Compendium of the most significant studies with reference to properties, intake, effects.

Santana, M., Oliveira, G., Yoshida, V., Sabha, M., & Oshima-Franco, Y. (2011). Naturally occurring ingredients as potential antiaging cosmetics. Lat Am J Pharm, 30(8), 1531-1535.

Abstract. The criteria adopted for establishing whether a determined substance has potential as a cosmetic constituent are based on the present legislation of each country. In this study, natural antiaging constituents as Fomes officinalis, rice protein and glutamic acid were pharmacologically evaluated using neuromuscular preparation. These constituents induced a neuromuscular blockade, individually and also inmixture, simulating a Botox®, but not, dimethylaminoethanol-effect. The pharmacological knowledge is beneficial since the real effect of each ingredient becomes apparent, increasing the consumer’s confidence on the antiaging cosmetic.

Jara CP, de Andrade Berti B, Mendes NF, Engel DF, Zanesco AM, Pereira de Souza GF, de Medeiros Bezerra R, de Toledo Bagatin J, Maria-Engler SS, Morari J, Velander WH, Velloso LA, Araújo EP. Glutamic acid promotes hair growth in mice. Sci Rep. 2021 Jul 29;11(1):15453. doi: 10.1038/s41598-021-94816-y. 

Abstract. Glutamic acid is the main excitatory neurotransmitter acting both in the brain and in peripheral tissues. Abnormal distribution of glutamic acid receptors occurs in skin hyperproliferative conditions such as psoriasis and skin regeneration; however, the biological function of glutamic acid in the skin remains unclear. Using ex vivo, in vivo and in silico approaches, we showed that exogenous glutamic acid promotes hair growth and keratinocyte proliferation. Topical application of glutamic acid decreased the expression of genes related to apoptosis in the skin, whereas glutamic acid increased cell viability and proliferation in human keratinocyte cultures. In addition, we identified the keratinocyte glutamic acid excitotoxic concentration, providing evidence for the existence of a novel skin signalling pathway mediated by a neurotransmitter that controls keratinocyte and hair follicle proliferation. Thus, glutamic acid emerges as a component of the peripheral nervous system that acts to control cell growth in the skin. These results raise the perspective of the pharmacological and nutritional use of glutamic acid to treat skin diseases. © 2021. The Author(s).

Garattini S. Glutamic acid, twenty years later. J Nutr. 2000 Apr;130(4S Suppl):901S-9S. doi: 10.1093/jn/130.4.901S. 

Abstract. This review examines progress in understanding the physiologic functions of glutamic acid in the body since the first symposium on glutamic acid physiology and biochemistry was held at the Mario Negri Institute in Milan in 1978. The topics reviewed, although not exhaustive, include the metabolism of glutamic acid, umami taste, the role of glutamic acid as a neurotransmitter, glutamate safety and the development of new drugs resulting from the knowledge of the neurodegeneration induced by high doses of glutamic acid.

Wang M, Zhang E, Yu C, Liu D, Zhao S, Xu M, Zhao X, Yue W, Nie G. Dendrobium officinale Enzyme Changing the Structure and Behaviors of Chitosan/γ-poly(glutamic acid) Hydrogel for Potential Skin Care. Polymers (Basel). 2022 May 19;14(10):2070. doi: 10.3390/polym14102070. 

Abstract. Hydrogels have been widespreadly used in various fields. But weak toughness has limited their further applications. In this study, Dendrobium officinale enzyme (DOE) was explored to improve chitosan/γ-poly(glutamic acid) (CS/γ-PGA) hydrogel in the structure and properties. The results indicated that DOE with various sizes of ingredients can make multiple noncovalent crosslinks with the skeleton network of CS/γ-PGA, significantly changing the self-assembly of CS/γ-PGA/DOE hydrogel to form regular protuberance nanostructures, which exhibits stronger toughness and better behaviors for skin care. Particularly, 4% DOE enhanced the toughness of CS/γ-PGA/DOE hydrogel, increasing it by 116%. Meanwhile, water absorption, antioxygenation, antibacterial behavior and air permeability were increased by 39%, 97%, 27% and 52%.

Ghali N, Baker D, Brady AF, Burrows N, Cervi E, Cilliers D, Frank M, Germain DP, Hulmes DJS, Jacquemont ML, Kannu P, Lefroy H, Legrand A, Pope FM, Robertson L, Vandersteen A, von Klemperer K, Warburton R, Whiteford M, van Dijk FS. Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers-Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility. Genet Med. 2019 Sep;21(9):2081-2091. doi: 10.1038/s41436-019-0470-9. 

Abstract. Purpose: The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance. Methods: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed. Results: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS. Conclusion: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.

Dall'Asta V, Gazzola GC, Franchi-Gazzola R, Bussolati O, Longo N, Guidotti GG. Pathways of L-glutamic acid transport in cultured human fibroblasts. J Biol Chem. 1983 May 25;258(10):6371-9. 

Abstract, The transport of L-glutamic acid has been studied in skin-derived diploid human fibroblasts. Competition analysis in the presence and absence of Na+ and mathematical discrimination by nonlinear regression indicated that L-glutamic acid enters the cell by at least three transport systems: 1) a high affinity Na+-dependent system which has been found to be identical to the previously described system for anionic amino acids (Gazzola, G. C., Dall'Asta, V., Bussolati, O., Makowske, M., and Christensen, H. N. (1981) J. Biol. Chem. 256, 6054-6059) and which is provisionally designated as System X-AG; this route was shared by L-aspartic acid; 2) a low affinity Na+-dependent system resembling the ASC System for neutral amino acids (Franchi-Gazzola, R., Gazzola, G. C., Dall'Asta, V., and Guidotti, G. G. (1982) J. Biol. Chem. 257, 9582-9587); its reactivity toward L-glutamic acid was strongly inhibited by L-serine, but not by 2-(methyl-amino)isobutyric acid; and 3) a Na+-independent system similar to System XC- described in fetal human lung fibroblasts (Bannai, S., and Kitamura, E. (1980) J. Biol. Chem. 255, 2372-2376). The XC- system served for L-glutamic acid and L-cystine, the latter amino acid behaving as a potent inhibitor of L-glutamic acid uptake. Amino acid starvation did not change the uptake of L-glutamic acid by the two Na+-dependent systems, but enhanced the activity of System XC- by increasing its Vmax. L-Glutamic acid transport was also affected by the density of the culture. An increased cell density lowered the uptake of the amino acid by Systems ASC and XC- and promoted the uptake by System X-AG. All these variations were dependent upon changes in Vmax.

Nowowiejska J, Baran A, Hermanowicz JM, Sieklucka B, Krahel JA, Kiluk P, Pawlak D, Flisiak I. Fatty Acid-Binding Protein 7 (FABP-7), Glutamic Acid and Neurofilament Light Chain (NFL) as Potential Markers of Neurodegenerative Disorders in Psoriatic Patients-A Pilot Study. J Clin Med. 2022 Apr 26;11(9):2430. doi: 10.3390/jcm11092430.

Abstract. Psoriasis and neurodegenerative diseases (NDs) are important medical, social and economic issues. The possible relationship of psoriasis and NDs has not been established yet. This study involved 60 patients with plaque-type psoriasis. Serum concentrations of fatty acid-binding protein 7 (FABP-7), glutamic acid (GA) and neurofilament light chain (NFL), which have been hardly studied in psoriasis before, were measured by ELISA before and after 12 weeks of treatment with acitretin or methotrexate. The concentration of FABP-7 and NFL in patients before the treatment was significantly higher than in the controls (p < 0.01, p < 0.001, respectively). After the treatment their concentration decreased, although FABP-7 did so insignificantly. The concentration of GA did not differ significantly between patients and controls and before and after the treatment but we found its negative correlation with CRP (p < 0.05). The duration of psoriasis does not seem to directly affect the risk of neurodegeneration and the severity only in patients with worse skin condition. Elevated FABP-7 and NFL, which are present in the brain, may be considered as potential indicators of NDs development in psoriatics, although it surely requires further research. GA might correspond with neuroinflammation in psoriasis. Systemic antipsoriatic therapy could be studied in order to improve cognitive impairment through lowering NDs biomarkers in some cases.

Ma Q, Zhou D, DeLyria ES, Wen X, Lu W, Thapa P, Liu C, Li D, Bassett RL, Overwijk WW, Hwu P, Li C. Synthetic Poly(L-Glutamic Acid)-conjugated CpG Exhibits Antitumor Efficacy With Increased Retention in Tumor and Draining Lymph Nodes After Intratumoral Injection in a Mouse Model of Melanoma. J Immunother. 2017 Jan;40(1):11-20. doi: 10.1097/CJI.0000000000000145. 

Abstract. There is an urgent need for new clinically applicable drug-delivery methods to enhance accumulation of immune-activating drugs in tumors. We synthesized a poly(L-glutamic acid)-CpG ODN2216 conjugate (PG-CpG) and injected it intratumorally into C57BL/6 mice bearing subcutaneous B16-ovalbumin melanoma. PG-CpG elicited the same potent antitumoral activity as CpG with respect to reducing tumor growth and triggering antigen-specific CD8 T-cell responses in this well-established solid tumor model. Moreover, PG-CpG was retained significantly longer in both tumor and draining lymph nodes than was free CpG after intratumoral injection. Specifically, 48 hours after injection, 26.5%±16.9% of the injected PG-CpG dose versus 4.72%±2.61% of free CpG remained at the tumor, and 1.53%±1.22% of the injected PG-CpG versus 0.37%±0.33% of free CpG was retained in the draining inguinal lymph nodes. These findings indicate that PG is an effective synthetic polymeric carrier for delivery of immunostimulatory agents to tumors and lymph nodes.

Glutamic acid is an amino acid that occurs naturally and in the human body and is in close correlation with glutamine which regulates the balance of the skin. It is an α-amino acid.

Amino acids play a key metabolic function in the human body and are constituents of proteins. 

As food additives they perform different functions: preservatives, flavour enhancers, food supplements and more.

Amino acids together with their salts are used in cosmetics as conditioning agents for both hair and skin (e.g. as moisturisers and other similar functions). Moisturisers are different in nature: the best are the natural ones that exploit the mechanism of integration between the ingredient and the skin by moisturising the horny hydrolipid film, i.e. the thin protective layer that covers the epidermis protecting it from harmful external microbes, keeping the skin moisturised and supple and its pH or acidity value between 4 and 6.  Then there are the occlusive moisturisers, usually derived from petroleum (Paraffinum, Paraffinum liquidum and others), but also triglycerides, lanolin oil, natural or synthetic waxes, fatty acid esters and others that create an artificial occlusive layer on the stratum corneum of the skin with the advantage of accelerating the protective process but with the disadvantage of preventing the skin's natural transpiration.

α-amino acids that have similar physical structures undergo similar changes with regard to solubility in water/ethanol mixtures, and technologies to separate α-amino acids from industrial residues, which may not even be innocuous, are constantly being improved. However, many data on the solubility in water-ethanol and ethanol of some α-amino acids are contradictory or even lacking, and the effects of ethanol on the solubility of amino acids may be different. Overall, the scientific literature considers that α-amino acids do not pose significant problems for human health when taken orally, except in people with certain genetic diseases.

Industrially it appears in the form of a white powder.

What it is used for and where

In the plant world, it regulates the growth of plants (1).

Food

Ingredient included in the list of European food additives as E620 with the function of flavour enhancer, in practice to improve flavour.

Food safety: amino acid α generally considered safe.

Animal feeding

In animal nutrition, used as a food supplement, it improves the quality of meat (2).

Some glutamic acid derivatives have shown efficacy in blood and brain circulation in animals undergoing stress (3).

Medicine

The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. It also possesses anticancer activity. So the transportation and metabolism of glutamine are also discussed for better understanding the role of glutamic acid. Glutamates are the carboxylate anions and salts of glutamic acid. Here the roles of various enzymes required for the metabolism of glutamates are also discussed (4).

Animal studies have shown that glutamine supplementation may decrease colon carcinogenesis, but any relation with glutamine or its precursors has not been studied in humans. The primary aim of this study was to assess whether dietary glutamic acid intake was associated with colorectal cancer (CRC) risk in community-dwelling adults. A secondary aim was to evaluate whether the association could be modified by the body mass index (BMI). Our data suggest that baseline dietary glutamic acid intake is associated with a lower risk of developing CRC, but this association may be mainly present in nonoverweight subjects (5).

Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed (6).

This study presents an efficient lead ion removal from water by a novel chitosan gel-based sorbent modified with glutamic acid ionic liquid (7).

Cosmetics

 Moisturising and adsorbing. In clinical studies it showed water retention capacity and inhibited the growth of certain bacteria. It is biodegradable, water-soluble and non-toxic to humans and the environment.

Antistatic agent. Static electricity build-up has a direct influence on products and causes electrostatic adsorption. The antistatic ingredient reduces static build-up and surface resistivity on the surface of the skin and hair.

Hair conditioning agent. A significant number of ingredients with specific and targeted purposes may co-exist in hair shampoo formulations: cleansers, conditioners, thickeners, matting agents, sequestering agents, fragrances, preservatives, special additives. However, the indispensable ingredients are the cleansers and conditioners as they are necessary and sufficient for hair cleansing and manageability. The others act as commercial and non-essential auxiliaries such as: appearance, fragrance, colouring, etc. Hair conditioning agents have the task of increasing shine, manageability and volume, and reducing static electricity, especially after treatments such as colouring, ironing, waving, drying and brushing. They are, in practice, dispersants that may contain cationic surfactants, thickeners, emollients, polymers. The typology of hair conditioning agents includes: intensive conditioners, instant conditioners, thickening conditioners, drying conditioners. They can perform their task generally accompanied by other different ingredients.

Humectant. Hygroscopic compound used to minimise water loss in the skin and to prevent it from drying out by facilitating faster and greater absorption of water into the stratum corneum of the epidermis.  The epidermis is the most superficial of the three layers that make up human skin (epidermis, dermis and hypodermis) and is the layer that maintains hydration in all three layers. In turn, the epidermis is composed of five layers: horny, the most superficial, granular, spinous, shiny, and basal. Humectants have the ability to retain the water they attract from the air in the stratum corneum and have the function of moisturising the skin. They are best used before emollients, which are oil-based.

The most relevant studies on this ingredient have been selected with a summary of their contents:

Glutamic acid studies

• Molecular Formula :C₅H₉NO₄
• Molecular  Weight   147.13
• CAS  56-86-0   6899-05-4
• EC number    200-293-7

Synonyms:  (2S)-2-Aminopentanedioic acid; L-Glutaminic acid; Glutaminol; Glutamicol; Acidum glutamicum; Poly-L-glutamate

References_________________________________________________________________________

(1) Zhang L, Yang X, Gao D, Wang L, Li J, Wei Z, Shi Y. Effects of poly-γ-glutamic acid (γ-PGA) on plant growth and its distribution in a controlled plant-soil system. Sci Rep. 2017 Jul 20;7(1):6090. doi: 10.1038/s41598-017-06248-2.

(2) Hu CJ, Jiang QY, Zhang T, Yin YL, Li FN, Deng JP, Wu GY, Kong XF. Dietary supplementation with arginine and glutamic acid modifies growth performance, carcass traits, and meat quality in growing-finishing pigs. J Anim Sci. 2017 Jun;95(6):2680-2689. doi: 10.2527/jas.2017.1388.

(3) Perfilova VN, Popova TA, Prokofiev II, Mokrousov IS, Ostrovskii OV, Tyurenkov IN. Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade. Bull Exp Biol Med. 2017 Jun;163(2):226-229. doi: 10.1007/s10517-017-3772-4. 

(4) Dutta S, Ray S, Nagarajan K. Glutamic acid as anticancer agent: An overview. Saudi Pharm J. 2013 Oct;21(4):337-43. doi: 10.1016/j.jsps.2012.12.007. Review.

(5) Viana Veloso GG, Franco OH, Ruiter R, de Keyser CE, Hofman A, Stricker BC, Kiefte-de Jong JC. Baseline dietary glutamic acid intake and the risk of colorectal cancer: The Rotterdam study. Cancer. 2016 Mar 15;122(6):899-907. doi: 10.1002/cncr.29862. Epub 2015 Dec 30.

(6) Ali I, Wani WA, Haque A, Saleem K. Glutamic acid and its derivatives: candidates for rational design of anticancer drugs. Future Med Chem. 2013 May;5(8):961-78. doi: 10.4155/fmc.13.62.

(7) Ren H, Li B, Neckenig M, Wu D, Li Y, Ma Y, Li X, Zhang N. Efficient lead ion removal from water by a novel chitosan gel-based sorbent modified with glutamic acid ionic liquid. Carbohydr Polym. 2019 Mar 1;207:737-746. doi: 10.1016/j.carbpol.2018.12.043.