title: 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 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.
authors.affiliation: CoCensys, Inc., Irvine, CA 92718, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Hawkinson
authors.forename: M
authors.initials: M
authors.lastname: Acosta-Burruel
authors.forename: P L
authors.initials: PL
authors.lastname: Wood
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012694:Serine / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C000211:2-amino-3-phosphonopropionic acid; D012694:Serine; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase; D000409:Alanine