Saturated fatty acid- and/or monounsaturated fatty acid-containing-phosphatidic acids selectively interact with and activate phosphoglycerate mutase 1.

This study aimed to identify the target proteins of 16:0/16:0-phosphatidic acid (PA), which is produced by diacylglycerol kinases (DGKs) α, δ, and ζ. We identified phosphoglycerate mutase 1 (PGAM1), a key glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate, as a PA-binding protein with a stronger affinity for PA than for other phospholipids, including phosphatidylinositol, phosphatidylinositol 4-monophosphate, phosphatidylinositol 4,5-bisphosphate, cardiolipin, phosphatidylserine, phosphatidylglycerol, phosphatidylcholine, and sphingomyelin. PGAM1 preferentially binds to saturated fatty acid (SFA)- and/or monounsaturated fatty acid (MUFA)-containing PAs, such as 16:0/16:0-, 16:0/18:1-, 18:0/18:0-, 18:0/18:1-, and 18:1/18:1-PA, compared to polyunsaturated fatty acid-containing PAs, such as 18:0/20:4- and 18:0/22:6-PA. Notably, 16:0/16:0- and 16:0/18:1-PA altered the secondary conformation of PGAM1 and substantially enhanced its activity. Interestingly, PGAM1 interacted with DGKδ and ζ, but not with DGKα. These findings indicate that SFA- and/or MUFA-containing-PAs selectively interact with PGAM1, a promising therapeutic target for cancer, type 2 diabetes mellitus, and senescence, to regulate its activity.