Structure, Function, and Regulation of Pah1 Phosphatidate Phosphatase in Yarrowia lipolytica

Phosphatidate phosphatase (PAP) governs a critical branchpoint in glycerolipid synthesis by catalyzing the Mg2+-dependent dephosphorylation of phosphatidate (PA) to diacylglycerol (DAG), thereby controlling the partitioning of lipid flux between membrane phospholipid synthesis and triacylglycerol (TAG) storage. While the structure, regulation, and function of ScPah1 have been extensively characterized in the non-oleaginous yeast Saccharomyces cerevisiae, far less is known about its ortholog in the oleaginous yeast Yarrowia lipolytica. This review provides a comparative analysis of Pah1 between the two yeasts, encompassing domain architecture, phosphorylation-dependent regulation, enzymatic characterization, and genetic and multi-omics studies. ScPah1 and YlPah1 share a conserved HAD-like catalytic core but diverge substantially in their regulatory domains: YlPah1 features compressed intrinsically disordered regions, an attenuated regulation of phosphorylation (RP) domain, and a massively expanded acidic tail. Unlike ScPah1, which is hyperphosphorylated and cytosolically sequestered during growth, YlPah1 maintains membrane association and increasing protein levels throughout growth. Deletion of PAH1 in Y. lipolytica produces a moderate reduction in TAG levels with evidence of metabolic redundancy, contrasting with the near-complete TAG loss observed in S. cerevisiae. Total PAP activity in Y. lipolytica peaks during exponential growth and does not correlate temporally with TAG accumulation, a dissociation attributable to the contributions of non-Pah1 PAP enzymes. Whether the Nem1–Spo7 homologs in Y. lipolytica form a functional phosphatase complex and the individual contributions of all PAP-encoding genes to lipid homeostasis remain important unresolved questions.