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J Med Chem. 2009 Oct 8;52(19):6032-41. doi: 10.1021/jm900775q.

Hydroxamic acids as a novel family of serine racemase inhibitors: mechanistic analysis reveals different modes of interaction with the pyridoxal-5'-phosphate cofactor.

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Gilead Sciences and IOCB Research Center, Institute of Organic Chemistry and Biochemistry of the ASCR, Prague, Czech Republic.


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.

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