Enzymatic and structural aspects on glutamate decarboxylase

Glutamate decarboxylase (GAD) is a sole enzyme to synthesize γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in higher animals. Two distinct enzymes are encoded in the mammalian genomes, namely GAD65 and GAD67. These isozymes resemble in their primary structure except for significant heterogeneity found in the N-terminal 100 residues, which suggests certain differences in the cellular localization and functions. Other than brain cells, GAD is found in pancreatic cells. Pancreatic GAD65 is found to be a target antigen for autoantibody produced in diabetes and stiff man syndrome (SMS) patients. Extensive structural information on GAD helps to develop or improve early diagnostic tools for diabetes. GAD is found in a variety of living organisms. Insect has analogous neuronal system to mammals where GAD is responsible for GABA production. Plant GAD is regulated by Ca2+ levels since it has a calmodulin-binding site in the C-terminal region, which is found only in the plant enzymes. Escherichia coli GAD, a hexameric enzyme with significant structural differences from mammalian GAD, has two types, GAD-α and GAD-β. In this review, structural similarities of GAD enzymes from various sources are compared and some of the characteristic features are described.