ArticleScientific reports2017
Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 64 citations in OpenAlex.
- Blood-storage duration affects hematological and metabolic profiles in patients with sickle cell disease receiving transfusions.The Journal of clinical investigation · 2025Trial
- Functional and multi-omics signatures of mitapivat efficacy upon activation of pyruvate kinase in red blood cells from patients with sickle cell disease.Haematologica · 2024Trial
- Stored RBC metabolism as a function of caffeine levels.Transfusion · 2020Trial
- Effects of red blood cell (RBC) transfusion on sickle cell disease recipient plasma and RBC metabolism.Transfusion · 2018Trial
- High-Throughput Metabolomics in Transfusion Medicine.Methods in molecular biology (Clifton, N.J.) · 2026Article
- 2,3-Diphosphoglycerate: the forgotten metabolic regulator of oxygen affinity.The British journal of nutrition · 2025Review
- Comparative Proteomic Analysis Reveals Altered Ciliary Proteins in Sickle Cell Disease.Journal of proteome research · 2025Article
- Hemoglobin Variants as Targets for Stabilizing Drugs.Molecules (Basel, Switzerland) · 2025Review
- Erythrocytes enhance oxygen-carrying capacity through self-regulation.Frontiers in physiology · 2025Review
- Metabolic insights into hypoxia adaptation in adolescent athletes at different altitudes: a cross-sectional study.Frontiers in molecular biosciences · 2025Article
- Endogenous small molecule effectors in GATA transcription factor mechanisms governing biological and pathological processes.Experimental hematology · 2024Review
- Myeloid Cells and Sphingosine-1-Phosphate Are Required for TCRαβ Intraepithelial Lymphocyte Recruitment to the Colon Epithelium.Journal of immunology (Baltimore, Md. : 1950) · 2024Article
- Nitric Oxide Binding Geometry in Heme-Proteins: Relevance for Signal Transduction.Antioxidants (Basel, Switzerland) · 2024Review
- Effect of Hb conformational changes on oxygen transport physiology.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2024Review
- Significant Increase in Oxidative Stress Indices in Erythrocyte Membranes of Obese Patients with Metabolically-Associated Fatty Liver Disease.Journal of personalized medicine · 2024Article
- Metabolic regulation of erythrocyte development and disorders.Experimental hematology · 2024Article
- Sphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells.Nature communications · 2023Article
- Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients as a function of therapeutic transfusion and hydroxyurea treatment.Haematologica · 2023Article
- Modeling Red Blood Cell Metabolism in the Omics Era.Metabolites · 2023Review
- Article
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Authors and funding
28 authors at 5 institutions in 2 countries.
Funding
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.
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