Objective Polyphosphate (polyP) was widely studied in microorganism as potential high-energy phosphate source and stringent response-related regulatory factor.It was discovered in mammalian brain by Arthur Kornberg in 1995.We have found a decrease of endogenous by transfection of polyP degrading enzyme (exopolyphosphatase, PPX) would cause the transfected cells to respond differently to ischemia.Our study is to characterize computationally the possible polyP-related proteins to interpret the underlying mechanisms in cellular response to ischemia.Methods In this study, the precomputed structural neighbourhoods provided by DALI database were applied for identifying the structural analogues.We then attempted to use bioinforrmatics approaches including sequence motif-based search, molecular docking calculation and gene ontology enrichment to identify polyP-related proteins.Phylogenic analyses were also used to trace the evolutionary history of polyP-related enzymes.Results The major enzymes in synthesizing and metabolizing polyP-polyphosphate kinase (PPK) and polyphosphatases were not being identified in higher organisms.We identified 280 human genes whose products may be structurally analogous to the PPK family proteins by DALI program.We further computationally predicted the polyP binding potential of these gene products.Some of them were shown to have the binding capacity and possess derivative sequences from polyP-related motifs.Conclusion Our strategy could be used for the prediction experiment and help the future characterization of polyP-related proteins.The further study would provide important insight for understanding polyP metabolism and its regulatory functions in higher organisms.