Submitted on February 15, 2007
Accepted on September 18, 2007
A novel phosphatase upregulated in Akp3 knockout mice
Sonoko Narisawa1, Marc F Hoylaerts2, Kutbuddin S Doctor1, Michiko N Fukuda3, David H. Alpers4, and Jose Luis Millan1*
1 Burnham Institute for Medical Research, La Jolla, California, United States
2 University of Leuven, Leuven, Belgium
3 Burnham Institute for medical Research, La Jolla, California, United States
4 Medicine, University of Washington School of Medicine, St. Louis, Missouri, United States
* To whom correspondence should be addressed. E-mail: millan{at}burnham.org.
Re-examination of the Akp3-/- mouse intestine showed that despite the lack of IAP, the Akp3-/- gut still had considerable 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 kcat and a 30% drop in Km, leading to a 4-fold reduction kcat/Km compared to 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 its up-regulated in the jejunum/ileum of Akp3-/- mice. Developmentally, Akp3 expression is turned on during postnatal days 13-15 and exclusively in the duodenum, while Akp6 and Akp5 are expressed from birth throughout the gut with enhanced expression at weaning. Post-translational modifications of gIAP have a pronounced effect on its catalytic properties. Given the low catalytic efficiency of gIAP, its up-regulation during fat feeding, its sequence similarity with rat IAP I and the fact that rat IAP I has been implicated in the up-regulation 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.
