Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) and carbon dioxide (CO2). GAD uses pyridoxal-phosphate (PLP) as a cofactor. The reaction proceeds as follows:
HOOC−CH2−CH2−CH(NH2)−COOH → CO2 + HOOC−CH2−CH2−CH2NH2
In mammals, GAD exists in two isoforms with molecular weights of 67 and 65 kDa (GAD67 and GAD65), which are encoded by two different genes on different chromosomes (GAD1 and GAD2 genes, chromosomes 2 and 10 in humans, respectively).[1][2] GAD67 and GAD65 are expressed in the brain where GABA is used as a neurotransmitter, and they are also expressed in the insulin-producing β-cells of the pancreas, in varying ratios depending upon the species.[3] Together, these two enzymes maintain the major physiological supply of GABA in mammals,[2] though it may also be synthesized from putrescine in the enteric nervous system,[4] brain,[5][6] and elsewhere by the actions of diamine oxidase and aldehyde dehydrogenase 1a1.[4][6]
Several truncated transcripts and polypeptides of GAD67 are detectable in the developing brain,[7] however their function, if any, is unknown.
^ abLangendorf CG, Tuck KL, Key TL, Fenalti G, Pike RN, Rosado CJ, et al. (January 2013). "Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates". Bioscience Reports. 33 (1): 137–44. doi:10.1042/BSR20120111. PMC 3546353. PMID 23126365.
^Kim J, Richter W, Aanstoot HJ, Shi Y, Fu Q, Rajotte R, et al. (December 1993). "Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets". Diabetes. 42 (12): 1799–808. doi:10.2337/diab.42.12.1799. PMID 8243826. S2CID 29615710.
^ abKrantis A (December 2000). "GABA in the Mammalian Enteric Nervous System". News in Physiological Sciences. 15 (6): 284–290. doi:10.1152/physiologyonline.2000.15.6.284. PMID 11390928.
^Sequerra EB, Gardino P, Hedin-Pereira C, de Mello FG (May 2007). "Putrescine as an important source of GABA in the postnatal rat subventricular zone". Neuroscience. 146 (2): 489–93. doi:10.1016/j.neuroscience.2007.01.062. PMID 17395389. S2CID 43003476.
^ abKim JI, Ganesan S, Luo SX, Wu YW, Park E, Huang EJ, et al. (October 2015). "Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons" (PDF). Science. 350 (6256): 102–6. Bibcode:2015Sci...350..102K. doi:10.1126/science.aac4690. PMC 4725325. PMID 26430123.
^Szabo G, Katarova Z, Greenspan R (November 1994). "Distinct protein forms are produced from alternatively spliced bicistronic glutamic acid decarboxylase mRNAs during development". Molecular and Cellular Biology. 14 (11): 7535–45. doi:10.1128/mcb.14.11.7535. PMC 359290. PMID 7935469.
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