Polyphosphate metabolism: Enzymatic pathways and regulation

Polyphosphate (polyP) is an ancient, evolutionarily conserved inorganic polymer found in all domains of life. PolyP functions in energy storage, metal chelation, phosphate buffering, and regulation of fundamental physiological processes such as blood coagulation, bone mineralisation, and mitochondrial energy metabolism. Here, we summarize current knowledge of polyP-metabolizing enzymes. In prokaryotes, polyP synthesis is primarily catalysed by polyphosphate kinases (PPK1 and PPK2), which synthesize long-chain polymers from adenosine triphosphate (ATP) or guanosine triphosphate (GTP); notable these enzymes are absent in higher eukaryotes. In yeast, the vacuolar transporter chaperone (VTC) complex functions as a polyP polymerase-translocase, coupling synthesis with vacuolar import. In mammals, the enzymatic machinery responsible for polyP formation remains elusive, although mitochondrial F 1 F 0 -ATP synthase and inositol pyrophosphate signalling have been implicated. PolyP degradation is mediated by two major enzyme families: exo - and endopolyphosphatases. Members of these families - including exopolyphosphatases (PPX) and endopolyphosphatases (PPN) in yeast and bacteria as well as Nudix hydrolases and h-Prune in mammals – play key roles in maintaining intracellular phosphate homeostasis and regulating the dynamic turnover of polyP. Defining the molecular pathways of polyP synthesis and degradation will reveal novel therapeutic targets in infection, thrombosis, and metabolic disease.