Insights and progress on the biosynthesis, metabolism, and physiological functions of gamma-aminobutyric acid (GABA): a review

Abstract

GABA (γ-aminobutyric acid) is a non-protein amino acid that occurs naturally in the human brain, animals, plants and microorganisms. It is primarily produced by the irreversible action of glutamic acid decarboxylase (GAD) on the α-decarboxylation of L-glutamic acid. As a major neurotransmitter in the brain, GABA plays a crucial role in behavior, cognition, and the body's stress response. GABA is mainly synthesized through the GABA shunt and the polyamine degradation pathways. It works through three receptors (GABA_A, GABA_B, and GABA_C), each exhibiting different pharmacological and physiological characteristics. GABA has a variety of physiological roles and applications. In plants, it regulates growth, development and stress responses. In mammals, it influences physiological functions such as nervous system regulation, blood pressure equilibrium, liver and kidneys enhancement, hormone secretion regulation, immunity enhancement, cancer prevention, as well as anti-aging effects. As a biologically active ingredient, GABA possesses unique physiological effects and medicinal value, leading to its widespread application and substantially increased market demand in the food and pharmaceutical industries. GABA is primarily produced through chemical synthesis, plant enrichment and microbial fermentation. In this review, we first make an overview of GABA, focusing on its synthesis, metabolism, GABA receptors and physiological functions. Next, we describe the industrial production methods of GABA. Finally, we discuss the development of ligands for the GABA receptor binding site, the prospects of GABA production and application, as well as its clinical trials in potential drugs or compounds targeting GABA for the treatment of epilepsy. The purpose of this review is to attract researchers from various fields to focus on GABA research, promote multidisciplinary communications and collaborations, break down disciplinary barriers, stimulate innovative research ideas and methods, and advance the development and application of GABA in medicine, agriculture, food and other fields.

Keywords: Biosynthesis; Metabolism; Neurotransmitter; Physiological function; γ-Aminobutyric acid.

Figure 1. Chemical formulas of three isomers of aminobutyric acid (AABA, BABA, GABA).

AABA, α-aminobutyric acid; BABA, β-aminobutyric acid; GABA, γ-aminobutyric acid.

Figure 2. Timeline of GABA-related development and key milestones.

Figure 3. GABA synthesis: decarboxylation of L-Glutamate by glutamate decarboxylase (GAD) and pyridoxal-5-phosphate (PLP).

Figure 4. Interconnection of the GABA shunt and polyamine degradation (PA) pathway in metabolic regulation.

Orange arrows indicate the GABA shunt; Green arrows indicate the PA pathway. GABA shunt: GABA biosynthesis begins with the transamination of α-ketoglutarate (α-KG), catalyzed by glutamate dehydrogenase (GDH), to produce glutamate. Subsequently, the irreversible decarboxylation at the α- carbon of glutamate, catalyzed by glutamic acid decarboxylase (GAD), yields GABA. This reaction consumes a proton and releases carbon dioxide and can occur in both the mitochondria and the cytoplasm. GABA catabolism is then catalyzed by GABA transaminase (GABA-T), converting GABA into succinic semialdehyde (SSA). SSA is subsequently oxidized by succinate-semialdehyde dehydrogenase (SSADH) and enters the tricarboxylic acid (TCA) cycle as succinate. PA pathway: In this pathway, glutamate is converted to α-KG by GABA-T. This α-KG then undergoes a series of enzymatic reactions to produce glutathione and, ultimately, ornithine. Ornithine is transported to the cytoplasm, where it is converted into putrescine by ornithine decarboxylase (ODC). Through further enzymatic reactions, putrescine is converted to spermidine and spermine. Putrescine, spermidine, and spermine are then converted by diamine oxidase (DAO) and polyamine oxidase (PAO), respectively, to produce 4-aminobutyraldehyde. This 4-aminobutyraldehyde is dehydrogenated by 4-aminobutyraldehyde dehydrogenase (AMADH) to form GABA. The PA pathway intersects with the GABA shunt, and their metabolites eventually enter the TCA cycle.

Figure 5. Schematic representation of the GABA_A receptor and its subunits.

(A) The generic topological structure of a GABA_A receptor subunit. The mature GABA_A receptor comprises 450 amino acid residues. It possesses a large hydrophilic extracellular domain (ECD) at the N-terminus, four hydrophobic transmembrane domains (TMDs) (including TM1-TM4) in the middle, and a smaller intracellular domain (ICD) at the C-terminus. TM1 is connected to TM2 by a short intracellular loop; TM2 is connected to TM3 by a short extracellular loop; and TM3 is connected to TM4 by a long intracellular loop, which is phosphorylatable. (B) GABA_A receptors are heteropentameric chloride-ion channels. They consist of five subunits, typically arranged in a heterodimeric fashion, forming a cylindrical channel. At the center of this channel is a pore permeable to chloride ions; the GABA_A receptor exerts an inhibitory effect in the central nervous system by modulating the cell membrane’s depolarization. GABA_A receptors are formed from 16 subunits: α1–6, β1–3, γ1–3, δ, ε, θ, and π. Functional GABA receptors contain at least one α-subunit, one β-subunit, and one γ-subunit. The most common pentameric combinations are 2α2β1γ, 2α1β2γ, and 1α2β2γ. 2α2β1γ is most frequently expressed in the central nervous system. (C) Distribution of GABA and benzodiazepine (BZD) binding sites in the GABA_A receptor. Two GABA binding sites are located at the β+/α− interface, while one BZD binding site is located at the α+/γ− interface. Additionally, more than 10 potential ligand-binding sites are distributed throughout the receptor.

Figure 6. Heterodimeric and tetrameric structures of the GABA_B receptor.

GABA_B receptors exist in equilibrium as heterodimers, tetramers (dimers of dimers), and octamers (tetramers of dimers). Heterodimers are stabilized by strong noncovalent interactions, while higher-order oligomers are formed through weaker, and possibly transient, dimeric interactions. GABA_B receptor tetramers are formed through GABA_B1-GABA_B1 interactions between dimers. Each subunit comprises a large extracellular Venus Flytrap (VFT) domain, a seven-transmembrane domain, and an intracellular C-terminus. The GABA_B1 and GABA_B2 subunits interact via their C-terminal coiled-coil domains; neither subunit can signal independently. The VFT domain at the N-terminus of GABA_B1 is responsible for ligand binding (such as GABA and baclofen), whereas the VFT domain of GABA_B2 does not bind any known ligand. Positive allosteric modulators can bind to thetransmembrane domain of GABA_B2 to potentiate the agonist’s effects.