The Science of Childhood Lecture Series on February 27 will feature Jan-Henning Klusmann👇

Congrats to the first authors @JunhuaLyu @GuZhimin @YuannyuZhang, and @MinNiLab_stjude for co-leading this project. We thank @RJDLab @CRI_UTSW @LilyHuangLab for collaborations, many other collaborators, and support from @NIDDKgov @StJudeResearch.

Based on these findings, we propose that the need to assimilate and detoxify ammonium from heme biosynthesis and other metabolic processes led to the selective activation of glutamine synthesis as a specialized metabolic adaptation for generating red blood cells.

We also showed that the clinical improvements in erythropoiesis following a therapeutic agent are associated with enhanced glutamine metabolism. Therefore, this specialized metabolic adaptation could potentially be leveraged to mitigate common RBC disorders.

We showed that GS activity is impaired by protein oxidation in β-thalassemia, leading to glutamate and ammonium accumulation, whereas enhancing GS activity alleviates β-thalassemia-associated metabolic and pathological defects.

In parallel studies with Mitch Weiss @StJudeResearch, we performed metabolomics of healthy and β-thalassemic erythroid cells in mice and human. We noted increased glutamate and decreased glutamine-to-glutamate ratios, consistent with defective glutamine synthesis.

Could excessive ammonium produced from heme biosynthesis require immediate removal by GS? Supporting this idea, GS-catalyzed glutamine synthesis assimilates ammonium produced from heme biosynthesis in isotope tracing experiments.

We thought that GS activation may have something to do with ammonium, but how? During erythropoiesis, heme synthesis is massively upregulated, and in an intermediate step catalyzed by hydroxymethylbilane synthase, four ammonium molecules are released.

GS is one of the oldest genes in evolution that converts glutamate and ammonium to glutamine. Inactivation of GS in mouse erythroid precursors led to ammonium accumulation and oxidative stress, causing defective erythropoiesis and delayed recovery from anemia.

Using metabolomics, we identified pervasive metabolic changes, including a metabolic switch from glutamine catabolism (breakdown) to synthesis during erythropoiesis. This switch is controlled by the activation of glutamine synthetase (GS), encoded by Glul.

The production of red blood cells, or erythropoiesis, poses unique metabolic challenges as they mature into highly specialized cells lacking most organelles and a nucleus. We began with a simple question: How does metabolism support erythropoiesis?.

Excited to share our latest work: A glutamine metabolic switch supports erythropoiesis, published today @ScienceMagazine .

RT @StJudeResearch: Scientists reveal a metabolic switch that could inform treatments for blood disorders. By reversing glutamine metabolis….

RT @bloodgenes: Wonderful Hemoglobin Switching Meeting in Puerto Rico!!! Amazing science and people! Fantastic to organize this meeting wit….

The power of non-coding alterations in cancer genomics! Congratulations to @PolonenPetri @CMullighan and team for this landmark study.

RT @ASH_hematology: A huge #ASHKudos to the 2024 ASH Honorific Award recipients! This year’s recipients are a group of pioneering scientist….

RT @StJudeResearch: Explore the Science of Childhood Cancer lecture archive hosted by the St. Jude Comprehensive Cancer Center to discover….

RT @Cell_Metabolism: New! Online now: Electron transport chain inhibition increases cellular dependence on purine transport and salvage ht….

Also loved these acknowledgments 👇👇

Congrats Michael Lee for this milestone and accomplishment! It has been blessing working with you in the last 4 years. I’m grateful to @RJDLab for co-mentoring and his dissertation committee @Zhu_Lab @BanaszynskiLab & @genescene60.