bims-smemid 2026-05-10 papers

Nat Metab. 2026 May 04.

Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.

Madeleine L Hart, David Sokolov, Serwah Danquah, Eric Zheng, Alex D Doan, Kristian Davidsen, David MacPherson, Lucas B Sullivan.

Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.

DOI: https://doi.org/10.1038/s42255-026-01524-w

Trends Biochem Sci. 2026 May 07. pii: S0968-0004(26)00108-8. [Epub ahead of print]

Emerging roles and regulatory mechanisms involved in glutamine metabolism.

Keun Woo Ryu, Tak Shun Fung, Craig B Thompson.

Glutamine is the most abundant circulating amino acid and a central nutrient supporting carbon and nitrogen metabolism. It donates nitrogen for nucleotide and amino acid biosynthesis, protein glycosylation, and provides carbon for the tricarboxylic acid cycle anaplerosis. Glutamine catabolism maintains redox homeostasis via glutathione production, as well as the synthesis of polyamines, urea cycle precursors, and neurotransmitters. Glutamine residues in proteins serve as sites for post-translational modification, while de novo glutamine synthesis is essential for ammonia detoxification. Although glutamine metabolism is regulated by mass action and product inhibition, emerging evidence reveals additional post-translational mechanisms, including regulation through higher-order structural assemblies of enzymes. In this review, we highlight the multifaceted roles of glutamine and emphasize emerging regulatory mechanisms that govern glutamine metabolism.

Keywords: carbon metabolism; enzyme filaments; glutamine; nitrogen metabolism; post-translational regulation

DOI: https://doi.org/10.1016/j.tibs.2026.04.008

Nat Metab. 2026 May 04.

Succinate calls a time-out on pyrimidine biosynthesis.

Désirée Schatton, Christian Frezza.

DOI: https://doi.org/10.1038/s42255-026-01523-x