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Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease.

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Sun K, D'Alessandro A, Ahmed MH, Zhang Y, Song A, Ko TP, Nemkov T, Reisz JA, Wu H, Adebiyi M, Peng Z, Gong J, Liu H, Huang A, Wen YE, Wen AQ, Berka V, Bogdanov MV, Abdulmalik O, Han L, Tsai AL, Idowu M, Juneja HS, Kellems RE, Dowhan W, Hansen KC, Safo MK, Xia Y
OpenAccess logo Sci Rep 7 15281 (2017)
Cited: 29 times
EuropePMC logo PMID: 29127281

Abstract

Elevated sphingosine 1-phosphate (S1P) is detrimental in Sickle Cell Disease (SCD), but the mechanistic basis remains obscure. Here, we report that increased erythrocyte S1P binds to deoxygenated sickle Hb (deoxyHbS), facilitates deoxyHbS anchoring to the membrane, induces release of membrane-bound glycolytic enzymes and in turn switches glucose flux towards glycolysis relative to the pentose phosphate pathway (PPP). Suppressed PPP causes compromised glutathione homeostasis and increased oxidative stress, while enhanced glycolysis induces production of 2,3-bisphosphoglycerate (2,3-BPG) and thus increases deoxyHbS polymerization, sickling, hemolysis and disease progression. Functional studies revealed that S1P and 2,3-BPG work synergistically to decrease both HbA and HbS oxygen binding affinity. The crystal structure at 1.9 Å resolution deciphered that S1P binds to the surface of 2,3-BPG-deoxyHbA and causes additional conformation changes to the T-state Hb. Phosphate moiety of the surface bound S1P engages in a highly positive region close to α1-heme while its aliphatic chain snakes along a shallow cavity making hydrophobic interactions in the "switch region", as well as with α2-heme like a molecular "sticky tape" with the last 3-4 carbon atoms sticking out into bulk solvent. Altogether, our findings provide functional and structural bases underlying S1P-mediated pathogenic metabolic reprogramming in SCD and novel therapeutic avenues.

Articles - 5ksi mentioned but not cited (1)

  1. Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease. Sun K, D'Alessandro A, Ahmed MH, Zhang Y, Song A, Ko TP, Nemkov T, Reisz JA, Wu H, Adebiyi M, Peng Z, Gong J, Liu H, Huang A, Wen YE, Wen AQ, Berka V, Bogdanov MV, Abdulmalik O, Han L, Tsai AL, Idowu M, Juneja HS, Kellems RE, Dowhan W, Hansen KC, Safo MK, Xia Y. Sci Rep 7 15281 (2017)


Reviews citing this publication (8)

  1. Hemoglobin: Structure, Function and Allostery. Ahmed MH, Ghatge MS, Safo MK. Subcell Biochem 94 345-382 (2020)
  2. Metabolomic and molecular insights into sickle cell disease and innovative therapies. Adebiyi MG, Manalo JM, Xia Y. Blood Adv 3 1347-1355 (2019)
  3. Erythrocyte adaptive metabolic reprogramming under physiological and pathological hypoxia. D'Alessandro A, Xia Y. Curr Opin Hematol 27 155-162 (2020)
  4. Modulating hemoglobin allostery for treatment of sickle cell disease: current progress and intellectual property. Pagare PP, Rastegar A, Abdulmalik O, Omar AM, Zhang Y, Fleischman A, Safo MK. Expert Opin Ther Pat 32 115-130 (2022)
  5. Metabolic Reprogramming in Sickle Cell Diseases: Pathophysiology and Drug Discovery Opportunities. Alramadhani D, Aljahdali AS, Abdulmalik O, Pierce BD, Safo MK. Int J Mol Sci 23 7448 (2022)
  6. Red Blood Cell Omics and Machine Learning in Transfusion Medicine: Singularity Is Near. D'Alessandro A. Transfus Med Hemother 50 174-183 (2023)
  7. Modeling Red Blood Cell Metabolism in the Omics Era. Key A, Haiman Z, Palsson BO, D'Alessandro A. Metabolites 13 1145 (2023)
  8. Red Blood Cell Metabolism In Vivo and In Vitro. D'Alessandro A, Anastasiadi AT, Tzounakas VL, Nemkov T, Reisz JA, Kriebardis AG, Zimring JC, Spitalnik SL, Busch MP. Metabolites 13 793 (2023)

Articles citing this publication (20)

  1. Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients. Thomas T, Stefanoni D, Dzieciatkowska M, Issaian A, Nemkov T, Hill RC, Francis RO, Hudson KE, Buehler PW, Zimring JC, Hod EA, Hansen KC, Spitalnik SL, D'Alessandro A. J Proteome Res 19 4455-4469 (2020)
  2. Blood donor exposome and impact of common drugs on red blood cell metabolism. Nemkov T, Stefanoni D, Bordbar A, Issaian A, Palsson BO, Dumont LJ, Hay A, Song A, Xia Y, Redzic JS, Eisenmesser EZ, Zimring JC, Kleinman S, Hansen KC, Busch MP, D'Alessandro A, Recipient Epidemiology and Donor Evaluation Study III Red Blood Cell–Omics (REDS-III RBC-Omics) Study. JCI Insight 6 146175 (2021)
  3. Red Blood Cell Metabolic Responses to Torpor and Arousal in the Hibernator Arctic Ground Squirrel. Gehrke S, Rice S, Stefanoni D, Wilkerson RB, Nemkov T, Reisz JA, Hansen KC, Lucas A, Cabrales P, Drew K, D'Alessandro A. J Proteome Res 18 1827-1841 (2019)
  4. Effects of red blood cell (RBC) transfusion on sickle cell disease recipient plasma and RBC metabolism. Culp-Hill R, Srinivasan AJ, Gehrke S, Kamyszek R, Ansari A, Shah N, Welsby I, D'Alessandro A. Transfusion 58 2797-2806 (2018)
  5. Metabolic impact of red blood cell exchange with rejuvenated red blood cells in sickle cell patients. Gehrke S, Shah N, Gamboni F, Kamyszek R, Srinivasan AJ, Gray A, Landrigan M, Welsby I, D'Alessandro A. Transfusion 59 3102-3112 (2019)
  6. Stored RBC metabolism as a function of caffeine levels. D'Alessandro A, Fu X, Reisz JA, Kanias T, Page GP, Stone M, Kleinman S, Zimring JC, Busch M, Recipient Epidemiology and Donor Evaluation Study-III (REDS III). Transfusion 60 1197-1211 (2020)
  7. Elevated ecto-5'-nucleotidase: a missing pathogenic factor and new therapeutic target for sickle cell disease. Liu H, Adebiyi M, Liu RR, Song A, Manalo J, Wen YE, Wen AQ, Weng T, Ko J, Idowu M, Kellems RE, Eltzschig HK, Blackburn MR, Juneja HS, Xia Y. Blood Adv 2 1957-1968 (2018)
  8. VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions. Abdulmalik O, Pagare PP, Huang B, Xu GG, Ghatge MS, Xu X, Chen Q, Anabaraonye N, Musayev FN, Omar AM, Venitz J, Zhang Y, Safo MK. Sci Rep 10 20277 (2020)
  9. FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice. Shrestha A, Chi M, Wagner K, Malik A, Korpik J, Drake A, Fulzele K, Guichard S, Malik P. Blood Adv 5 2385-2390 (2021)
  10. O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells. Lee HJ, Jung YH, Choi GE, Kim JS, Chae CW, Lim JR, Kim SY, Lee JE, Park MC, Yoon JH, Choi MJ, Kim KS, Han HJ. Cell Death Dis 10 590 (2019)
  11. Genome-wide metabolite quantitative trait loci analysis (mQTL) in red blood cells from volunteer blood donors. Moore A, Busch MP, Dziewulska K, Francis RO, Hod EA, Zimring JC, D'Alessandro A, Page GP. J Biol Chem 298 102706 (2022)
  12. Plasma Levels of Acyl-Carnitines and Carboxylic Acids Correlate With Cardiovascular and Kidney Function in Subjects With Sickle Cell Trait. Nemkov T, Skinner S, Diaw M, Diop S, Samb A, Connes P, D'Alessandro A. Front Physiol 13 916197 (2022)
  13. Potential causal role of l-glutamine in sickle cell disease painful crises: A Mendelian randomization analysis. Ilboudo Y, Garrett ME, Bartolucci P, Brugnara C, Clish CB, Hirschhorn JN, Galactéros F, Ashley-Koch AE, Telen MJ, Lettre G. Blood Cells Mol Dis 86 102504 (2021)
  14. Red Blood Cell Metabolism in Pyruvate Kinase Deficient Patients. Roy MK, Cendali F, Ooyama G, Gamboni F, Morton H, D'Alessandro A. Front Physiol 12 735543 (2021)
  15. Sphingosine 1-phosphate has a negative effect on RBC storage quality. Hay A, Nemkov T, Gamboni F, Dzieciatkowska M, Key A, Galbraith M, Bartsch K, Sun K, Xia Y, Stone M, Busch MP, Norris PJ, Zimring JC, D'Alessandro A. Blood Adv 7 1379-1393 (2023)
  16. In vivo evaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction. D'Alessandro A, Nouraie SM, Zhang Y, Cendali F, Gamboni F, Reisz JA, Zhang X, Bartsch KW, Galbraith MD, Gordeuk VR, Gladwin MT. Am J Hematol 98 1017-1028 (2023)
  17. Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients as a function of therapeutic transfusion and hydroxyurea treatment. D'Alessandro A, Nouraie SM, Zhang Y, Cendali F, Gamboni F, Reisz JA, Zhang X, Bartsch KW, Galbraith MD, Espinosa JM, Gordeuk VR, Gladwin MT. Haematologica 108 3418-3432 (2023)
  18. Metabolic correlates to critical speed in murine models of sickle cell disease. Cendali FI, Nemkov T, Lisk C, Lacroix IS, Nouraie SM, Zhang Y, Gordeuk VR, Buehler PW, Irwin D, D'Alessandro A. Front Physiol 14 1151268 (2023)
  19. Nrf2 sensitizes ferroptosis through l-2-hydroxyglutarate-mediated chromatin modifications in sickle cell disease. Xi C, Pang J, Zhi W, Chang CS, Siddaramappa U, Shi H, Horuzsko A, Pace BS, Zhu X. Blood 142 382-396 (2023)
  20. Sphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells. Thomas N, Schröder NH, Nowak MK, Wollnitzke P, Ghaderi S, von Wnuck Lipinski K, Wille A, Deister-Jonas J, Vogt J, Gräler MH, Dannenberg L, Buschmann T, Westhoff P, Polzin A, Kelm M, Keul P, Weske S, Levkau B. Nat Commun 14 8329 (2023)


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