Glutamate decarboxylase
| glutamate decarboxylase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 4.1.1.15 | ||||||||
| CAS no. | 9024-58-2 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
| Glutamic acid decarboxylase 1 | |||||||
|---|---|---|---|---|---|---|---|
 | |||||||
| Identifiers | |||||||
| Symbol | GAD1 | ||||||
| Alt. symbols | glutamate decarboxylase 1 (brain, 67kD); GAD67 | ||||||
| NCBI gene | 2571 | ||||||
| HGNC | 4092 | ||||||
| OMIM | 605363 | ||||||
| RefSeq | NM_000817 | ||||||
| UniProt | Q99259 | ||||||
| Other data | |||||||
| EC number | 4.1.1.15 | ||||||
| Locus | Chr. 2 q31 | ||||||
| |||||||
| glutamic acid decarboxylase 2 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | GAD2 | ||||||
| Alt. symbols | GAD65 | ||||||
| NCBI gene | 2572 | ||||||
| HGNC | 11284 | ||||||
| OMIM | 4093 | ||||||
| RefSeq | NM_001047 | ||||||
| UniProt | Q05329 | ||||||
| Other data | |||||||
| EC number | 4.1.1.15 | ||||||
| Locus | Chr. 10 p11.23 | ||||||
| |||||||
Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2. GAD uses 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 encoded by two different genes - GAD1 and GAD2. These isoforms are GAD67 and GAD65 with molecular weights of 67 and 65 kDa, respectively.[1] GAD1 and GAD2 are expressed in the brain where GABA is used as a neurotransmitter, GAD2 is also expressed in the pancreas.
At least two more forms, GAD25 and GAD44 (embryonic; EGAD) are described in the developing brain. They are coded by the alternative transcripts of GAD1, I-80 and I-86: GAD25 is coded by both, GAD44 - only by I-80.[2]
Role in pathology
Diabetes
Both GAD67 and GAD65 are targets of autoantibodies in people who later develop type 1 diabetes mellitus or latent autoimmune diabetes.[3][4] Injections with GAD65 has been shown to preserve some insulin production for 30 months in humans with type 1 diabetes.[5][6]
Schizophrenia and bipolar disorder
Substantial dysregulation of GAD mRNA expression, coupled with downregulation of reelin, is observed in schizophrenia and bipolar disorder.[7] The most pronounced downregulation of GAD67 was found in hippocampal stratum oriens layer in both disorders and in other layers and structures of hippocampus with varying degrees.[8]
Parkinson disease
The bilateral delivery of glutamic acid decarboxylase (GAD) by an adeno-associated viral vector into the subthalamic nucleus of patients between 30 and 75 years of age with advanced, progressive, levodopa-responsive Parkinson disease resulted in significant improvement over baseline during the course of a six-month study.[9]
Cerebellar disorders
Intracerebellar administration of GAD autoantibodies to animals increase the excitability of motoneurons and impairs the production of nitric oxide (NO), a molecule involved in learning. Epitope recognition contributes to cerebellar involvement.[10]
Alteration by drugs
Pregabalin, an antiepileptic drug, increases neuronal GABA levels by producing a dose-dependent increase in glutamic acid decarboxylase activity.[1] Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity.[11]
References
- ^ Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ (1991). "Two genes encode distinct glutamate decarboxylases". Neuron. 7 (1): 91–100. doi:10.1016/0896-6273(91)90077-D. PMID 2069816.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Szabo G, Katarova Z, Greenspan R (1994). "Distinct protein forms are produced from alternatively spliced bicistronic glutamic acid decarboxylase mRNAs during development". Mol. Cell. Biol. 14 (11): 7535–45. PMC 359290. PMID 7935469.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P, Camilli PD (1990). "Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase". Nature. 347 (6289): 151–6. doi:10.1038/347151a0. PMID 1697648.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Kaufman DL, Erlander MG, Clare-Salzler M, Atkinson MA, Maclaren NK, Tobin AJ (1992). "Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus". J. Clin. Invest. 89 (1): 283–92. doi:10.1172/JCI115573. PMC 442846. PMID 1370298.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Ludvigsson J, Faresjö M, Hjorth M, Axelsson S, Chéramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R (2008). "GAD treatment and insulin secretion in recent-onset type 1 diabetes". N. Engl. J. Med. 359 (18): 1909–20. doi:10.1056/NEJMoa0804328. PMID 18843118.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ "Diamyd announces completion of type 1 diabetes vaccine trial with long term efficacy demonstrated at 30 months". Press Release. Diamyd Medical AB. 2008-01-28. Retrieved 2010-01-13.
- ^ Woo TU, Walsh JP, Benes FM (2004). "Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder". Arch. Gen. Psychiatry. 61 (7): 649–57. doi:10.1001/archpsyc.61.7.649. PMID 15237077.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M (2007). "Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars". Proc. Natl. Acad. Sci. U.S.A. 104 (24): 10164–9. doi:10.1073/pnas.0703806104. PMC 1888575. PMID 17553960.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Askandar EN; et al. (2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial". Lancet Neurol. 10 (4): 309–19. doi:10.1016/S1474-4422(11)70039-4. PMID 21419704.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Manto MU, Hampe CS, Rogemond V, Honnorat J. Respective implications of glutamate decarboxylase antibodies in stiff person and cerebellar ataxia. Orphanet J Rare Dis 6:3,2011
- ^ pmid18066140, F (2007). "Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system". Canadian Journal of Physiology and Pharmacology. 85 (9): 933–42. doi:10.1139/Y07-083. PMID 18066140.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: numeric names: authors list (link)
External links
Media related to Glutamate decarboxylase at Wikimedia Commons- Genetics, Expression Profiling Support GABA Deficits in Schizophrenia - Schizophrenia Research Forum, 25 June 2007.
