Alkaline phosphatase superfamily members: new pieces of the choline metabolism puzzle

Choline is an essential nutrient required for the synthesis of key molecules, such as phosphatidylcholine, sphingomyelin, acetylcholine, and S-adenosylmethionine. Choline metabolism encompasses two phases, namely the postprandial and postabsorptive states. The former enables the digestion, absorption, distribution, and storage of choline derivatives after a meal, while the latter allows the cellular utilization of choline and the mobilization of stored choline-containing molecules during fasting. Understanding choline metabolism is fundamental to the study of lipid disorders such as steatohepatitis or atherosclerosis, as well as neurodegenerative diseases, including Alzheimer's disease, and inflammatory signaling pathways. Members of the alkaline phosphatase (AP) superfamily are prominent contributors to extracellular choline metabolism. Within this family, several APs and ectonucleotide pyrophosphatases/phosphodiesterases (ENPP) members are required for physiological choline metabolism. While intestinal alkaline phosphatase (IAP) and alkaline sphingomyelinase/ENPP7 both participate in the digestion of choline-containing derivatives in the gut during the postprandial phase, circulating ENPP2, ENPP6, and tissue-nonspecific alkaline phosphatase (TNAP) act during the postabsorptive phase to generate choline. In this review we first provide a comprehensive overview of choline metabolism and then describe how APs and ENPPs have functionally and structurally co-evolved to catalyze sequential reactions within this metabolic pathway.