Rapid remodeling of NTP levels enables immediate translational adaptation to energy stress in yeast

In Saccharomyces cerevisiae, glucose depletion induces metabolic reprogramming through widespread transcriptional and translational reorganization. We report that initial, very rapid translational silencing is driven by a specialized metabolic mechanism. Following glucose withdrawal, intracellular NTP levels drop drastically over 30 s before stabilizing at a regulated, post-stress set point. Programmed translational control results from the differential NTP affinities of key enzymes; ATP falls below the (high) binding constants for DEAD-box helicase initiation factors, including eIF4A, driving mRNA release and blocking 80S assembly. Contrastingly, guanosine triphosphate (GTP) levels always greatly exceed the (low) binding constants for elongation factors, allowing ribosome run-off and orderly translation shutdown. Translation initiation is immediately lost on all pre-existing mRNAs before being preferentially re-established on newly synthesized, upregulated stress-response transcripts. We conclude that enzymatic constants are tuned for metabolic remodeling. This response counters energy depletion rather than being glucose specific, allowing hierarchical inhibition of energy-consuming processes on very rapid timescales.