Role of PS Product Inhibition in Accumulation of Phosphatidylserine (PS) in Neuronal Membranes

PS is a major membrane component in mammalian tissues. Neuronal tissues are highly enriched with docosahexaenoic acid (DHA, 22:6n‐3) and PS in comparison to non‐neuronal tissues. Such concentration of DHA and PS is known to be important for proper neuronal functions. In mammalian cells, PS synthase (PSS) 1 and 2 catalyze PS synthetic activity, which is inhibited by the product PS through the feedback mechanism. We have previously found that DHA containing PS species (DHA‐PS) highly accumulates in neuronal membranes mainly due to the substrate preference in PS synthesis towards DHA phospholipid species. To understand the biochemical mechanisms underlying enrichment of PS in neuronal membranes, we hypothesized that fatty acyl composition‐dependent product inhibition in PS synthesis also plays a role in PS accumulation. We found that DHA‐PS has weaker inhibitory effect compared to oleic acid (OA, 18:1n‐9) containing PS species (OA‐PS) when tested with mouse liver microsomes. Consistently, DHA‐PS inhibited PSS activity less effectively than OA‐PS when flag‐PSS2 were expressed in mammalian cells, successfully immuno‐purified, and subsequently used as an enzyme source. DHA‐PS as a weaker inhibitor of PSS together with the high specificity towards DHA‐PS synthesis may contribute to the high PS accumulation in neuronal membranes. Intramural Program of National Institutes of Health