Glutamic acid decarboxylase
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Glutamic Acid Decarboxylase: Enzyme Properties, Functions, and Clinical Significance
Isolation and Purification of Glutamic Acid Decarboxylase
Glutamic acid decarboxylase (GAD) has been isolated and purified from various bacterial sources, with significant advancements in purification techniques over time. Early attempts by researchers such as Taylor and Gale, Umbreit and Gunsalus, and Najjar and Fisher achieved an 8-fold purification from Escherichia coli1. Recent procedures have further refined the purification process, achieving higher purity levels and providing detailed insights into the enzyme's properties1.
Enzymatic Function and Biochemical Properties
GAD is a pyridoxal-5’-phosphate-dependent enzyme that catalyzes the irreversible α-decarboxylation of L-glutamic acid to γ-aminobutyric acid (GABA) and CO22. This enzyme is widely distributed across both eukaryotic and prokaryotic organisms, playing crucial roles in various physiological functions. In lactic acid bacteria (LAB), GAD is essential for GABA synthesis, which has potential applications in creating functional food products enriched with GABA2.
Role in Central Nervous System and Peripheral Organs
GAD catalyzes the production of GABA, the major inhibitory neurotransmitter in the vertebrate central nervous system6. This neurotransmitter is crucial for maintaining neuronal excitability and preventing overstimulation. Additionally, GAD and GABA have roles in peripheral organs, contributing to various physiological processes3.
Clinical Significance in Autoimmune Diseases
GAD has been identified as a significant autoantigen in autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and stiff-man syndrome (SMS)7 8. Autoantibodies against GAD are prevalent in these conditions, with distinct epitope recognition patterns observed between the two diseases. For instance, individuals with SMS exhibit higher titers of GAD autoantibodies compared to those with IDDM, and these antibodies target different regions of the GAD protein7. The presence of GAD autoantibodies is a critical marker for the diagnosis and prognosis of these autoimmune disorders3 9.
Industrial Applications of GAD
The decarboxylation of glutamic acid to GABA by GAD has significant industrial applications, particularly in the valorization of glutamic acid from biofuel production waste streams4. Immobilizing GAD on supports such as Eupergit and calcium alginate enhances its operational stability, making it feasible for large-scale GABA production. This process is cost-effective and scalable, with potential applications in producing nitrogen-containing bulk chemicals4.
Mechanism of Enzyme Inhibition
The inhibition of bacterial GAD by analogs such as 4-aminohex-5-ynoic acid has been studied to understand the enzyme's catalytic mechanism. This inhibition is stereospecific and involves the formation of a reactive alkylating agent at the enzyme's active site, leading to irreversible inhibition5. Such studies provide insights into the enzyme's functionality and potential therapeutic targets.
Genetic and Molecular Insights
The cloning and sequencing of GAD cDNA have revealed detailed information about the enzyme's structure and function. For example, the nucleotide sequence of feline brain GAD cDNA encodes an enzymatically active fusion protein, confirming its identity and catalytic activity10. These genetic studies are crucial for understanding the enzyme's role in various biological processes and its potential applications in biotechnology.
Conclusion
Glutamic acid decarboxylase is a pivotal enzyme with diverse roles in both central nervous system function and industrial applications. Its involvement in synthesizing GABA, a major inhibitory neurotransmitter, underscores its importance in maintaining neuronal balance. Additionally, GAD's role as an autoantigen in diseases like IDDM and SMS highlights its clinical significance. Advances in purification, genetic characterization, and industrial application of GAD continue to expand our understanding and utilization of this essential enzyme.
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Most relevant research papers on this topic
Glutamic acid decarboxylase. I. Isolation procedures and properties of the enzyme.
This study demonstrates a higher purity of glutamic decarboxylase from bacteria, achieving a higher degree of purity than previously achieved, and describing its properties.
Highly CitedGlutamate Decarboxylase from Lactic Acid Bacteria—A Key Enzyme in GABA Synthesis
GABA-producing lactic acid bacteria offer potential for new functional food products with health benefits, offering potential health benefits through the conversion of l-glutamic acid to -aminobutyric acid and CO2.
Rigorous JournalHighly CitedGlutamic Acid Decarboxylase – Gene to Antigen to Disease
GAD enzymes play a significant role in autoimmune diseases like neurological disorders and insulin-dependent diabetes, with potential for use in treating these diseases.
Highly CitedThe application of glutamic acid α-decarboxylase for the valorization of glutamic acid
Immobilized glutamic acid -decarboxylase in a fed batch reactor is a scalable process for industrial production of GABA from glutamic acid, with potential for reducing fossil fuel dependency.
Highly CitedMechanism of the stereospectific irreversible inhibition of bacterial glutamic acid decarboxylase by (R)-(--)-4-aminohex-5-ynoic acid, an analogue of 4-aminobutyric acid.
The stereospecific inhibition of bacterial glutamic acid decarboxylase by (R)-(--)-4-aminohex-5-ynoic acid is rationalized by the reversibility of the protonation step in the normal catalytic mechanism.
Brain glutamate decarboxylase cloned in lambda gt-11: fusion protein produces gamma-aminobutyric acid.
Glutamate decarboxylase (GAD) is a brain enzyme that converts glutamate to GABA and carbon dioxide, playing a crucial role in the central nervous system.
In Vitro StudyHighly CitedGlutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition.
GAD autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition, suggesting overlap in humoral response between the two diseases.
In Vitro StudyHighly CitedIdentification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase
The 64K autoantigen in insulin-dependent diabetes is the GABA-synthesizing enzyme glutamic acid decarboxylase, which also plays a role in stiff-man syndrome.
Highly CitedThe clinical significance of an autoimmune response against glutamic acid decarboxylase
An autoimmune response against glutamic acid decarboxylase (CAD) may help identify the disease mechanisms in stiff-man syndrome and insulin-dependent diabetes.
Highly CitedGlutamic acid decarboxylase cDNA: nucleotide sequence encoding an enzymatically active fusion protein
The feline GAD cDNA sequence reveals an enzymatically active fusion protein that catalyzes the conversion of glutamate to CO2 and GABA, with a similar amino acid composition and molecular size to GAD.
Highly Cited