Flipase

Flipase is a class of enzymes that catalyze the translocation of phospholipids across cellular membranes, thereby maintaining lipid asymmetry in bilayers. The term originates from the enzyme’s ability to “flip” phospholipids from one leaflet of a membrane to the other. Flipases are typically P4-ATPases, a subfamily of the P-type ATPase superfamily, which use ATP hydrolysis to drive the movement of anionic phospholipids such as phosphatidylserine, phosphatidylethanolamine, and sometimes phosphatidylinositol. Several non-ATP‑dependent flippases, such as the Cdc50 protein complexes in yeast, also exist and facilitate phospholipid movement via lipid–protein interactions distinct from the P4-ATPase mechanism.

The enzymatic activity is essential for numerous cellular processes, including membrane trafficking, vesicle formation, cell signaling, and apoptosis. During apoptosis, the externalization of phosphatidylserine exposes a “eat‑me” signal on the cell surface, enabling phagocytic clearance. Defects in flipase function can disturb membrane composition, leading to diseases such as Scott syndrome, a bleeding disorder characterized by impaired platelet activation. Additional genetic disorders, including certain neuropathies and inherited disorders of lipid metabolism, have also been linked to mutations in P4‑ATPases.

Flipases exhibit tissue‑specific distribution; for example, ATP8A2 is highly expressed in neuronal tissue, while ATP8B1 is prominent in the liver and intestine. Their regulatory mechanisms involve protein‑protein interactions with β‑subunits and phosphatidylinositol‑3‑phosphate binding, as well as phosphorylation and interactions with other lipid‑handling enzymes. Ongoing research focuses on elucidating the structural details of these enzymes, their substrate specificity, and their roles in complex diseases, which may open avenues for targeted therapies.