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MUCOSAL BIOLOGY

A novel phosphatase upregulated in Akp3 knockout mice

¹Burnham Institute for Medical Research, La Jolla, California; ²Center for Molecular and Vascular Biology, University of Leuven-Campus Gasthuisberg, Leuven, Belgium; and ³Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

Submitted 11 February 2007 ; accepted in final form 18 September 2007

Reexamination of the Akp3^–/– mouse intestine showed that, despite the lack of intestinal alkaline phosphatase (IAP), the Akp3^–/– gut still had considerable alkaline phosphatase (AP) activity in the duodenum and ileum. This activity is due to the expression of a novel murine Akp6 gene that encodes an IAP isozyme expressed in the gut in a global manner (gIAP) as opposed to duodenum-specific IAP (dIAP) isozyme encoded by the Akp3 gene. Phylogenetically, gIAP is similar to the rat IAP I isozyme. Kinetically, gIAP displays a 5.7-fold reduction in catalytic rate constant (k_cat) and a 30% drop in K_m, leading to a 4-fold reduction k_cat/K_m compared with dIAP, and these changes in enzymatic properties can all be attributed to a crucial R317Q substitution. Western and Northern blot analyses document the expression of Akp6 in the gut, from the duodenum to the ileum, and it is upregulated in the jejunum and ileum of Akp3^–/– mice. Developmentally, Akp3 expression is turned on during postnatal days 13–15 and exclusively in the duodenum, whereas Akp6 and Akp5 are expressed from birth throughout the gut with enhanced expression at weaning. Posttranslational modifications of gIAP have a pronounced effect on its catalytic properties. Given the low catalytic efficiency of gIAP, its upregulation during fat feeding, its sequence similarity with rat IAP I, and the fact that rat IAP I has been implicated in the upregulation of surfactant-like particles during fat intake, it appears likely that gIAP may have a role in mediating the accelerated fatty acid intake observed in Akp3^–/– mice fed a high-fat diet.

alkaline phosphatases; site-directed mutagenesis; computer modeling; fat absorption; intestinal physiology

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