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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)



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