{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:15:59Z","timestamp":1793369759590,"version":"4.5.0"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"16","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,4,22]]},"abstract":"<jats:p>\n                    The Rapoport\u2013Luebering glycolytic bypass comprises evolutionarily conserved reactions that generate and dephosphorylate 2,3-bisphosphoglycerate (2,3-BPG). For &gt;30 years, these reactions have been considered the responsibility of a single enzyme, the 2,3-BPG synthase\/2-phosphatase (BPGM). Here, we show that\n                    <jats:italic>Dictyostelium<\/jats:italic>\n                    , birds, and mammals contain an additional 2,3-BPG phosphatase that, unlike BPGM, removes the 3-phosphate. This discovery reveals that the glycolytic pathway can bypass the formation of 3-phosphoglycerate, which is a precursor for serine biosynthesis and an activator of AMP-activated protein kinase. Our 2,3-BPG phosphatase activity is encoded by the previously identified gene for multiple inositol polyphosphate phosphatase (MIPP1), which we now show to have dual substrate specificity. By genetically manipulating Mipp1 expression in\n                    <jats:italic>Dictyostelium<\/jats:italic>\n                    , we demonstrated that this enzyme provides physiologically relevant regulation of cellular 2,3-BPG content. Mammalian erythrocytes possess the highest content of 2,3-BPG, which controls oxygen binding to hemoglobin. We determined that total MIPP1 activity in erythrocytes at 37\u00b0C is 0.6 mmol 2,3-BPG hydrolyzed per liter of cells per h, matching previously published estimates of the phosphatase activity of BPGM. MIPP1 is active at 4\u00b0C, revealing a clinically significant contribution to 2,3-BPG loss during the storage of erythrocytes for transfusion. Hydrolysis of 2,3-BPG by human MIPP1 is sensitive to physiologic alkalosis; activity decreases 50% when pH rises from 7.0 to 7.4. This phenomenon provides a homeostatic mechanism for elevating 2,3-BPG levels, thereby enhancing oxygen release to tissues. Our data indicate greater biological significance of the Rapoport\u2013Luebering shunt than previously considered.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0710980105","type":"journal-article","created":{"date-parts":[[2008,4,14]],"date-time":"2008-04-14T21:10:43Z","timestamp":1208207443000},"page":"5998-6003","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":55,"title":["Dephosphorylation of 2,3-bisphosphoglycerate by MIPP expands the regulatory capacity of the Rapoport\u2013Luebering glycolytic shunt"],"prefix":"10.1073","volume":"105","author":[{"given":"Jaiesoon","family":"Cho","sequence":"first","affiliation":[{"name":"*Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Social Services, P.O. Box 12233, Research Triangle Park, NC 27709; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason S.","family":"King","sequence":"additional","affiliation":[{"name":"Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Qian","sequence":"additional","affiliation":[{"name":"*Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Social Services, P.O. Box 12233, Research Triangle Park, NC 27709; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian J.","family":"Harwood","sequence":"additional","affiliation":[{"name":"Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen B.","family":"Shears","sequence":"additional","affiliation":[{"name":"*Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Social Services, P.O. Box 12233, Research Triangle Park, NC 27709; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,4,22]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(02)75198-9"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1977.tb11333.x"},{"key":"e_1_3_3_3_2","first-page":"276","volume-title":"Biochemistry","author":"Stryer L","year":"1980","unstructured":"L Stryer Biochemistry (Freeman, 2nd Ed, San Francisco), pp. 276\u2013278 (1980).","edition":"2"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0079-6107(93)90001-Z"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20060277"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(67)90228-8"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.59.2.526"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00592506"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1993.75.4.1696"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3148.2005.00607.x"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3420597"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3420567"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00322.2006"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211692200"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.50.29724"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03481"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1110\/ps.9.6.1203"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/346580a0"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.17.6496-6507.2000"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53233-6"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)01636-6"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2006.04.028"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0305-0491(87)90167-2"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3050491"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1991.0052"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1993.tb17786.x"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3280075"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(78)90254-0"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1537-2995.2006.00893.x"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(87)90556-X"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)63045-5"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0764-4469(99)80083-3"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-201X.2004.01361.x"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10863-007-9083-0"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmrv.2006.11.004"},{"key":"e_1_3_3_36_2","unstructured":"JS King The effects of inositol metabolism on lithium sensitivity and chemotaxis in Dictyostelium discoideum .  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