Purification of serine racemase: Biosynthesis of the neuromodulator d -serine

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Abstract
High levels of d -serine occur in mammalian brain, where it appears to be an endogenous ligand of the glycine site of N -methyl- d -aspartate receptors. In glial cultures of rat cerebral cortex, d -serine is enriched in type II astrocytes and is released upon stimulation with agonists of non- N -methyl- d -aspartate glutamate receptors. The high levels of d -serine in discrete areas of rat brain imply the existence of a biosynthetic pathway. We have purified from rat brain a soluble enzyme that catalyzes the direct racemization of l -serine to d -serine. Purified serine racemase has a molecular mass of 37 kDa and requires pyridoxal 5′-phosphate for its activity. The enzyme is highly selective toward l -serine, failing to racemize any other amino acid tested. Properties such as pH optimum, K m values, and the requirement for pyridoxal phosphate resemble those of bacterial racemases, suggesting that the biosynthetic pathway for d -amino acids is conserved from bacteria to mammalian brain.