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An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor.

<div class='caption-title'>Crystal structure of M2PYK.</div>
<div class='caption-title'>Analytical gel-filtration and enzyme assays suggest M2PYK equilibrates between tetramer and monomer, whereas M1PYK retains its tetrameric form.</div>
<div class='caption-title'>Effects of amino acids and FBP on the activity of M1PYK (□) and M2PYK ().</div>
Yuan M, McNae IW, Chen Y, Blackburn EA, Wear MA, Michels PAM, Fothergill-Gilmore LA, Hupp T, Walkinshaw MD
OpenAccess logo Biochem J 475 1821-1837 (2018)
Related entries: 6gg3, 6gg5, 6gg6

Cited: 32 times
EuropePMC logo PMID: 29748232

Abstract

We have tested the effect of all 20 proteinogenic amino acids on the activity of the M2 isoenzyme of pyruvate kinase (M2PYK) and show that, within physiologically relevant concentrations, phenylalanine, alanine, tryptophan, methionine, valine, and proline act as inhibitors, while histidine and serine act as activators. Size exclusion chromatography has been used to show that all amino acids, whether activators or inhibitors, stabilise the tetrameric form of M2PYK. In the absence of amino-acid ligands an apparent tetramer-monomer dissociation Kd is estimated to be ∼0.9 µM with a slow dissociation rate (t1/2 ∼ 15 min). X-ray structures of M2PYK complexes with alanine, phenylalanine, and tryptophan show the M2PYK locked in an inactive T-state conformation, while activators lock the M2PYK tetramer in the active R-state conformation. Amino-acid binding in the allosteric pocket triggers rigid body rotations (11°) stabilising either T or R states. The opposing inhibitory and activating effects of the non-essential amino acids serine and alanine suggest that M2PYK could act as a rapid-response nutrient sensor to rebalance cellular metabolism. This competition at a single allosteric site between activators and inhibitors provides a novel regulatory mechanism by which M2PYK activity is finely tuned by the relative (but not absolute) concentrations of activator and inhibitor amino acids. Such 'allostatic' regulation may be important in metabolic reprogramming and influencing cell fate.

Articles - 6gg4 mentioned but not cited (6)

  1. An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor. Yuan M, McNae IW, Chen Y, Blackburn EA, Wear MA, Michels PAM, Fothergill-Gilmore LA, Hupp T, Walkinshaw MD. Biochem J 475 1821-1837 (2018)
  2. Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation. Macpherson JA, Theisen A, Masino L, Fets L, Driscoll PC, Encheva V, Snijders AP, Martin SR, Kleinjung J, Barran PE, Fraternali F, Anastasiou D. Elife 8 e45068 (2019)
  3. Biochemical and structural insights into how amino acids regulate pyruvate kinase muscle isoform 2. Nandi S, Dey M. J Biol Chem 295 5390-5403 (2020)
  4. Distinctive regulatory properties of pyruvate kinase 1 from Aedes aegypti mosquitoes. Petchampai N, Murillo-Solano C, Isoe J, Pizarro JC, Scaraffia PY. Insect Biochem Mol Biol 104 82-90 (2019)
  5. Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase. Battisti UM, Gao C, Akladios F, Kim W, Yang H, Bayram C, Bolat I, Kiliclioglu M, Yuksel N, Tozlu OO, Zhang C, Sebhaoui J, Iqbal S, Shoaie S, Hacimuftuoglu A, Yildirim S, Turkez H, Uhlen M, Boren J, Mardinoglu A, Grøtli M. Nutrients 15 577 (2023)
  6. Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase. Battisti UM, Gao C, Nilsson O, Akladios F, Lulla A, Bogucka A, Nain-Perez A, Håversen L, Kim W, Boren J, Hyvönen M, Uhlen M, Mardinoglu A, Grøtli M. Chembiochem 24 e202200339 (2023)


Reviews citing this publication (7)

  1. Pyruvate kinase M2: A simple molecule with complex functions. Alquraishi M, Puckett DL, Alani DS, Humidat AS, Frankel VD, Donohoe DR, Whelan J, Bettaieb A. Free Radic Biol Med 143 176-192 (2019)
  2. Metabolic reprogramming results in abnormal glycolysis in gastric cancer: a review. Liu Y, Zhang Z, Wang J, Chen C, Tang X, Zhu J, Liu J. Onco Targets Ther 12 1195-1204 (2019)
  3. A critical review of the role of M2PYK in the Warburg effect. Harris RA, Fenton AW. Biochim Biophys Acta Rev Cancer 1871 225-239 (2019)
  4. The molecular mechanisms of LncRNA-correlated PKM2 in cancer metabolism. Tao T, Wu S, Sun Z, Ma W, Zhou S, Deng J, Su Q, Peng M, Xu G, Yang X. Biosci Rep 39 BSR20192453 (2019)
  5. From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity. Chinopoulos C. Front Physiol 11 543564 (2020)
  6. Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents. Rathod B, Chak S, Patel S, Shard A. RSC Med Chem 12 1121-1141 (2021)
  7. The role of PKM2 in cancer progression and its structural and biological basis. Wu B, Liang Z, Lan H, Teng X, Wang C. J Physiol Biochem 80 261-275 (2024)

Articles citing this publication (19)

  1. Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages. Wang J, Yang P, Yu T, Gao M, Liu D, Zhang J, Lu C, Chen X, Zhang X, Liu Y. Int J Biol Sci 18 6210-6225 (2022)
  2. Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase. Hicks KG, Cluntun AA, Schubert HL, Hackett SR, Berg JA, Leonard PG, Ajalla Aleixo MA, Zhou Y, Bott AJ, Salvatore SR, Chang F, Blevins A, Barta P, Tilley S, Leifer A, Guzman A, Arok A, Fogarty S, Winter JM, Ahn HC, Allen KN, Block S, Cardoso IA, Ding J, Dreveny I, Gasper WC, Ho Q, Matsuura A, Palladino MJ, Prajapati S, Sun P, Tittmann K, Tolan DR, Unterlass J, VanDemark AP, Vander Heiden MG, Webb BA, Yun CH, Zhao P, Wang B, Schopfer FJ, Hill CP, Nonato MC, Muller FL, Cox JE, Rutter J. Science 379 996-1003 (2023)
  3. Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation. Coassolo S, Davidson G, Negroni L, Gambi G, Daujat S, Romier C, Davidson I. Nat Commun 12 1718 (2021)
  4. Cancer-associated mutations in human pyruvate kinase M2 impair enzyme activity. Liu VM, Howell AJ, Hosios AM, Li Z, Israelsen WJ, Vander Heiden MG. FEBS Lett 594 646-664 (2020)
  5. Profiling and Targeting of Energy and Redox Metabolism in Grade 2 Bladder Cancer Cells with Different Invasiveness Properties. Pasquale V, Ducci G, Campioni G, Campioni G, Ventrici A, Assalini C, Busti S, Vanoni M, Vago R, Sacco E. Cells 9 E2669 (2020)
  6. Redox regulation of pyruvate kinase M2 by cysteine oxidation and S-nitrosation. Mitchell AR, Yuan M, Morgan HP, McNae IW, Blackburn EA, Le Bihan T, Homem RA, Yu M, Loake GJ, Michels PA, Wear MA, Walkinshaw MD. Biochem J 475 3275-3291 (2018)
  7. S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling. Ko Y, Hong M, Lee S, Kumar M, Ibrahim L, Nutsch K, Stanton C, Sondermann P, Sandoval B, Bulos ML, Iaconelli J, Chatterjee AK, Wiseman RL, Schultz PG, Bollong MJ. Proc Natl Acad Sci U S A 120 e2300763120 (2023)
  8. Novel Specific Pyruvate Kinase M2 Inhibitor, Compound 3h, Induces Apoptosis and Autophagy through Suppressing Akt/mTOR Signaling Pathway in LNCaP Cells. Jiang C, Zhao X, Jeong T, Kang JY, Park JH, Kim IS, Kim HS. Cancers (Basel) 15 265 (2022)
  9. Creatine plus pyruvate supplementation prevents oxidative stress and phosphotransfer network disturbances in the brain of rats subjected to chemically-induced phenylketonuria. Bortoluzzi VT, Brust L, Preissler T, de Franceschi ID, Wannmacher CMD. Metab Brain Dis 34 1649-1660 (2019)
  10. Differences in Serum Amino Acid Phenotypes Among Patients with Diabetic Nephropathy, Hypertensive Nephropathy, and Chronic Nephritis. Zeng L, Yu Y, Cai X, Xie S, Chen J, Zhong L, Zhang Y. Med Sci Monit 25 7235-7242 (2019)
  11. Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes. Jain R, Özgümüş T, Jensen TM, du Plessis E, Keindl M, Møller CL, Falhammar H, Nyström T, Catrina SB, Jörneskog G, Jessen LE, Forsblom C, Haukka JK, Groop PH, Rossing P, Groop L, Eliasson M, Eliasson B, Brismar K, Al-Majdoub M, Nilsson PM, Taskinen MR, Ferrannini E, Spégel P, Berg TJ, Lyssenko V. Sci Rep 10 11561 (2020)
  12. PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes. Swint-Kruse L, Dougherty LL, Page B, Wu T, O'Neil PT, Prasannan CB, Timmons C, Tang Q, Parente DJ, Sreenivasan S, Holyoak T, Fenton AW. Database (Oxford) 2023 baad030 (2023)
  13. Regulation of glycolysis and cancer cell proliferation by PKM2 citrullination. Coassolo S, Davidson I. Mol Cell Oncol 8 1927446 (2021)
  14. Salvianolic acid A regulates pyroptosis of endothelial cells via directly targeting PKM2 and ameliorates diabetic atherosclerosis. Zhu J, Chen H, Le Y, Guo J, Liu Z, Dou X, Lu D. Front Pharmacol 13 1009229 (2022)
  15. Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study. Marciniec K, Rzepka Z, Chrobak E, Boryczka S, Latocha M, Wrześniok D, Beberok A. Molecules 28 2509 (2023)
  16. Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2. Nandi S, Dey M. PLoS One 18 e0282508 (2023)
  17. Metabolically regulated spiking could serve neuronal energy homeostasis and protect from reactive oxygen species. Chintaluri C, Vogels TP. Proc Natl Acad Sci U S A 120 e2306525120 (2023)
  18. Deciphering the interaction between PKM2 and the built-in thermodynamic properties of the glycolytic pathway in cancer cells. Jin C, Hu W, Wang Y, Wu H, Zeng S, Ying M, Hu X. J Biol Chem 300 107648 (2024)
  19. Targeted suppression of oral squamous cell carcinoma by pyrimidine-tethered quinoxaline derivatives. Choithramani A, Das R, Bothra G, Patel Vatsa P, Muthukumar V, Bhuvana BKS, Kapoor S, Moola D, Chowdhury MG, Mandoli A, Shard A. RSC Med Chem 15 2729-2744 (2024)


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