Introduction to Metabolomics
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P68-69
2025-07-21
431
Analytical measurements of blood metabolites such as glucose, urea, and cholesterol are part of clinical biochemistry to track diseases. Along these lines and facing the new era of personalized medicine emerges metabolomics, which evaluates metabolism with a com prehensive and quantitative analysis of all metabolites, as well as its impact on cell biology, and aims to discover novel biomarkers or targets for therapy. Recent technical innovations in mass spectrometry and nuclear magnetic resonance (NMR) have allowed the measurement of many metabolites simultaneously. These advances, in combination with metabolite flux analysis with isotopic tracers, have provided new information on many metabolic processes. The use of metabolomics also offers a tool to identify metabolic enzymes as drug targets, because they are poised for inhibition with small molecule drugs and possess allosteric sites that can be used to alter catalytic activity.
A major effort in metabolomics has been the identification of biomarkers for diseases and therapeutic targets. As an example, metabolomics was used to analyze plasma from diabetic patients showing increases in branch chain amino acids before hyperglycemia. Another example comes from the combination of genome wide sequencing analysis and metabolomics: sequence analysis of AMLs was able to identify IDH1 or IDH2 mutations in 20% of patients. Metabolomics analysis revealed accumulation of a noncanonical metabolite, 2-hydroxyglutarate, which promotes the tumorigenic process (see following discussion). In addition, recent blood metabolomics profiles in critically ill COVID-19 patients identified increased kynurenine and decreased arginine, sarcosine, and lysophosphatidylcholines. In fact, the arginine/kynurenine ratio provided a classification accuracy between patients and healthy controls. In general, there are two different metabolomic approaches: targeted, which measures known and specific metabolites; and nontargeted, which includes analytical measurements of unknown metabolites.
Metabolomics of Glucose Metabolism
Systematic and simultaneous quantitative targeted polar metabolite analysis of glucose metabolic pathways using metabolomic and flux measurement techniques has introduced new basic and clinically relevant information in hematology (Fig. 1). For example, increases in glucose metabolism signatures measuring serum metabolite linked to glycolysis and the TCA cycle have been correlated with a prognostic risk score in AML patients.
Fig1. METABOLITE PROFILING UPON T-CELL ACTIVATION. Metabolomic analysis has revealed that glycolytic fluxes and glutaminolysis are increased during activation of T cells. Polyamines that are required for T-cell proliferation are synthesized from glutamine. See text for further details. TCA, Tricarboxylic acid.
Metabolic reprogramming or switches are crucial for T-cell activation. Quiescent naive T cells obtain most of their ATP from mitochondrial oxidative phosphorylation for energy, whereas activated T cells switch to glycolytic, glutaminolysis, and anabolic metabolism to promote clonal expansion that appears to be dependent on the transcription factor Myc. Moreover, metabolomic signatures have revealed that T helper (Th)1, Th2, and Th17 cell lineages and T effectors exhibit an increased glycolytic metabolism. However, regulatory T cells and CD8+ memory T cells depend more on mitochondrial oxidative phosphorylation. In addition, T cells are exposed to different nutrient environments, from high nutrient levels in the lymphoid organs to a more restricted nutrient availability in the effector sites such as tumors or infection. Under these conditions, metabolic reprogramming through mTOR and AMP kinases controls and maintains survival and immune function of T cells. Based on untargeted metabolomic studies, RBCs from G6PDH donors do not meet the US Food and Drug Administration (FDA) guidelines for storage quality because of pyruvate/lactate ratios and glycolytic and PPP intermediates involved in NADPH production.
Metabolomics of Lipid Metabolism
Nonpolar metabolomics has provided metabolite profiles linked to lipid metabolism. In the case of fatty acids, de novo fatty acid syn thesis is necessary for differentiation of Th17. Bioactive lipids have also been profiled in different types of blood cells. For example, sphingosine-1-phosphate is stored in erythrocytes and is found highly elevated in the blood of sickle cell disease patients, owing to increased erythrocyte sphingosine kinase 1. Quantitative lipidomics platforms show that 20% of the platelet lipidomes is remodeled upon activation, including mainly arachidonic acid–containing lipids.
Metabolomics of Nucleotide Metabolism
Measurements of the different polar metabolites in nucleotide metabolism are linked to stages of cell growth. For example, unbiased metabolomics has identified that pyrimidine starvation is a mechanism for specific types of cell death in multiple myeloma cells. Hypoxanthine is one of the metabolite markers that is increased in plasma in different subtypes of lymphomas.
Metabolomics of Amino Acid Metabolism
Metabolomic studies have revealed that activated T cells reprogram their metabolism from fatty acid and pyruvate oxidation, and the TCA cycle, to aerobic glycolysis, the PPP, and glutaminolysis, and metabolic fingerprint-like tumor cells. Glutamine is used to increase polyamine biosynthesis, which is essential for T-cell proliferation, a process controlled by the transcription factor Myc. Metabolomic analysis of two cohorts of hematopoietic stem cell transplantation recipients and donors shows a significant change of host and micro biota indole metabolites related to tryptophan metabolism.
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