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

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 Ki of 151 microM. In contrast to AP3 enantioselectivity at metabotropic receptors, D-AP3 (Ki 48 microM) 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.