Human serine racemase: moleular cloning, genomic organization and functional analysis

Abstract

High levels of d-serine are found in mammalian brain, where it is an endogenous agonist of the strichinine-insensitive site of N-methyl d-aspartate type of glutamate receptors. d-serine is enriched in protoplasmic astrocytes that occur in gray matter areas of the brain and was shown to be synthesized from l-serine . We now report cloning and expression of human serine racemase, an enzyme that catalyses the synthesis of d-serine from l-serine. The enzyme displays a high homology to the murine serine racemase. It contains a pyridoxal 5′-phosphate attachment sequence similar to bacterial biosynthetic threonine dehydratase. Northern-blot analysis show high levels of human serine racemase in areas known to contain large amounts of endogenous d-serine, such as hippocampus and corpus callosum. Robust synthesis of d-serine was detected in cells transfected with human serine racemase, demonstrating the conservation of d-amino acid metabolism in humans. Serine racemase may be a therapeutic target in psychiatric diseases as supplementation of d-serine greatly improves schizophrenia symptoms. We identify the human serine racemase genomic structure and show that the gene encompasses seven exons and localizes to chromosome 17q13.3. Identification of the intron–exon boundaries of the human serine racemase gene will be useful to search for mutations in neuropsychiatric disorders.