A glutamine metabolic swap is crucial for erythropoiesis. Credit score: Science (2024). DOI: 10.1126/science.adh9215
Blood stem cells develop by way of completely different phases to develop into absolutely mature purple blood cells. This basic biologic course of is outlined by a sequence of advanced metabolic processes, which are sometimes dysregulated in blood issues equivalent to sickle cell illness and β-thalassemia.
St. Jude Youngsters’s Analysis Hospital scientists recognized a beforehand unrecognized position for the amino acid glutamine on this course of. Specifically, the work reveals that modulating glutamine metabolism is a possible therapeutic route for widespread purple blood cell issues. Moreover, glutamine abundance might function a software for evaluating therapeutic efficacy. The findings are revealed in Science.
These findings outcome from basic biologic analysis to know purple blood cell metabolism. Regardless of accounting for 84% of the full cells of a mature grownup, purple blood cells are distinctive of their metabolic perform.
“Mature red blood cells don’t have organelles, such as mitochondria,” mentioned co-corresponding creator Jian Xu, Ph.D., St. Jude Division of Pathology and Middle of Excellence for Leukemia Research. “This raises an important question about how mature red blood cells deal with metabolic needs in order to build such massive biomass.”
Xu, together with co-corresponding creator Min Ni, Ph.D., St. Jude Division of Oncology, got down to perceive the metabolic processes that regulate regular purple blood cell maturation and the way this is perhaps altered in numerous issues. The collaborative analysis workforce systematically profiled metabolic modifications by way of every purple blood cell maturation stage.
“We noted a very surprising finding regarding glutamine, which is usually broken down by stem cells for various metabolic needs,” Xu defined. “We found that this process is completely reversed during later differentiation. The cells stop breaking down glutamine and begin to synthesize it by completely reversing the reaction.”
Glutamine synthetase is essential to toxin elimination
Glutamine is damaged down as an vitality supply in early blood cell maturation. Nevertheless, the researchers discovered that the enzyme glutamine synthetase flips the script at later phases of growth. Heme is the primary part of hemoglobin, the protein in purple blood cells that carries oxygen.
Purple blood cell maturation depends upon heme manufacturing, however ammonium (a byproduct of heme manufacturing) can accumulate if not eliminated, inflicting oxidative stress. The researchers discovered that purple blood cells start producing glutamine synthetase to facilitate the elimination of ammonium by combining glutamate with the ammonium to provide glutamine.
“We have genetic and biochemical molecular studies to show that this metabolic process is completely reversed in order to detoxify ammonium that is generated to support heme biosynthesis,” Xu mentioned.
This work impacts the remedy of purple blood cell issues, equivalent to β-thalassemia, as a result of medication used to deal with these issues are related to improved purple blood cell maturation. Nevertheless, as a result of glutamine synthetase is discovered all through the physique, its elimination is deadly.
“In our genetic studies, we rarely see patients with glutamine synthetase gene mutations,” defined Ni. “This gene is also critical for embryonic development, so the entire body is affected.”
By conditional inactivation of the enzyme, the researchers recognized a direct hyperlink between disruption of glutamine metabolism and purple blood cell issues.
“We show this process is impaired in various red blood cell disorders, such as β-thalassemia,” Xu mentioned. “This causes a metabolic phenotype that resembles a glutamine synthetase deficiency, which can be characterized by increased glutamate and ammonia levels and decreased glutamine levels.”
Lacking hyperlink between glutamine and blood issues
The researchers recognized glutamine synthetase oxidation because the supply of this deficiency in β-thalassemia. Additional, by rising the protein’s expression, the researchers regained enzyme exercise to deal with the situation. Presently, anemia in β-thalassemia may be handled with the drug luspatercept; nevertheless, how this drug works shouldn’t be absolutely understood.
Working with Mitchell Weiss, MD, Ph.D., St. Jude Division of Hematology chair and different collaborators, Xu and Ni recognized elevated glutamine–to–glutamate ratios in research involving luspatercept, indicating that the drug seemingly works by recovering glutamine ranges.
“This will be the first report to make a connection that the therapeutic benefit of this drug is associated with improved glutamine metabolism,” Xu mentioned.
L-glutamine can be used to alleviate signs of sickle cell illness, however how this drug works has equally been contentious. The findings point out that the efficacy of L-glutamine dietary supplements seemingly happens by fixing glutamine synthetase disruption.
“By supplementing glutamine, you’re providing the red blood cells with additional glutamine for various needs,” Xu defined. “This may explain why L-glutamine is beneficial for sickle cell patients; this is something we are actively studying.”
Past its direct influence on treating purple blood cell issues, the findings recommend that metabolic options equivalent to glutamine–to–glutamate ratios can be utilized as biomarkers for a lot of different ailments.
Extra data:
Junhua Lyu et al, A glutamine metabolic swap helps erythropoiesis, Science (2024). DOI: 10.1126/science.adh9215
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St. Jude Youngsters’s Analysis Hospital
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Glutamine metabolic swap is essential to purple blood cell growth and illness, researchers reveal (2024, November 15)
retrieved 16 November 2024
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