Non-consecutive enzyme interactions within TCA cycle supramolecular assembly regulate carbon-nitrogen metabolism.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : Nature Pub. Group
    • Subject Terms:
      Citric Acid Cycle* ; Nitrogen*/metabolism ; Carbon*/metabolism ; Malate Dehydrogenase*/metabolism ; Malate Dehydrogenase*/genetics ; Bacillus subtilis*/metabolism ; Bacillus subtilis*/genetics ; Bacillus subtilis*/enzymology ; Isocitrate Dehydrogenase*/metabolism ; Isocitrate Dehydrogenase*/genetics ; Ketoglutaric Acids*/metabolism; Bacterial Proteins/metabolism ; Bacterial Proteins/genetics ; Ammonium Compounds/metabolism
    • Abstract:
      Enzymes of the central metabolism tend to assemble into transient supramolecular complexes. However, the functional significance of the interactions, particularly between enzymes catalyzing non-consecutive reactions, remains unclear. Here, by co-localizing two non-consecutive enzymes of the TCA cycle from Bacillus subtilis, malate dehydrogenase (MDH) and isocitrate dehydrogenase (ICD), in phase separated droplets we show that MDH-ICD interaction leads to enzyme agglomeration with a concomitant enhancement of ICD catalytic rate and an apparent sequestration of its reaction product, 2-oxoglutarate. Theory demonstrates that MDH-mediated clustering of ICD molecules explains the observed phenomena. In vivo analyses reveal that MDH overexpression leads to accumulation of 2-oxoglutarate and reduction of fluxes flowing through both the catabolic and anabolic branches of the carbon-nitrogen intersection occupied by 2-oxoglutarate, resulting in impeded ammonium assimilation and reduced biomass production. Our findings suggest that the MDH-ICD interaction is an important coordinator of carbon-nitrogen metabolism.
      (© 2024. The Author(s).)
    • Comments:
      Erratum in: Nat Commun. 2024 Jul 23;15(1):6196. doi: 10.1038/s41467-024-50599-0. (PMID: 39043701)
    • References:
      Elife. 2016 Dec 10;5:. (PMID: 27938662)
      Bioessays. 2013 Dec;35(12):1050-5. (PMID: 24114984)
      Mol Biol Cell. 2015 Nov 5;26(22):3932-9. (PMID: 26543202)
      Sci Rep. 2017 Nov 9;7(1):15143. (PMID: 29123156)
      Trends Biochem Sci. 2001 Oct;26(10):597-604. (PMID: 11590012)
      Metab Eng. 2011 Jan;13(1):18-27. (PMID: 20933603)
      Enzyme Microb Technol. 2000 Jun 1;26(9-10):688-698. (PMID: 10862874)
      Microbiol Mol Biol Rev. 2015 Dec;79(4):419-35. (PMID: 26424716)
      FEBS J. 2014 Feb;281(4):1132-43. (PMID: 24325460)
      Curr Opin Biotechnol. 2011 Aug;22(4):566-75. (PMID: 21600757)
      Physiol Rev. 2006 Apr;86(2):465-514. (PMID: 16601267)
      Biophys J. 2023 Dec 5;122(23):4555-4566. (PMID: 37915170)
      J Bacteriol. 2005 Jul;187(14):4813-21. (PMID: 15995196)
      J Chem Phys. 2014 Mar 14;140(10):105101. (PMID: 24628210)
      Angew Chem Int Ed Engl. 2015 Feb 2;54(6):1851-4. (PMID: 25537779)
      Nat Commun. 2018 May 30;9(1):2136. (PMID: 29849027)
      Annu Rev Biochem. 1987;56:89-124. (PMID: 2441660)
      J Biol Chem. 2007 Apr 20;282(16):11893-903. (PMID: 17314104)
      Nat Chem Biol. 2009 Aug;5(8):593-9. (PMID: 19561621)
      Research (Wash D C). 2018 Nov 21;2018:1539325. (PMID: 31549022)
      Plant Commun. 2020 Jun 05;2(1):100081. (PMID: 33511342)
      Curr Opin Biotechnol. 2013 Dec;24(6):987-93. (PMID: 23571096)
      Mol Microbiol. 2012 Jul;85(2):213-24. (PMID: 22625175)
      Nat Rev Microbiol. 2011 May;9(5):330-43. (PMID: 21464825)
      Mol Syst Biol. 2010 Nov 30;6:432. (PMID: 21119627)
      Curr Opin Biotechnol. 2015 Aug;34:189-201. (PMID: 25731751)
      FEMS Microbiol Rev. 2005 Sep;29(4):765-94. (PMID: 16102602)
      EMBO J. 2004 Jul 21;23(14):2745-54. (PMID: 15229654)
      Microb Cell Fact. 2015 May 21;14:72. (PMID: 25990516)
      Nat Chem Biol. 2011 Oct 16;7(12):894-901. (PMID: 22002719)
      Science. 2008 Apr 4;320(5872):103-6. (PMID: 18388293)
      Curr Opin Microbiol. 2005 Apr;8(2):168-73. (PMID: 15802248)
      J Biol Chem. 2007 Sep 28;282(39):28791-28799. (PMID: 17573341)
      Trends Biochem Sci. 1991 Jun;16(6):203-6. (PMID: 1891800)
      Nat Commun. 2021 Nov 1;12(1):6293. (PMID: 34725341)
      Nat Rev Microbiol. 2014 May;12(5):327-40. (PMID: 24658329)
      Cell. 2014 Aug 14;158(4):822-832. (PMID: 25126787)
      Biochemistry. 2008 May 27;47(21):5724-35. (PMID: 18459799)
      Plant Cell. 2007 Nov;19(11):3723-38. (PMID: 17981998)
      J Phys Chem Lett. 2010 May 6;1(9):1332-1335. (PMID: 20454551)
      Eur J Biochem. 1997 Jun 01;246(2):283-90. (PMID: 9208916)
      Mol Syst Biol. 2013 Nov 26;9:709. (PMID: 24281055)
      Adv Microb Physiol. 2009;55:1-79, 317. (PMID: 19573695)
      Nat Biotechnol. 2014 Oct;32(10):1011-8. (PMID: 25262299)
      Mol Syst Biol. 2011 Mar 29;7:477. (PMID: 21451587)
      Biochem J. 1992 Jun 15;284 ( Pt 3):861-7. (PMID: 1320381)
      Curr Opin Plant Biol. 2005 Jun;8(3):280-91. (PMID: 15860425)
      Nat Commun. 2017 May 16;8:15212. (PMID: 28508886)
    • Grant Information:
      593/21 Israel Science Foundation (ISF)
    • Accession Number:
      N762921K75 (Nitrogen)
      7440-44-0 (Carbon)
      EC 1.1.1.37 (Malate Dehydrogenase)
      EC 1.1.1.41 (Isocitrate Dehydrogenase)
      0 (Ketoglutaric Acids)
      0 (Bacterial Proteins)
      0 (Ammonium Compounds)
    • Publication Date:
      Date Created: 20240620 Date Completed: 20240620 Latest Revision: 20240726
    • Publication Date:
      20240726
    • Accession Number:
      PMC11189929
    • Accession Number:
      10.1038/s41467-024-49646-7
    • Accession Number:
      38902266