekeeping function in regulating the pH of these tissues (Pushkin et al. 2000).

SLC4A7 (aka NBC3, NBCn1) encodes a protein which performs electroneutral cotransport of Na+ and HCO3- with a 1:1 stoichiometry. It is highly expressed in testes and spleen and, to a lesser extent, in many other tissues including heart, muscle, kidney and GI tract (Pushkin et al. 1999).

SLC4A9 (aka AE4) was originally thought to exchange Cl- with HCO3- (hence the name AE4) but this has not been reported. Consensus has emerged that it is indeed a Na+/HCO3- co-transporter (Lipovich et al. 2001). It is predominantly expressed in the kidney, salivary glands, testes, thyroid glands and trachea (Parker et al. 2001). 11305939 Pubmed 2001 A novel sodium bicarbonate cotransporter-like gene in an ancient duplicated region: SLC4A9 at 5q31 Lipovich, L Lynch, ED Lee, MK King, Mary-Claire Genome Biol 2:RESEARCH0011 10978526 Pubmed 2000 克隆、鉴定和染色体assignment of NBC4, a new member of the sodium bicarbonate cotransporter family Pushkin, A Abuladze, N Newman, D Lee, I Xu, G Kurtz, I Biochim Biophys Acta 1493:215-8 11788353 Pubmed 2002 Functional characterization of NBC4: a new electrogenic sodium-bicarbonate cotransporter Sassani, P Pushkin, A Gross, E Gomer, A Abuladze, N Dukkipati, R Carpenito, G Kurtz, I Am J Physiol Cell Physiol 282:C408-16 10362779 Pubmed 1999 Characterization of Na+/HCO-3 cotransporter isoform NBC-3 Amlal, H Burnham, CE Soleimani, M Am J Physiol 276:F903-13 10347222 Pubmed 1999 Cloning, tissue distribution, genomic organization, and functional characterization of NBC3, a new member of the sodium bicarbonate cotransporter family Pushkin, A Abuladze, N Lee, I Newman, D Hwang, J Kurtz, I J Biol Chem 274:16569-75 inferred by electronic annotation IEA GO IEA SLC4A4 cotransports Na+ with 3HCO3- SLC4A4 cotransports Na+ with 3HCO3- This event has been computationally inferred from an event that has been demonstrated in another species.

The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 111627 3 Reactome DB_ID: 83910 1 Reactome DB_ID: 425425 3 Reactome DB_ID: 74113 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10484552 UniProt:A0A1D5NX03 SLC4A4 UniProt A0A1D5NX03 Chain Coordinates 1 EQUAL 1079 EQUAL Reactome Database ID Release 77 10484553 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10484553 Reactome Database ID Release 77 10484559 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10484559 Reactome R-GGA-8878664 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-8878664.1 SLC4A family members 4, 5, 7, and 9 can each couple the transport of bicarbonate (HCO3-) with sodium ions (Na+). SLC4A4 (aka NBCE1) is an electrogenic sodium/bicarbonate cotransporter with a Na+:HCO3- stoichiometry of 1:3, although it can also be 1:2 (Burnham et al. 1997). SLC4A4 encodes a protein which is expressed in the kidney and pancreas, with lesser expression in many other tissues (Abuladze et al. 1998). Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis (pRTA) (results in accumulation of acid in the body due to a failure of the kidneys to effectively acidify urine) with ocular abnormalities (Igarashi et al. 1999).

Adenosylhomocysteinase 2 (AHCYL2) can upregulate ion-transporting proteins such as the electrogenic sodium bicarbonate cotransporter 1 (SLC4A4, aka NBCE1) (Yamaguchi & Ishikawa 2014). 9235899 Pubmed 1997 Cloning and functional expression of a human kidney Na+:HCO3- cotransporter Burnham, CE Amlal, H Wang, Z Shull, GE Soleimani, M J Biol Chem 272:19111-4 10545938 Pubmed 1999 Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities Igarashi, T Inatomi, J Sekine, T Cha, SH Kanai, Y Kunimi, M Tsukamoto, K Satoh, H Shimadzu, M Tozawa, F Mori, T Shiobara, M Seki, G Endou, H Nat Genet 23:264-6 9651366 Pubmed 1998 Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter Abuladze, N Lee, I Newman, D Hwang, J Boorer, K Pushkin, A Kurtz, I J Biol Chem 273:17689-95 24472682 Pubmed 2014 AHCYL2 (long-IRBIT) as a potential regulator of the electrogenic Na(+)-HCO3(-) cotransporter NBCe1-B Yamaguchi, Soichiro Ishikawa, Toru FEBS Lett. 588:672-7 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 77 10484560 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10484560 Reactome DB_ID: 10484557 UniProt:F1NUT5 AHCYL2 UniProt F1NUT5 2 EQUAL 611 EQUAL Na+-driven Cl-/HCO3- exchanger transport Na+-driven Cl-/HCO3- exchanger transport This event has been computationally inferred from an event that has been demonstrated in another species.

The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 425425 1 Reactome DB_ID: 352022 1 Reactome DB_ID: 74113 1 Reactome DB_ID: 70106 1 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 188972 1 Reactome DB_ID: 111627 1 Reactome DB_ID: 351626 1 Reactome DB_ID: 83910 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10435997 Na+-driven Cl-/HCO3- exchanger proteins [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity SLC4A8 [plasma membrane] SLC4A10 [plasma membrane] UniProt A0A1D5PBM1 UniProt A0A1D5NXZ7 Reactome Database ID Release 77 10435998 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10435998 Reactome Database ID Release 77 10436000 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10436000 Reactome R-GGA-425577 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-425577.1 Two genes encode Na+-dependent Cl-/HCO3- exchangers; SLC4A8 (NDCBE1) and 10 (NCBE). SLC4A8 (NDCBE1) encodes a exchanger protein which mediates Na+:HCO3- transport with a stoichiometry of 1:2:1 (Na+/HCO3-/Cl-). This protein is highly expressed in brain and spine and moderately expressed in trachea, thyroid, and kidney (Amlal H et al, 1999). SLC4A10 (NCBE, NBCn2) encodes a Na+-driven Cl-/HCO3- exchanger protein (Parker MD et al, 2008). It transports extracellular Na+ and HCO3- into cells in exchange for intracellular Cl- and H+, thus raising the intracellular pH. 18319254 Pubmed 2008 Characterization of human SLC4A10 as an electroneutral Na/HCO3 cotransporter (NBCn2) with Cl- self-exchange activity Parker, MD Musa-Aziz, R Rojas, JD Choi, I Daly, CM Boron, WF J Biol Chem 283:12777-88 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10494210 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10494210 Reactome R-GGA-425381 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-425381.1 GO 0015701 GO biological process Respiratory oxidation in the mitochondria produces carbon dioxide (CO2) as a waste product. CO2 is in equilibrium with bicarbonate (HCO3-) and is the body's central pH buffering system. HCO3- is charged so cannot move across membranes unaided. The bicarbonate transport proteins move bicarbonate across the membrane. There are 14 genes which encode these transport proteins in mammals. Applying the Human Genome Organization's sytematic nomenclature to human genes, the bicarbonate transporters belong to the SLC4A and SLC26A families. Within SLC4A, there are two distinct subfamilies, functionally corresponding to the electroneutral Cl-/HCO3- exchangers and Na+-coupled HCO3- co-transporters (Romero MF et al, 2004; Cordat E and Casey JR, 2009). 14722772 Pubmed 2004 The SLC4 family of HCO 3 - transporters Romero, MF Fulton, CM Boron, WF Pflugers Arch 447:495-509 19099540 Pubmed 2009 Bicarbonate transport in cell physiology and disease Cordat, E Casey, JR Biochem J 417:423-39 inferred by electronic annotation IEA GO IEA