The metabotropic glutamate receptor antagonist l-2-amino-3-phosphonopropionic acid inhibits phosphoserine phosphatase

Abstract

Phosphoserine phosphatase catalyzes the final step in the major pathway of l-serine biosynthesis in brain. Using d-phosphoserine as substrate, the metabotropic glutamate receptor antagonist l-2-amino-3-phosphonopropionic acid ( l-AP3) inhibits phosphoserine phosphatase partially purified from rat brain with a K i of 151 μM. In contrast to AP3 enantioselectivity at metabotropic receptors, d-AP3 ( K i 48 μm) is more potent as an inhibitor of phosphoserine phosphatase than l-AP3, whereas dl-AP3 has intermediate potency. d-, l-,and dl-AP3 are 6- to 8-fold more potent inhibitors using d-phosphoserine rather than l-phosphoserine as substrate, suggesting that AP3 may have selectivity for isoforms of phosphoserine phosphatase which preferentially cleave d-phosphoserine. d-AP3 decreases the apparent affinity of d- and l-phosphoserine with little or no change in maximal velocity indicating that it is a competitive inhibitor of the enzyme. Whereas l-AP3 has similar potency at metabotropic glutamate receptors and phosphoserine phosphatase, d-AP3 is selective for phosphoserine phosphatase and is the most potent and only known competitive inhibitor of this enzyme.