Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase.

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  • Additional Information
    • Source:
      Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 101676043 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2059-7983 (Electronic) Linking ISSN: 20597983 NLM ISO Abbreviation: Acta Crystallogr D Struct Biol Subsets: MEDLINE
    • Publication Information:
      Publication: <2018-> : Medford, MA : John Wiley & Sons
      Original Publication: [Malden, MA] : John Wiley & Sons, [2016]-
    • Subject Terms:
      Bisphosphoglycerate Mutase* ; Glycolates*/metabolism; Binding Sites ; Phosphoric Monoester Hydrolases
    • Abstract:
      Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific multifunctional enzyme that is responsible for the regulation of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells through its synthase and phosphatase activities; the latter enzymatic function is stimulated by the endogenous activator 2-phosphoglycolate (2-PG). 2,3-BPG is a natural allosteric effector of hemoglobin (Hb) that is responsible for decreasing the affinity of Hb for oxygen to facilitate tissue oxygenation. Here, crystal structures of BPGM with 2-PG in the presence and absence of 3-phosphoglycerate are reported at 2.25 and 2.48 Å resolution, respectively. Structure analysis revealed a new binding site for 2-PG at the dimer interface for the first time, in addition to the expected active-site binding. Also, conformational non-equivalence of the two active sites was observed as one of the sites was found in an open conformation, with the residues at the active-site entrance, including Arg100, Arg116 and Arg117, and the C-terminus disordered. The kinetic result is consistent with the binding of 2-PG to an allosteric or noncatalytic site as well as the active site. This study paves the way for the rational targeting of BPGM for therapeutic purposes, especially for the treatment of sickle cell disease.
      (open access.)
    • References:
      Arch Biochem Biophys. 1967 Jul;121(1):96-102. (PMID: 6035074)
      J Biol Chem. 1973 Mar 10;248(5):1513-9. (PMID: 4694722)
      J Biol Chem. 1976 Aug 25;251(16):4817-22. (PMID: 8447)
      Acta Crystallogr D Struct Biol. 2019 Oct 1;75(Pt 10):861-877. (PMID: 31588918)
      Blood. 1995 Jun 1;85(11):3289-96. (PMID: 7756662)
      Biochimie. 1990 May;72(5):337-43. (PMID: 2145041)
      J Biol Chem. 1985 Nov 15;260(26):13897-900. (PMID: 4055763)
      J Biol Chem. 1989 Nov 15;264(32):18966-72. (PMID: 2553728)
      Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42. (PMID: 21460441)
      Adv Protein Chem. 1990;40:63-279. (PMID: 2195851)
      Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Nov 1;66(Pt 11):1415-20. (PMID: 21045285)
      Biochem Biophys Res Commun. 1967 Jan 23;26(2):162-7. (PMID: 6030262)
      J Biol Chem. 1970 Jun;245(12):3232-41. (PMID: 4317427)
      J Pharmacol Exp Ther. 1990 Jan;252(1):192-200. (PMID: 2153800)
      Eur J Biochem. 1976 Jul 15;66(3):515-22. (PMID: 182493)
      J Biol Chem. 1968 Sep 25;243(18):4810-20. (PMID: 5687724)
      Arch Biochem Biophys. 1986 Oct;250(1):106-11. (PMID: 3021059)
      Biochem Biophys Res Commun. 2005 Jun 17;331(4):1207-15. (PMID: 15883004)
      Philos Trans R Soc Lond B Biol Sci. 1981 Jun 26;293(1063):121-30. (PMID: 6115412)
      J Clin Invest. 2014 Jun;124(6):2750-61. (PMID: 24837436)
      Nat Commun. 2016 Jul 15;7:12086. (PMID: 27417539)
      N Engl J Med. 1997 Sep 11;337(11):762-9. (PMID: 9287233)
      Anal Biochem. 2013 Sep 1;440(1):81-95. (PMID: 23711724)
      J Mol Biol. 1997 Sep 26;272(3):398-407. (PMID: 9325099)
      J Struct Biol. 2016 Jun;194(3):446-50. (PMID: 27085422)
      J Biol Chem. 2004 Sep 10;279(37):39132-8. (PMID: 15258155)
      Proteins. 1998 Feb 1;30(2):144-54. (PMID: 9489922)
      Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002)
      J Biol Chem. 1978 Dec 10;253(23):8583-92. (PMID: 213437)
      ScientificWorldJournal. 2008 Dec 25;8:1295-324. (PMID: 19112541)
      Curr Protoc Protein Sci. 2013 Feb;Chapter 20:Unit20.12. (PMID: 23377850)
      Nature. 1969 Feb 15;221(5181):618-22. (PMID: 5774935)
      Mol Cell Biochem. 1983;53-54(1-2):247-56. (PMID: 6312283)
      J Biol Chem. 1951 Apr;189(2):683-94. (PMID: 14832286)
      Acta Crystallogr D Biol Crystallogr. 2012 Apr;68(Pt 4):352-67. (PMID: 22505256)
      Acta Pharmacol Sin. 2017 Dec;38(12):1673-1682. (PMID: 28748916)
      J Biol Chem. 2006 Dec 22;281(51):39642-8. (PMID: 17052986)
      Adv Enzymol Relat Areas Mol Biol. 1980;51:211-53. (PMID: 6255773)
    • Grant Information:
      R01 MD009124 United States MD NIMHD NIH HHS; S10 OD021756 United States OD NIH HHS; S10OD021756 (MKS) United States NH NIH HHS; R01MD009124 (MKS) United States MD NIMHD NIH HHS
    • Contributed Indexing:
      Keywords: 2,3-bisphosphoglycerate; 2-phosphoglycolate; X-ray crystallography; bisphosphoglycerate mutase; kinetics; phosphatases; synthases
    • Accession Number:
      0 (Glycolates)
      EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
      EC 5.4.2.4 (Bisphosphoglycerate Mutase)
      H8593JOP13 (phosphoglycolate)
    • Publication Date:
      Date Created: 20220401 Date Completed: 20220404 Latest Revision: 20220430
    • Publication Date:
      20240104
    • Accession Number:
      PMC8972806
    • Accession Number:
      10.1107/S2059798322001802
    • Accession Number:
      35362470