Human serine racemase (hSR) is a pyridoxal 5’-phosphate (PLP)-dependent enzyme that is both a racemase and a b-eliminase for L-serine, giving rise to D-serine and pyruvate, respectively. The hSR enzyme is the only bona fide racemase enzyme in human biology and the D-serine that it produces is the major co-agonist of the NMDA receptor, binding at the glycine site with 100-fold higher potency. In so doing, D-serine mediates synaptic plasticity and long-term potentiation (LTP). Reduced levels of D-serine are associated with schizophrenia, whereas elevated levels have been seen in ALS, Alzheimer’s disease and in neuronal damage pursuant to ischemic stroke. Interestingly, recent studies indicate the high levels of hSR-derived pyruvate, may be associated with the etiology of colorectal cancer, suggesting that both the racemization and the b-elimination reactions catalyzed by hSR are biologically significant. Given these observations, there is currently great interest in identifying inhibitors and/or activators of hSR for use as chemical biology tools to study hSR function in model systems. We report here on the development of a new hSR assay that provides information on both catalytic activities of hSR in parallel. This assay has been deployed across a library of 1000 compounds consisting of small molecules across a variety of chemotypes, with considerably structural diversity that was designed with consideration of both Lipinski’s rules and of ‘privileged scaffolds’ for protein binding. We outline here the optimization of this bifurcated assay, along with the results of this inhibitor candidate screen and describe preliminary structure-activity relationships developed from the initial hits.

Development of a new, information-rich assay for human serine racemase (hSR)-application to library screening

ACS Spring 2022

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