Hydroxamic acids as a novel family of serine racemase inhibitors: mechanistic analysis reveals different modes of interaction with the pyridoxal-5'-phosphate cofactor.
Mammalian serine racemase (SR) is a pyridoxal-5'-phosphate (PLP) dependent enzyme responsible for the biosynthesis of the neurotransmitter D-serine, which activates N-methyl-D-aspartate (NMDA) receptors in the CNS. Aberrant regulation of NMDA receptor signaling has been implicated in a variety of neuropathologies, and inhibitors of SR would therefore be a worthwhile tool for further investigation or treatment of such conditions. Here, we identify a series of small aliphatic hydroxamic acids (HAs) that act as potent SR inhibitors. However, specificity studies showed that some of these HAs can act as nonspecific inhibitors of PLP-dependent enzymes. We employed NMR, MS, and UV/vis spectroscopic techniques to reveal that the nonspecific effect is likely due to irreversible interaction of the HA moiety with PLP to form aldoxime species. We also characterize L-aspartic acid beta-hydroxamate as a competitive and selective SR inhibitor that could be used as a scaffold for further inhibitor development.
Gilead Sciences and IOCB Research Center, Institute of Organic Chemistry and Biochemistry of the ASCR, Prague, Czech Republic.
Hillary E
HE
Hoffman
Jana
J
Jirásková
Petr
P
Cígler
Miloslav
M
Sanda
Jan
J
Schraml
Jan
J
Konvalinka
D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives; D001667:Binding, Competitive; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D010091:Oximes / Q000138:chemical synthesis; D011732:Pyridoxal Phosphate / Q000737:chemistry / Q000378:metabolism*; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099300:Serine Racemase
D001216:Asparagine; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D010091:Oximes; D011732:Pyridoxal Phosphate; D019998:Racemases and Epimerases; D000099300:Serine Racemase; C024848:beta-aspartylhydroxamic acid; C023728:acetaldehyde oxime