Glutamate and Its Role in the Metabolism of Plants and Animals

Abstract

Glutamate is one of the major naturally occurring non-essential amino acids. The aim of this review is to provide a comprehensive analysis of the role of glutamate as a key metabolite in the metabolism of plant and animal organisms. Its role in nutrition and neurotransmission has intrigued researchers for many years. In both plants and animals, glutamate primarily exists in a monoanionic form characterised by unique physical and chemical properties. In plants, it is involved in the glutamine synthetase/glutamate synthase (GS/GOGAT) cycle, while in animals, it plays a role in the glutamine/glutamate cycle, which is closely related to the urea cycle. Glutamate is also closely linked to the Krebs cycle in both groups of organisms through α-ketoglutarate. Glutamate is essential in both biosynthetic and catabolic pathways and participates in numerous physiological processes in plants and animals. Animals acquire glutamate from food, while plants acquire it from the soil; however, both also synthesise it de novo. Once present in the body, it is transported across cell membranes by specific transporters driven by ionic gradients (a mechanism known as secondary active transport). It is involved in cellular and systemic signalling pathways by interacting with ionotropic and metabotropic receptors. Additionally, glutamate is an important ‘building block’ of many proteins, including storage proteins. It also occurs in the form of monosodium glutamate (MSG), a flavour enhancer that is widely used but often criticised. Due to its important role in metabolism and signalling, the significance of glutamate in nutrition and its impact on human health are vital areas of research in food biochemistry. These investigations contribute to the development of nutritious food products and the design of effective pharmaceuticals. In this paper, we also address unresolved questions in glutamate research and consider its practical applications.

1. Introduction

Currently, the developing global society is paying greater attention to health and healthy food. Knowledge related to the biochemistry of nutrients and nutrition itself is exerting a growing influence on the development and implementation of healthy diets. Protein nutrients, particularly the key amino acid glutamate, have long been a central focus in food biochemistry research. Glutamate, present in both plant and animal tissues, plays an essential role in the metabolism of living organisms. It participates in numerous physiological processes that support growth, development, and responses to environmental stimuli [1,2,3,4]. Widely used around the world, glutamate serves not only as a nutrient but also as a flavour enhancer. It contributes to nutrient metabolism and also acts as a signalling molecule in neurotransmission [1,2].

In plants, glutamate is a crucial compound in nitrogen assimilation. It is a key substrate in the synthesis of amino acids and proteins, thus contributing to the processes of growth and development [5,6,7,8]. It is also implicated in chlorophyll synthesis pathways and is therefore indirectly involved in the processes of photosynthesis and energy acquisition [9,10]. Furthermore, glutamate has been demonstrated to play a significant role in osmotic responses as a precursor of osmoprotectants such as proline [5,11,12]. It is also associated with oxidoreductive processes through its participation in glutathione synthesis [5,13].

Glutamate is the main neurotransmitter in the central nervous system (CNS) of vertebrates, and it is responsible for neuronal transmission. Consequently, it is involved in the perception of stimuli, learning, and memory [13,14]. The maintenance of optimal glutamate concentrations and their metabolic processes is essential for overall bodily health. Disturbances to concentration and glutamate metabolism can contribute to the development of diseases, including those related to the nervous system [5,15].

The aim of this review is to provide a comprehensive analysis of the role of glutamate as a key metabolite in plant and animal metabolism. The objective of the present study is to provide a synthesised overview of the current state of knowledge on the biosynthesis and catabolism of glutamate, its involvement in nitrogen metabolism, amino acid biosynthesis, and its signalling function. The significance of glutamate as a signalling molecule in plants is also discussed. Furthermore, the effects of glutamate in a healthy diet and its potential applications in medicine are presented.

2. Glutamate as a Chemical—Structure and Features

2.1. Physical and Chemical Properties of Glutamate

Glutamate is the anionic form of glutamic acid, one of the naturally occurring amino acids that is involved in metabolic processes. The chemical formula of glutamic acid is C₅H₉NO₄, as presented in Figure 1. Glutamate occurs in various ionic forms, depending on the pH of the solution, as shown in

Table 1. The ionic form of glutamate at different pH levels of the solution is based on [18,19]. α—carbon α, R—amino acid side chain; pKa—the negative logarithm of Ka (Ka—acid dissociation constant).

Glutamate form
Net charge	+1		0		−1		−2
Ion name	mono-cation		isoelectric		mono-anion		di-anion
pH	under 2		2–4		4–9 (physiological condition 7.4)		above 9
pKa value		pK1 ~ 2.19	isoelectric point 3.22	pKR ~ 4.25		pK2 ~ 9.67
Dissociation	lack of dissociation	dissociation of H+ from the COOH group at carbon α		dissociation of H+ from the COOH group at side chain (R)		dissociation of H+ from the NH3+ group

. The molecular weight of glutamic acid is 147.13 g/mol [16]. The glutamic acid molecule is approximately 8 Å long and 3.5 Å wide [17]. It is in the form of white crystals or a crystalline powder, sparingly soluble in water (8.6 g/L at 25 °C) and practically insoluble in ethanol or ether [16]. The substance is characterised as odourless and sour in taste, described as “umami” (glutamate-like) [16]. Glutamate in monosodium glutamate (MSG) (Figure 1) appears as a white or off-white crystalline powder with a slight pep-tone-like odour. Freely soluble in water, MSG is practically insoluble in oil or organic solvents [16]. Glutamate is a molecule with a clearly hydrophilic character and very low lipophilicity. Its relatively good hydrophilicity is due to the presence of two carboxyl groups (–COO⁻) and one amino group (–NH₃⁺) at a physiological pH of 7.4 (Table 1). These polar groups attract water molecules, and MSG dissolves particularly well in water. At physiological pH, glutamic acid exists as glutamate, i.e., in its ionic form, facilitating its passage through amino acid transporters. However, the very low lipophilicity of glutamate means that it cannot passively cross lipid membranes (e.g., cell membranes or the blood–brain barrier; BBB) and requires active transport. Due to its functional structure and physical and chemical properties, glutamate is one of the most abundant and significant amino acids in organisms [4].

2.2. Glutamates

Glutamate/glutamic acid (E620) is known in several salt forms, such as MSG (E621), monopotassium glutamate (E622), calcium glutamate (E623), monoammonium glutamate (E624), and magnesium glutamate (E625). Glutamic acid and its salts (E620–625), commonly referred to as glutamates, used as flavour enhancers in food, are recognised as safe for use in food [20].

According to the Joint Expert Committee on Food Additives (JECFA) of the Food and Agriculture Organisation (FAO) and the World Health Organisation (WHO), the U.S. Food and Drug Administration (FDA), and the European Food Safety Association (EFSA), the addition of glutamates to foods is “generally recognized as safe” (GRAS) [21], with no evidence of adverse effects at lower doses (normal human dietary consumption of up to 1 g/day; ~14 mg/kg of body weight/day; for a 70 kg adult) [22,23,24]. The acceptable daily intake for all six of these food additives (E620–625) has been assessed as 30 mg/kg body weight per day [25]. However, sensitive individuals who consume more than 30 mg/kg of body weight [26] of MSG without food may experience some mild symptoms, such as headache, numbness, flushing, tingling, palpitations, and drowsiness, as reported by the Federation of American Societies for Experimental Biology (FASEB). It has been calculated that the average adult consumes ~13 g of glutamate from that which naturally occurs as protein in food each day and ~0.55 g of externally added MSG [27].

3. Glutamate Content and Bioavailability

Glutamic acid is found mainly as a structural component of peptides and proteins in plant and animal organisms, but it is also present in free form in blood, extracellular fluid, vascular sap of plants, and as a free substrate of cellular metabolism. Animal protein can contain from 11 to 22% glutamate by weight, while plant protein can contain up to 40% [4,5]. On average, 100 g of protein provides 4 to 12 g of glutamate. Plant proteins contain slightly more glutamate than animal proteins, with the highest glutamate content found in gliadin (45.7 g of glutamate per 100 g of protein) and α-casein (16.5 g of glutamate per 100 g of protein) [3,24]. Glutamate is ubiquitous in plant- and animal-derived foods, occurring in three forms: protein-bound, naturally occurring free form, and free form added as an additive [2]. It is highly metabolized and used as an energy source in the visceral region; therefore, its presence in food does not directly affect its concentration in the blood [2]. This situation is maintained by enterocytes, i.e., the epithelial cells that line the mucosa of the small intestine. They act as a physiological and anatomical barrier between the intestinal lumen and the blood circulation. Enterocytes participate in maintaining the selective permeability of the intestines. The glutamate concentration in the blood of healthy adults ranges from approximately 40 to 60 μM [28,29]. In the extracellular fluid of the brain, the concentration is approximately 1–10 μM. This is about 50 μM lower than in the blood due to the presence of the BBB. This very low concentration of glutamate in the brain is the basis of its signalling significance, and exceeding these values leads to excitotoxicity, which is the primary cause of many diseases of the nervous system [28]. The glutamate concentration in astrocytes and neurons is approximately 10–100 mM [28].

As shown in

Table 2. Content of free glutamate in plant- and animal-derived products [1,24,30,31].

Source	Free Glutamate Content (mg/100g)	Reference
plants
tomatoes (fresh)	140–246	[1,24]
peas	106–200	[1,30]
corn	106–130	[1,30]
spinach	39–48	[1]
carrots	33	[30]
green peppers	32	[30]
potatoes	10–180	[1,24,30]
plant-derived products
fruits	5–18	[1]
soy sauce (depending on the country)	412–1264	[1]
fermented beans (depending on the region) region)	136–1700	[1]
red algae (Porphyra) dried form	1378	[1]
meat
beef	10–33	[1,31]
pork	9–23	[1,31]
chicken	22–44	[1,31]
duck	69	[30]
mackerel	36	[30]
salmon	20	[30]
animal-derived products
milk	2–22	[1,30,31]
cheese (Ementaler-Parmesan)	308–1200	[1,24,30]
seafood
scallop	140	[1]
snow crab	19	[1]
Alaskan king crab	72	[1]
white shrimp	20	[1]
fish sauce (depending on the country)	727–1383	[1]

, glutamic acid is present in many plant- and animal-derived foods in its free form [1,24,30,31]. The FDA states that natural MSG occurs in hydrolysed vegetable protein, protein isolate, autolysed or hydrolysed yeast, yeast or soy extracts, tomatoes, and cheeses [32]. It is worth noting that the level of free glutamate is much higher in fermented products (e.g., soy sauce, mature cheeses) due to enzymatic processes that break down proteins. Ripening, fermenting, and drying plant-, animal-, and seafood-derived products significantly increases free glutamate, thus enhancing their taste sensation. Free glutamate is responsible for the characteristic “umami” taste that gives food a stronger taste sensation [1,24,30,31]. Additionally, MSG is a flavouring agent used in the food industry to impart a meat-like flavour [25].

In plant organisms, glutamate is produced through the assimilation of inorganic nitrogen from the soil by root cells in a process known as de novo synthesis. It then serves as the primary substrate for the synthesis of other amino acids and nitrogen compounds. Plants can also absorb free glutamate from the soil [33]. In animals, it can be synthesised de novo (in cells of the nervous system) or taken up as a component of food, with the consumption of glutamate taking place in the small intestine. Glutamate taken with food reaches the intestine, where it acts as a source of energy for intestinal cells (enterocytes), regulates intestinal hormones (cholecystokinin—CCK, glucagon-like peptide—1GLP-1), and affects the feeling of satiety [34,35]. The vast majority of dietary glutamate is used locally in the intestine and does not enter the bloodstream or general circulation [4,13].

Intestinal Microbiota as a Source of Glutamate

Intestinal microbiota are an additional source of glutamate in animal organisms [23,36,37]. Bacteria belonging to the Lactobacillus and Bifidobacterium groups synthesise glutamate in the intestinal lumen (and also γ-aminobutyric acid, GABA, through the decarboxylation of glutamate by glutamate decarboxylase (GAD)) [23,38]. The action of glutamate is both local and systemic [36,37]. Intestinal microbiota also have therapeutic potential for neurological and neurodegenerative diseases [39,40].

4. Glutamate—Mechanism of Action

Glutamate is involved in many metabolic processes, playing a major role in nitrogen metabolism, serving as a nutrient, an energy-providing substrate, a structural determinant, and an excitatory molecule [4,13]. As shown in Figure 2, glutamate can act in three main ways within the plant and animal body: structural, metabolic, and signalling. Firstly, glutamate is a structural component of peptides and proteins, contributing to their specific structure. Secondly, it participates in metabolic processes as a substrate and product of many metabolic pathways, as well as being a precursor of various chemicals. This includes its crucial role in interactions between carbon and nitrogen metabolism. Glutamate links nitrogen metabolism (via ammonium assimilation through the GS/GOGAT cycle) with carbon metabolism (via the use of α-ketoglutarate from the Krebs cycle, also known as the tricarboxylic acid cycle or citric acid cycle). It serves as a key amino donor for biosynthetic processes, integrating nitrogen and carbon fluxes (Figure 3). Thirdly, glutamate is a signalling molecule that functions as an agonist of ionotropic and metabotropic receptors, which are found in the neuronal and extra-neuronal (mainly visceral) areas.

5. Glutamate Receptors

In animals, glutamate receptors are divided into two major classes: ionotropic and metabotropic receptors (iGluRs and mGluRs, respectively) [41,42]. Both classes play a key role in neurotransmission and, in the context of the gastrointestinal tract, in satiety signalling and the regulation of visceral function. Ionotropic glutamate receptors are ion channels that are opened by glutamate. They are responsible for the rapid excitation of neurons. The main types are N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate (KA), and delta receptors [41,42,43]. Metabotropic glutamate receptors are G protein-coupled receptors that act more slowly than iGluRs [41,42]. Based on signal transduction pathways and pharmacological profiles, the eight types of mGluRs (mGluR1-mGluR8) have been divided into three groups in the CNS [44]. Group I mGluRs (mGluR1 and mGluR5) are stimulatory and are associated with the activation of phospholipase C and the production of secondary messengers. Group II (mGluR2 and mGluR3) and group III (mGluR4 and mGluRs6-8) are inhibitory and negatively coupled to adenylyl cyclase [44]. The modulation of mGluRs is promising in the treatment of several CNS diseases, with the potential for fewer side effects compared to iGluRs [44]. Glutamate also functions as a signaling molecule in the enteric nervous system (ENS) [23]. Multiple mGluRs have been found in the ENS. The mGluR4 and GluR1 receptor types are found in the stomach and intestine [23]. The analysis of group III mGluRs expression reveals that mGlu4, mGlu6, mGlu7, and mGlu8 receptors are present not only in the brain but also throughout the gastrointestinal tract. There, they participate in various neural functions and digestive processes [23].

The third class comprises the “umami” taste receptors T1R1/T1R3 (taste receptor type 1 member 1). Although they are not formally glutamate receptors in the classical sense, T1R1/T1R3 respond to glutamate, signalling the “umami” taste. They are located on the taste buds [45,46]. In addition to regulating cognitive functions through neurotransmission, glutamate receptors are also involved in regulating satiety and digestive processes. Glutamate in the stomach activates taste and metabotropic receptors, initiating the secretion of satiety hormones and transmitting signals via the vagus nerve to the brain. This leads to a reduction in appetite.

In plants, the glutamate receptor is known as the glutamate receptor-like channel (GLRs) and shares structural and functional similarities with iGluRs found in animals [33,47].

6. Glutamate Transporters

Due to its molecular size, negative electrical charge, and lipophobic properties, glutamate does not pass through cell membranes. Its transport requires special transmembrane transporters. These transporters are crucial for regulating glutamate homeostasis in both animals and plants. In animals, two main types are distinguished: vesicular glutamate transporters (VGLUTs) and excitatory amino acid transporters, EAATs [48]. In plants, glutamate cotransport is observed [49,50,51].

In the nervous system of animals, glutamate is produced in the cytoplasm of neurons and loaded into synaptic vesicles by VGLUTs, which rely on the proton electrochemical gradient to drive uptake [48]. Following the release through exocytosis, glutamate binds to iGluRs to mediate fast excitatory neurotransmission and to mGluRs to induce slower modulatory effects on synaptic transmission. To terminate glutamate signalling and prevent the extracellular concentration from reaching excitotoxic levels, sodium-dependent, high-affinity glutamate transporters, EAATs, located on neuronal and glial plasma membranes, rapidly clear glutamate from the extracellular space, thereby preventing glutamate-induced excitotoxicity [15,48,52,53]. In humans, there are five Na⁺-dependent glutamate transporters (EAATs 1–5), which are polypeptides consisting of 500–600 amino acid residues and exhibiting 50–60% amino acid homology [48].

VGLUTs function as H⁺-anion exchangers that operate at variable stoichiometry [48,54]. VGLUTs utilize the proton electrochemical gradient across the vesicle membrane, which is established by the vacuolar-type H⁺-ATPase, as the driving force for glutamate uptake into synaptic vesicles [48]. This process is further modulated by physiological concentrations of chloride ions (1–5 mM) [48,54]. Glutamate uptake from the synaptic cleft via EAAT is electrogenic and occurs through a transport mechanism involving the simultaneous import of three sodium ions (Na⁺) and one proton (H⁺), coupled with the export of one potassium ion (K⁺) [48,55].

In plants, H⁺-coupled glutamate carriers can transport glutamate from the apoplast across the plasma membrane into the cytoplasm of mesophyll and phloem cells [49,50,51]. These cotransporters are involved in the regulation of the intracellular pH of mesophyll cells [49,50].

7. Glutamate Metabolism in Plants and Animals

7.1. Glutamate Synthesis and Catabolism in Plants and Animals

7.1.1. Glutamate Synthesis

In plants, glutamate is involved in the assimilation of inorganic nitrogen forms from the soil, serving as a primary pathway for nitrogen assimilation. The two main forms of nitrogen available in the soil are nitrate (NO₃^-) and ammonium (NH₄⁺) ions. These ions are absorbed by the plant roots from the soil. Once inside the plant, nitrate ions are reduced to ammonium ions, and nitrogen is incorporated into glutamate and glutamine (an organic nitrogen form) via the glutamine synthetase (GS) and glutamate synthase (GOGAT) cycle (GS/GOGAT cycle) (Figure 3). The carbon skeleton is supplied by α-ketoglutarate, which comes from the Krebs cycle of respiratory processes [33,56,57,58]. The GS/GOGAT cycle is the primary route to synthesise glutamine and glutamate in plants [57]. Additionally, glutamate and α-ketoglutarate are the key metabolites lying at the interface between C and N metabolism [56]. Glutamate serves as a nitrogen donor for synthesising many other amino acids and nitrogen compounds. In animals, glutamate can be synthesised in two distinct ways: from α-ketoglutarate or from other amino acids such as glutamine, arginine, proline, and histidine [13]. Glutamate is synthesised from α-ketoglutarate in the Krebs cycle by glutamate dehydrogenase (GDH) using NH₃ and NADPH [4,5,14]. Glutamic acid can also be synthesised from glutamine by glutamate synthase (GOGAT) in the presence of NADPH, when the NH₃ concentration is low and limiting [5]. The main supplier of glutamate is glutamine/glutamate metabolism, which is connected to the Krebs cycle (Figure 3) [6,59,60,61]. Glutamine/glutamate metabolism serves numerous vital functions. These include acting as substrates for protein synthesis, helping to regulate acid–base balance in the kidneys, and contributing to ureagenesis in the liver. Additionally, both molecules act as oxidative fuels for the intestine and immune cells and function as precursors for the synthesis of neurotransmitters, nucleotides, and nucleic acids, as well as glutathione [6,62].

7.1.2. Glutamate Catabolism

Glutamate catabolism involves its conversion into α-ketoglutarate, primarily through the action of glutamate dehydrogenase (GDH) and ammonia release [63]. In both plants and animals, this reaction links nitrogen metabolism to the Krebs cycle, providing energy (ATP) and carbon skeletons [2,57]. In plants, glutamate can also be catabolized via transamination reactions or through the GABA shunt, especially under stress conditions [64]. In animals, glutamate is a primary source of oxidative energy for the gut and is extensively metabolized into α-ketoglutarate during its first pass through the intestine [63]. This intermediate then enters the Krebs cycle, leading to ATP production [63]. In the liver and in the kidneys, the conversion of glutamate into α-ketoglutarate, primarily through the action of GDH, releases ammonia. This toxic ammonia enters the urea cycle, where it is converted into urea for excretion [63]. Additionally, glutamate acts as a crucial precursor for the synthesis of other amino acids, such as glutamine, alanine, and proline, as well as bioactive compounds, such as glutathione [63].

7.2. Role of Glutamate in Amino Acid and Protein Synthesis

Glutamate plays a central role in transamination reactions by transferring its amino group to α-keto acids, leading to the formation of other amino acids (Figure 4) [5,6,7,8]. Together, glutamate, glutamine, proline, histidine, arginine, and ornithine make up 25% of dietary amino acid intake. These amino acids are part of the so-called “glutamate family” and are synthesised and metabolized through conversion to or from glutamate [5,6,7,8]. As previously mentioned, glutamate is also an important component of proteins [4,5].

7.3. GABA Synthesis

Glutamate can be catabolized by glutamate decarboxylase (GAD) to GABA [56] (Figure 3 and Figure 4). In plants, GABA participates in plants’ responses to environmental stress, in the regulation of reactive oxygen species (ROS) levels, in the control of stomatal opening and closing, and in their interaction with other organisms [56,64,65,66]. In animals, GABA is the primary inhibitory neurotransmitter in the CNS, playing a key role in reducing neuronal excitability [67,68].

7.4. Chlorophyll and Heme Biosynthesis

Glutamate plays a key role in the chlorophyll biosynthesis in plants. It is the initial molecule in the synthesis of 5-aminolevulinic acid (ALA), which is the first specific porphyrin precursor in chlorophyll formation [9,10]. Recently, pathways for heme biosynthesis via glutamate have also been described in animals [69,70].

7.5. Glutamate Is a Precursor of Proline (Osmoprotection)

The conversion of glutamate into a cyclic structure results in the formation of proline. In animals, proline is an amino acid that is essential for the synthesis of collagen and connective tissue [5]. Proline plays an important role in osmoprotection in response to saline and osmotic stress in plants [11,12].

7.6. Glutamate Is a Precursor of Glutathione (Oxidoreduction Protection)

Glutathione, an extremely important tripeptide composed of three amino acids, glutamate, cysteine, and glycine (γ-glutamyl-cysteinyl-glycine) (GSH), is a major intracellular antioxidant found in virtually all tissues [5,13]. Glutamate is required for its synthesis, and glutathione protects cells from oxidative damage.

8. Glutamate-Related Signalling

8.1. Animal Signalling

8.1.1. Neuronal Transmission

Glutamate occupies a central position in metabolism, but its most important role is as a signalling molecule. It is the primary excitatory neurotransmitter in the CNS of vertebrates [13]. It is the most abundant free amino acid in the brain and serves as the primary excitatory neurotransmitter. The majority of free glutamic acid in the brain is produced locally by astrocytes and neurons from glutamine and α-ketoglutarate (an intermediate of the Krebs cycle). Glutamate acts in the CNS through two main types of receptors: iGluRs and mGluRs.

Both types of glutamate response play an essential role in synaptic plasticity, which underlies processes such as learning and memory [13]. The concentration of glutamate in the human brain is about 10-12 mM [71]. The glutamate concentration is around 1 μM in cerebrospinal fluid and 100 mM in secretory granules [72]. In addition, glutamate is a metabolic precursor of GABA. This occurs via decarboxylation of glutamate. GABA is the major inhibitory neurotransmitter in the mammalian CNS [13,14].

8.1.2. Extra-Neural Transmission

The signalling role of glutamate is revealed through its action on extra-neural cells, such as the β cells in the pancreas, taste buds, and the intestines. Glutamate is a part of a regulatory system whereby the protein ingestion stimulates the insulin secretion by pancreatic β cells, involving ion channels and the ATP/ADP ratio [13]. Additionally, glutamate plays a role in the appetite response to protein-rich foods. Through taste sensations elicited by taste bud receptors, glutamate triggers stimulation in specific areas of the brain that control appetite. These responses are fundamental to assessing the nutritional value of food [13].

Glutamate also plays a role in regulating the brain–gut axis, which is a two-way communication pathway between the CNS and the gastrointestinal tract [73]. Glutamate signalling occurs in the stomach and small intestine. Taste-like glutamate receptors and cells are located there. These receptors signal the presence of protein digestion in the gastrointestinal tract via glutamate. Both iGluRs and mGluRs have been found in the stomach, and binding to glutamate may stimulate gastric vagal afferents [13]. Recently, the role of dietary glutamate in activating the gut–brain axis and regulating energy homeostasis has been investigated [74]. Glutamate signalling by taste and gut glutamate receptors may influence multiple physiological functions, such as thermoregulation and energy homeostasis. Activation of glutamate receptors via luminal glutamate stimulates vagal afferent nerve fibres, which in turn signal to brain regions that are directly or indirectly influenced by these vagal pathways [73,74,75,76]. Together with GABA, glutamate participates in the complex mechanism of appetite regulation [77].

8.2. Plant Signalling

In addition to its roles in plant structure and metabolism, glutamate can act as a signalling molecule [33]. A glutamate receptor associated with ion flow has been identified in plants [47,78]. The ability to generate action potentials under the influence of exogenous glutamate has also been demonstrated [51,79,80]. Glutamate may play a signalling role in nitrogen nutrition and metabolism in plants [33]. Glutamate pretreatment enhanced the survival of maize seedlings under heat stress [81]. Glutamate affects root system architecture, systemic wound signalling, plant immunity, stress tolerance, and gene expression [56]. Overall, plants use glutamate, the primary metabolite, as a danger signal [56].

9. Glutamate in Food and Medicine Design

9.1. Glutamate in Food

Glutamate accounts for approximately 8–10% of the total amino acids in the human diet, either as a component of proteins or in its free form, with adult intake averaging around 10–20 g per day (143–286 mg/kg/day for a 70 kg adult) [23]. Plasma glutamate levels are not significantly affected by dietary glutamate, due to its catabolism in the gut. Although glutamate acts as a neurotransmitter in the brain, only a small amount of dietary glutamate reaches it, precisely because it is largely catabolised in the small intestine [13]. Finally, the body blocks almost all ingested glutamate/MSG from entering the bloodstream. Also, very little passes from maternal to fetal circulation through the placenta or crosses the BBB [82]. Moreover, MSG has low permeability to the BBB. However, the presence of high-affinity glutamate transporters at the luminal membrane of BBB capillaries may facilitate MSG uptake into the brain [83]. Consequently, dietary MSG appears unable to access the brain significantly. It seems that normal dietary use of MSG is not likely to affect energy intake, body weight, or fat metabolism [82].

The main products of glutamate metabolism are ornithine, glutamine, and aspartate, except for carbon dioxide production [84]. Glutamate, which is naturally present in many foods, and MSG undergo the same absorption and metabolic processes in the organism [84]. Recently, it has been emphasized that glutamate found in food is primarily a nutrient and that its salts should only be treated as food additives [2]. Although it is widely believed that glutamate may trigger asthma, migraine headaches, and Chinese Restaurant Syndrome (CRS), within 20 min of consumption [85], there is a lack of consistent clinical evidence to support this claim [1,85]. Given the enormous importance of glutamate in neurotransmission and nutrition, we considered its potential as a supplement and medicine. Glutamate itself (excluding MSG as a flavour enhancer) is not commonly used as a dietary supplement; rather, glutamine is used, as it is a precursor to glutamate [5,86].

Despite being classified as a GRAS substance, consumers’ negative perception of MSG in food appears to outweigh its benefits [87,88,89]. Systematic reviews of animal studies have shown that excessive or long-term consumption of MSG can increase the risk of cardiovascular disease, disrupt gut microbiome function, and affect renal and hepatic metabolism. MSG has also been linked to the development of glucose intolerance, obesity, hyperglycaemia, and hyperinsulinemia [90].

A total of 67 genes related to glutamate sensing and metabolism were identified in the human population [91]. Notable differences were observed between populations, not in terms of minor allele frequencies but in the two functional groups of glutamate sensing and metabolism, particularly in Latino/admixed American and Ashkenazi Jewish populations. Significant differences in the single-nucleotide polymorphisms of glutamate metabolism genes were found between African and East Asian populations, but not in glutamate-sensing genes. Therefore, glutamate-sensing and glutamate metabolism genes exhibit contrasting evolutionary patterns. Glutamate-sensing genes evolve more conservatively, indicating their functional importance [91]. Reports concerning glutamate gene polymorphism suggest that it can be responsible for differences among populations. For example, the rs2284411 T allele is significantly associated with reduced susceptibility to attention-deficit hyperactivity disorder (ADHD), particularly in the Korean population [92]. Altered functioning of the mGluR5 receptors is known to be involved in obsessive-compulsive disorder (OCD), major depressive disorder, bipolar disorder [93], and autism [43,94].

Glutamine from the diet has the potential to affect the functioning of the glutamine/glutamate cycle and glutamatergic elements and thus disorders related to the nervous system, such as depression [86,95]. Major depressive disorder is a leading contributor to global distress, disability, and suicide. According to the latest WHO report, it affects over 260 million people worldwide [86,95]. Recent advances in treatment strategies for depression that target glutamate and GABA synthesis pathways in the brain have been considered [86,95].

9.2. Glutamate and Glutamine in Clinical Studies

In the USA, products containing glutamine are used not only as food additives but also in the treatment of, e.g., conditions such as short bowel syndrome and sickle cell anaemia. Thus, the FDA categorises L-glutamine as a substance added to food for use as a flavour enhancer, flavouring agent, adjuvant, and nutrient supplement [96]. However, what is more important for ill people is its medicinal use. If a molecule appears to have a promising action profile of great medical importance, it will undergo four phases of clinical study. Phase 4 clinical trials involve studies conducted after a drug has been officially approved and made available on the market. According to a registry of clinical trials [97], there are 267 and 409 clinical studies involving the terms “glutamine” and “glutamate” as intervention/treatment, respectively (Table S1). Of the 31 phase 4 studies with the term “glutamate” (Table S2), 1 is not yet recruiting, 20 are completed, and 2 are terminated, while in the category “other” of the 8 studies, 5 are of unknown status. Out of the 24 phase 4 studies with the term “glutamine” (Table S2), 17 are completed, 3 are terminated, and 4 are of unknown status [97]. Phase 4 studies involving the term “glutamate” concern the following conditions: heart disfunctions (myocardial ischemia, heart transplantation), brain tumour, infections of the respiratory tract, dry eye disease, Parkinson’s disease, mental illnesses (depression, anxiety, schizophrenia, psychosis, Tourette syndrome, addiction to cocaine or alcohol), and varicella (Table S3). Phase 4 studies with the term “glutamine” cover topics such as critical patients, nutrition/starvation, inflammation, transplantation, neurological/brain injuries, insulin resistance/diabetes, depression, sickle cell disease, and gastrointestinal and breast cancers (Table S4). In 2004, the FDA approved L-glutamine under the NutreStore label to treat short bowel syndrome [98]. The recommended dosage is the oral application of 30 g daily in divided doses (5 g powder taken 6 times a day) for up to 16 weeks. In 2017, the FDA approved L-glutamine, registered as Endari, for the treatment of a rare disease called sickle cell anaemia. It is administered to relieve complications of pain and swelling in patients aged 5 years and over [99]. The recommended dose of L-glutamine is 10-30 g per day (based on body weight) in powder form, taken orally twice daily. Each dose should be mixed into a cold or room temperature beverage or food before ingestion. Glutamine is also being studied in the context of cancer because it is a good source of energy utilized by cancer cells [100]. Therefore, glutaminase is a promising target for developing antitumor molecules [100].

Clinical studies on MSG include its impact on appetite and energy metabolism, as well as its effects on obesity, pain symptoms, the nervous system, the taste of food, and microbiota [84]. Adding MSG, either alone or in combination with whey protein, to carrot soup had no effect on the food intake of healthy young men. However, MSG increased feelings of fullness and reduced the desire to eat. When added to protein, it decreased blood glucose and increased insulin [101]. Many studies demonstrated that MSG intake was associated with weight gain or obesity [102,103,104], whereas some reports highlight a lack of such a connection in the population of Vietnamese adults [105]. An increase in the concentration of interstitial glutamate in the masseter muscle, caused by ingesting MSG, significantly increased the intensity of spontaneous pain in patients with myofascial temporomandibular disorders (TMDs) [106]. Conversely, dietary MSG had no effect on pain in fibromyalgia patients [107]. Continuous ingestion of MSG had no significant effect on cognitive function in people with dementia before or after a 12-week dietary intervention. However, four weeks after they stopped ingesting MSG, participants showed improved cognitive function [108]. Further advanced clinical studies are needed to ensure the safety of MSG doses for people with various illnesses.

10. Unresolved Questions and Practical Applications

10.1. Unresolved Questions for Future Research

Despite the extensive study of glutamate metabolism, significant gaps in our understanding persist in both plant and animal systems. These gaps define key priorities for future research.

• Glutamate metabolic pathways: Cross-kingdom comparisons of glutamate metabolism reveal conserved metabolic pathways that are common to plants and animals. The deep biochemical pathways of glutamate synthesis and catabolism are also shared by the occurrence of α-ketoglutarate, GABA, proline, and glutathione;
• Glutamate receptors: Plant GLR receptors are somewhat similar to animal iGLU receptors. However, the specific roles and signalling mechanisms of GLR proteins in plant metabolism, stress responses, and long-distance signalling remain unclear;
• Glutamate transporters: Although there is diversity among plant transporters and animal VGLUTs, they share the use of the proton motive force. Further study is required to identify other similarities and differences;
• Glutamate non-neuronal roles in animals: While the neurotransmitter function of glutamate is well established, its metabolic roles in non-neuronal tissues (e.g., ENS and brain–gut microbiota) require further study;
• Integrated approaches needed: More integrative studies combining biochemistry, molecular biology, physiology, and ethology are needed.

10.2. Practical Applications

• Searching for pharmaceuticals: Preclinical and comparative medical studies investigating the role of glutamate metabolism and signalling pathways in the development and treatment of many important social diseases are necessary. This is especially important for diseases related to the nervous system and nutrition-associated disorders, which may be related to glutamate metabolism and signalling;
• Searching for a good diet: A good, balanced diet should take into account the latest knowledge about glutamate metabolism and sensing, especially with regard to its content in food and its function in the ENS. Generally, plant proteins are richer in glutamate (40%) than animal proteins (11–22%). This could help to determine the potential impact of consumed foods on nervous system function and mental health. We should also consider the existence of the enterocyte barrier in the intestine and the BBB in the CNS, as well as brain–gut axis communication;
• Intestine microbiome and glutamate/glutamine cycle: This provides a solid physiological and biochemical foundation for the development of neurodietetics.

11. Conclusions

Some of the functions and modes of action of glutamate are shared by both plants and animals. It plays a central role in nutrition and signalling in plants and animals. Not only is glutamate involved in feeding and metabolism, where it acts as a substrate for synthesising other amino acids, proteins, and energy production, but it also plays a role in responding to environmental stimuli as an important signalling molecule. It is involved in the processes of excitation and inhibition, as well as in the processes related to the reception of stimuli (especially taste) and the processes of learning and memory. As a food component, glutamate regulates the taste and the feeling of satiety. Based on the aforementioned data, glutamate can be considered a genuinely functional amino acid and a functional food component. Many clinical studies are investigating elements of glutamate metabolic and neuronal pathways, which may contribute to the development of new drugs in the future.