Metabolic Consequences of Polyphosphate Synthesis and Imminent Phosphate Limitation

Cells stabilize intracellular inorganic phosphate (P(i)) to compromise between large biosynthetic needs and detrimental bioenergetic effects of P(i). P(i) homeostasis in eukaryotes uses Syg1/Pho81/Xpr1 (SPX) domains, which are receptors for inositol pyrophosphates. We explored how polymerization and storage of P(i) in acidocalcisome-like vacuoles supports Saccharomyces cerevisiae metabolism and how these cells recognize P(i) scarcity. Whereas P(i) starvation affects numerous metabolic pathways, beginning P(i) scarcity affects few metabolites. These include inositol pyrophosphates and ATP, a low-affinity substrate for inositol pyrophosphate-synthesizing kinases. Declining ATP and inositol pyrophosphates may thus be indicators of impending P(i) limitation. Actual P(i) starvation triggers accumulation of the purine synthesis intermediate 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which activates P(i)-dependent transcription factors. Cells lacking inorganic polyphosphate show P(i) starvation features already under P(i)-replete conditions, suggesting that vacuolar polyphosphate supplies P(i) for metabolism even when P(i) is abundant. However, polyphosphate deficiency also generates unique metabolic changes that are not observed in starving wild-type cells. Polyphosphate in acidocalcisome-like vacuoles may hence be more than a global phosphate reserve and channel P(i) to preferred cellular processes.