5615-93-0Relevant academic research and scientific papers
Hydroxamic acids as a novel family of serine racemase inhibitors: Mechanistic analysis reveals different modes of interaction with the pyridoxal-5′-phosphate cofactor
Hoffman, Hillary E.,Jirásková, Jana,Cígler, Petr,?anda, Miloslav,Schraml, Jan,Konvalinka, Jan
experimental part, p. 6032 - 6041 (2010/03/24)
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 β-hydroxamate as a competitive and selective SR inhibitor that could be used as a scaffold for further inhibitor development. 2009 American Chemical Society.
