Human serine racemase (hSR) is an important pyridoxal 5’-phosphate (PLP) dependent enzyme responsible for the production of D-serine in the brain. D-serine is a crucial neurotransmitter that acts as a co-agonist of the NMDA receptor, binding to the ‘glycine’ site. Alterations in D-serine levels have been linked to schizophrenia (reduced), neuronal cell damage caused by ischemic stroke (elevated), and other neurodegenerative diseases such as Alzheimer’s and ALS (elevated). We have developed a new construct that significantly increases solubility of the protein without altering the kinetics. This presentation will describe a systematic structure-activity relationship (SAR) study of hSR chemistry that involves alteration of both the structure of the substrate and the structure of the <i>re</i>-face base in the active site. Enzyme kinetics reveal fascinating cases of ‘matched’ and ‘mismatched’ E’-S’ pairs. The results are analyzed with a combination of molecular dynamics simulation and molecular docking and suggest that the dramatic changes in E’-S’ complementarity may result from significant changes in active site topology and may have important stereoelectronic underpinnings.

Use of small molecule probe substrates, active site mutagenesis and molecular modeling to gain mechanistic insight into the PLP-enzyme, human serine racemase

254th National Meeting (2017)

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