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Although many prokaryotes have glycolysis alternatives, it's considered as the only energy-generating glucose catabolic pathway in eukaryotes. Here, we managed to create a hybrid-glycolysis yeast. Subsequently, we identified an inositol pyrophosphatase encoded by OCA5 that could regulate glycolysis and respiration by adjusting 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP 7) levels. 5-InsP 7 levels could regulate the expression of genes involved in glycolysis and respiration, representing a global mechanism that could sense ATP levels and regulate central carbon metabolism. The hybrid-glycolysis yeast did not produce ethanol during growth under excess glucose and could produce 2.68 g/L free fatty acids, which is the highest reported production in shake flask of Saccharomyces cerevisiae. This study demonstrated the significance of hybrid-glycolysis yeast and determined Oca5 as an inositol pyrophosphatase controlling the balance between glycolysis and respiration, which may shed light on the role of inositol pyrophosphates in regulating eukaryotic metabolism. [Display omitted] • Hybrid of glycolysis with the phosphoketolase pathway made an efficient cell factory • Oca5, identified as an inositol pyrophosphatase, degrading 5-InsP 7 to InsP 6 • InsPs control gene expression involved in glycolysis and respiration to balance fluxes • The mechanism of Oca5 regulating glycolysis and respiration was elaborated Glycolysis is considered as the only energy-generating glucose catabolic pathway in eukaryotes. Qin et al. establish a hybrid-glycolysis yeast that disrupts the Embden-Meyerhof-Parnas glycolysis pathway and introduced components of the phosphoketolase pathway. They further identify Oca5 as an inositol pyrophosphatase controlling the balance between glycolysis and respiration activities. [ABSTRACT FROM AUTHOR]