Tyrosine Amino Acids: Properties, Function, Benefits, and Sources

What is tyrosine?

Living systems rely on L-tyrosine (Tyr), also known as tyrosine or 4-hydroxyphenylalanine, one of the twenty standard amino acids and one of the non-essential ones utilized by cells in protein synthesis. One example of a hydrophobic amino acid is the casein protein found in cheese; the name tyrosine comes from the Greek word for cheese, tyrós. Additionally, it has a higher water-repellent affinity than phenylalanine. Proteins involved in signal transduction mechanisms rely on tyrosine for its specific function, which is made possible by the phenol functionality. They are responsible for receiving the phosphate group that is delivered by protein kinases. The activity of the target protein can be altered by phosphorylating its hydroxyl group. The role of the tyrosine residue in photosynthesis is to reduce oxidized chlorophyll by donating an electron. The process involves the reduction of the hydrogen radical, which is created when the phenolic OH-group loses an atom of hydrogen, in photosystem II by use of the four core manganese clusters. The RDA for tyrosine and phenylalanine is 42 milligrams per kilogram of body weight. As an illustration, 2.31 g of (tyrosine+phenylalanine) is required for a 70 kg individual. You can get tyrosine in high-protein foods like yogurt, poultry, fish, milk, avocados, bananas, etc., however it can also be made in the body from phenylalanine. As an illustration, tyrosine is abundant in egg whites (250 mg/egg), while it is present in smaller amounts in lean beef, lamb, chicken, fish, and pig (approximately 1 g/85 g serving). Precursor tyrosine raises plasma concentrations of neurotransmitters including dopamine and norepinephrine; nonetheless, it has little impact on mood in healthy individuals. Since tyrosine lowers levels of the stress hormone, it could be useful in situations where you're under a lot of pressure, are chilly, exhausted (in mice), have to work for long hours, or don't get enough sleep.

Tyrosine structure

Tyrosine is an amino acid characterized by a typical backbone of an α-amino group (–NH₂), an α-carboxyl group (–COOH), and an α-carbon. The distinctive side chain features a phenolic group (–C₆H₄OH), comprising a benzene ring linked to a hydroxyl group, rendering tyrosine polar and enabling hydrogen bond formation. This side chain participates in phosphorylation and is crucial for enzyme control and signal transduction. Tyrosine is essential for the synthesis of dopamine, serotonin, and various other neurotransmitters. The compound has the chemical formula C₉H₁₁NO₃ and participates in multiple biological roles, such as the control of protein activity and cellular communication.

Structure of amino acids. (Ha C E., et al., 2011)

Tyrosine pKa

Tyrosine possesses three critical pKa values: the α-carboxyl group exhibits a pKa of 2.2, the α-amino group has a pKa of 9.1, and the phenolic hydroxyl group on the side chain displays a pKa of 10.1. At physiological pH (~7.4), tyrosine is present in a zwitterionic state, characterized by a deprotonated carboxyl group (–COO^–) and a protonated amino group (–NH₃⁺). The phenolic hydroxyl group is protonated (–OH) at this pH. The hydroxyl group of tyrosine can engage in hydrogen bonding and is also implicated in phosphorylation processes, rendering it significant for enzyme activity and cellular signaling. This aromatic amino acid's phenolic hydroxyl group is unionized at physiological pH due to its weakly acidic pKα of approximately 10. The hydroxyl group of phenols in enzymes can establish hydrogen bonds with nitrogen and oxygen atoms in some cases. Some oncogene products, like as gastrin and cholecystokinin, sulfate the phenolic hydroxyl group of tyrosine residues in protein, while others, like the tyrosine specific protein kinase, catalyze a reaction that phosphorylates the group.

Tyrosine solubility

The isothermal dissolution equilibrium method was used experimentally within the temperature range of 283.15 to 323.15 K under atmospheric pressure (101.1 kPa) to determine the equilibrium solubility of l-tyrosine in solvent mixtures of methanol (1) + water (2), ethanol (1) + water (2), n-propanol (1) + water (2), and dimethyl sulfoxide (DMSO, 1) + water (2). For the same temperature and mass fraction of methanol, the solubility of L-tyrosine in mole fraction was highest in the (DMSO + water) mixture, compared to ethanol, n-propanol, or DMSO alone. Interactions between solutes and solvents, as well as between solvents and each other, were used to explain the solvent effect. Using the inverse Kirkwood-Buff integrals approach, the thermodynamic solution properties were used to obtain the favored solvation parameters. In mixtures with extremely varied compositions, the preference solvation values (δx1,3) for methanol, ethanol, n-propanol, or DMSO were negative. This suggested that water was the solvent of choice for l-tyrosine. For the DMSO (1) + water (2) combinations, l-tyrosine was not preferentially solvated by either water or DMSO. The examined solutions' favored solvation magnitudes are relatively unaffected by temperature. One possible explanation for the increased solvation by water is that the solvent interacts with the Lewis basic groups of the l-tyrosine in a more acidic manner. The mathematical representation of the medications' solubility was also done using the Jouyban-Acree model, the van't Hoff-Jouyban-Acree model, and the Apelblat-Jouyban-Acree model. For the correlation studies, the average relative deviations were less than 1.47%. Thermodynamic study of the corresponding dissolving and particular solvation processes is made possible by the solubility data offered in this work, which also adds to the growing body of physicochemical information about the solubility of pharmaceuticals in binary solvent mixtures.

Solubility of l-tyrosine in solvent mixtures. (He Q., et al., 2018)

Tyrosine amino acids at Creative Peptides

Tyrosine phosphorylation

An essential aspect of cellular communication, tyrosine phosphorylation is a type of posttranslational alteration that is subject to strict regulation. In the human genome, there are two categories of proteins called substrate proteins and the enzyme protein tyrosine kinases facilitates the transfer of γ-phosphate of ATP to the tyrosine residues of the former.

The emergence of fast DNA sequencing and polymerase chain reaction (PCR) expedited the fast expansion of the number of unique tyrosine kinases after the 1979 finding that Src is a tyrosine kinase. Similar to the catalytic domains of serine/threonine kinases, the sequence of all the cloned tyrosine kinases had a number of conserved motifs that were later found to play an important role in catalysis. Just as quickly, our knowledge of tyrosine phosphorylation's role in the cell was expanding. Tyrosine phosphorylation is involved in growth factor signaling, proliferation, and, consequently, oncogenesis by hijacking pathways for growth factor tyrosine phosphorylation, as suggested by the early finding that ligand binding induced a rapid increase in EGF and PDGF receptor tyrosine kinase (RTK) autophosphorylation. The identification that activated RTKs' phosphotyrosine (P.Tyr) residues are recognized by a phosphodependent-binding domain, the SH2 domain, in a way dictated by the primary sequence of the amino acids immediately downstream of the P.Tyr was a major step in understanding how RTKs initiate intracellular signaling. Downstream signaling cannot begin or progress without SH2 domain protein binding to plasma membrane autophosphorylated RTKs. Proteins with an SH2 domain can serve several purposes. These include acting as adaptors to bring in other signaling proteins, as membrane-interacting enzymes like phospholipases, as signal-relaying cytoplasmic tyrosine kinases, as E3 ubiquitin ligases, and as transcription factors. It was also discovered that proteins with a second sort of P.Tyr-binding domain, PTB, play a role in RTK signaling. Afterwards, more P.Tyr-binding domains were discovered, such as a portion of catalytically inactive protein phosphatases of the PTP and DSP families, the C2 domain of PKCδ, and pyruvate kinase M2.

Tyrosine kinase can be categorized into two groups. A receptor tyrosine kinase is a type I transmembrane protein with a catalytic domain located in the cytoplasm, one transmembrane domain, and an extracellular domain at the N-terminus that can bind activating ligands. The majority of nonreceptor tyrosine kinases are soluble intracellular proteins without a transmembrane domain. However, there is a subset that can bind to membranes through a posttranslational modification that targets membranes, like an N-terminal myristoyl group. This subset can then serve as the catalytic subunit for receptors that do not have their own catalytic domain. Of the 90 tyrosine kinases found in the human genome, 58 are RTKs. The majority of these proteins are activated when their extracellular domain binds to particular protein ligands, which can include both membrane-anchored proteins and non-proteins like cytokines and growth factors. The process begins with ligand binding, which triggers RTK oligomerization. Then, the cytoplasmic catalytic domain is activated through C-tail phosphorylation and transphosphorylation of Tyr in the activation loop or juxtamembrane domain. Tyrosine phosphorylation of recruited cytoplasmic proteins occurs, which allows extracellular signals to be transduced across the plasma membrane. Similar mechanisms are used to activate nonreceptor tyrosine kinases, which are catalytic subunits of receptors devoid of a kinase domain. This activation occurs when the attached receptors undergo conformational remodeling or ligand-induced oligomerization.

Phosphorylation of receptor proteins or their associated subunits determines the signaling specificity downstream of each receptor tyrosine kinase system. This, in turn, recruits a variety of SH2/PTB proteins that are expressed in the cell's repertoire. Both nuclear and cytoplasmic responses are a part of the specific cellular responses that emerge from the integration of the constellation of signaling pathways activated downstream of the various SH2/PTB proteins. The PI-3 kinase pathway and the Ras/ERK MAP kinase cascade are two important signaling pathways that are triggered by RTKs. The first MAP kinase cascade was found biochemically as a set of actions triggered by EGF or insulin upon activation of their respective receptor RTKs, and the identification of PI-3 kinases came from the analysis of a lipid kinase activity connected with tyrosine kinases.

Beyond its involvement in growth factor receptor signaling, tyrosine phosphorylation has been found to play a role in a wide variety of other cellular processes. These include, but are not limited to, cell adhesion via integrin signaling, metabolic regulation through the insulin RTK, cell cycle control through inhibitory tyrosine phosphorylation of CDKs, transcriptional activation through tyrosine phosphorylation of latent cytoplasmic STAT family transcription factors, neural transmission, and even aging via the IGF-1R. During the process of metazoan development and cellular differentiation, tyrosine kinases are essential. From an evolutionary standpoint, it is reasonable to assume that all metazoans contain tyrosine kinases, as they are involved in cell-cell signaling and transmembrane signal transduction, which are essential for the formation of multicellular organisms.

Timeline of some important discoveries in tyrosine phosphorylation. (Hunter T., 2009)

Tyrosine metabolism

It is the phenylalanine-hydroxylase (PAH) enzyme that hydroxylates phenylalanine in living organisms, resulting in tyrosine. Tyrosine biosynthesis is extremely important because it is one of the twenty amino acids that can be used to make proteins. Among the many things that tyrosine is involved in making are neurotransmitters, thyroid hormones, melanins, catecholamines (dopamine, adrenaline, norepinephrine), and neurotransmitters. The non-essential amino acid tyrosine can be obtained through two pathways: the dietary intake of phenylalanine and the hydroxylation of phenylalanine. Melanin, thyroxine, and DOPA are all built from it, and it also forms an essential component of proteins. Protein phosphorylation and sulfation, two post-translational changes of tyrosine residues, play critical roles in signal transduction and protein interaction modulation. Because fumarate and acetoacetate are formed during tyrosine's breakdown, which mainly occurs in the liver cytosol, the compound is glucogenic and ketogenic. Cytosolic tyrosine aminotransferase converts tyrosine to 4-hydroxyphenylpyruvate, the first product of tyrosine catabolism. Under typical circumstances, mitochondrial aspartate aminotransferase plays a limited role in tyrosine transamination, but it is capable of doing so in various organs, including the liver. After being converted to succinylacetoacetate, fumarylacetoacetate, and maleylacetoacetate, the penultimate intermediates of tyrosine catabolism are decarboxylated to succinylacetone. This second compound inhibits 5-aminolevulinic acid dehydratase, an enzyme involved in heme biosynthesis, more effectively than any other known compound.

The tyrosine metabolic pathway. (Chakrapani A., et al., 2022)

Metabolic pathways of tyrosine oxidation and their biological role. (Buglak A A., et al., 2022)

Tyrosine function

The phenylalanine hydroxylase enzyme converts the non-essential amino acid phenylalanine into the glucogenic and ketogenic amino acid tyrosine. The neurotransmitters norepinephrine and dopamine are derived from tyrosine. An analysis of human plasma metabolomics revealed that glutamine and tyrosine levels rose with age, whereas histidine, threonine, tryptophan, leucine, and serine levels fell. People with hypertension and rats both showed a reduction in blood pressure after taking tyrosine supplements. A higher dietary tyrosine level was associated with better cognitive performance in a single adult research. High dietary tyrosine levels reduced cognitive performance in older persons, while supplementation of intermediate tyrosine levels had no effect, according to another study. Supplementing with tyrosine may only improve cognitive performance under stressful situations, when levels of dopamine or norepinephrine are low, according to a recent review. Supplemental tyrosine does not appear to mitigate the negative effects of stress on mental or physical performance, according to the available evidence. Supportive evidence suggests that tyrosine supplementation may improve thermoregulatory function by increasing the vasoconstriction response to body cooling in older persons. Research has demonstrated that tyrosine supplementation can improve dopaminergic neurotransmission in individuals with Parkinson's disease. Having said that, the risk of type 2 diabetes is enhanced just as much by elevated plasma tyrosine levels as by elevated levels of any of the three BCAAs individually. Adding tyrosine to C. elegans lengthened life expectancy somewhat at the 1 mM dose, but marginally at the two higher doses.

What is Tyrosine used for?

(1) Improve exercise capacity

Prolonged exercise tolerance in hot weather is enhanced by an increase in brain dopamine availability. Whether or if taking an amino acid supplement boosts heat exercise ability is debatable. The eight male volunteers, who were in good health and had the following measurements: mean age 32 ± 11 years, body mass 75.3 ± 8.1 kg, and peak oxygen uptake (VO2peak) 3.5 ± 0.3 L/min, participated in a randomized crossover design and completed two sets of exercises at least seven days apart. In a double-blind fashion, one hour before to cycling to exhaustion at a constant exercise intensity equal to 68 ± 5% V˙O2peak in 30°C and 60% relative humidity, subjects either drank 500 mL of a sugar-free drink with a flavor (PLA) or the same drink with 150 mg kg body mass−1 tyrosine (TYR). TYR had a 2.9-fold rise in pre-exercise plasma tyrosine:large neutral amino acids (P < 0.01), but PLA did not show any change (P > 0.05). In the TYR group, subjects cycled for a longer duration than in the PLA group (800.3 ± 19.7 min vs. 69.2 ± 14.0 min; P < 0.01). Despite TYR exercising for a longer duration, PLA and TYR had comparable core, mean weighted skin, heart rate, subjective exertion, and thermal feeling ratings both during and after exercise (P > 0.05). The results demonstrate that moderately trained participants who took acute tyrosine supplements had an improved ability to withstand heat. In addition, this study provides the first evidence that dietary tyrosine, a precursor to dopamine, can affect perceived heat tolerance during extended submaximal constant-load exercise.

Ratings of thermal sensation and perceived exertion. (Tumilty L., et al., 2011)

(2) Mitigate working memory decrements

Supplementing the food of rats with the amino acid tyrosine (TYR) stops the loss of central catecholamines that happens during stressful situations. Animals' stress-related behavioral alterations raise the possibility that TYR may influence central catecholamines and cognition in humans under stress. The purpose of this research was to find out whether people's cognitive abilities are negatively affected by prolonged exposure to cold and whether taking TYR supplements will help. Through the use of a double-blind, within-subjects design, 19 volunteers participated in three separate test sessions on separate days. The temperatures of the control and placebo groups were 35 °C, while the temperature of the TYR group was approximately 10 °C. At the beginning of each session, participants took a 150 mg/kg TYR or placebo snack bar, for a total of 300 mg/kg TYR, and then submerged themselves in water for 90 minutes. We measured cortisol in the saliva, mood, and cognitive function. Cortisol levels were higher in chilly conditions (p<0.01). In chilly conditions, participants' accuracy dropped on a Match-to-Sample memory test (p <0.05), while their reaction time (RT) and the number of mistakes on a choice RT test both rose (p <0.01). In addition, the cold was associated with an increase in self-reported stress (p <0.01), despair (p <0.05), and bewilderment (p <0.01). The results showed that the volunteers processed information more quickly and accurately after consuming TYR, as the number of correct replies on a Match-to-Sample memory test increased (p <0.05) and the study time for the sample decreased (p <0.05). Lastly, a consistent trend was observed throughout immersions for TYR and thermoneutral settings but cold/placebo conditions did not (p <0.05), according to RT on the memory measure. Supplementation with TYR mitigates working memory declines brought on by cold exposure, according to one study.

Reaction time for hits during the match-to-sample task. (Mahoney C R., et al., 2007)

(3) Ameliorate murine aGVHD

Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of several immune-mediated illnesses that can affect a host's susceptibility, and digestive microbial communities and their metabolic components play a crucial role in maintaining immune homeostasis. Due to the complexity of the gastrointestinal environment, little is known about the functional relationships between the microbiome and metabolome in aGVHD. The relative abundance of Clostridium XI, Clostridium XIVa, and Enterococcus increased, but Lachnospiraceae_unclassified decreased significantly in the aGVHD group. At the same time, aGVHD mice's guts had a reduced tyrosine content. In the presence of aGVHD, the correlation analysis showed that tyrosine-related metabolites were negatively associated with Clostridium XIVa, and that Blautia and Enterococcus did the same. Various tyrosine diets were given to transplanted mice in addition to studying tyrosine's significance and function. The structure and makeup of the gut microbiota as well as the fecal metabolic phenotype can be altered, and overall survival can be improved by taking more tyrosine supplements. These supplements can also alleviate symptoms in the early stages of aGVHD. Furthermore, compared to the vehicle diet group, aGVHD animals deficient in tyrosine showed more severe symptoms. An underlying biomarker for the diagnosis and therapy of aGVHD, the results showed the roles and mechanisms of gut bacteria, essential metabolites, and tyrosine in the evolution of the disease.

Amelioration of aGVHD by tyrosine supplement. (Li X., et al., 2020)

FAQ

Is tyrosine polar?

Indeed, tyrosine is classified as a polar amino acid. This results from the presence of a phenolic hydroxyl group (-OH) bonded to the benzene ring in its side chain. The hydroxyl group can create hydrogen bonds, imparting polar properties to tyrosine. Although the benzene ring is hydrophobic, the hydroxyl group renders tyrosine polar, enabling interactions with water and other polar compounds. Consequently, tyrosine is frequently located on the exterior of proteins, enabling its involvement in hydrogen bonding and other interactions. Consequently, although it possesses certain hydrophobic properties attributed to the aromatic ring, its overall polarity is primarily influenced by the hydroxyl group on its side chain.

Is tyrosine acidic or basic?

Tyrosine is classified as a neutral amino acid at normal pH (about 7.4). It comprises a carboxyl group (–COOH) with a pKa of around 2.2, which deprotonates to yield –COO^–, and an amino group (–NH₂) with a pKa of around 9.1, which protonates to generate –NH₃⁺. The phenolic hydroxyl group on the side chain possesses a pKa of around 10.1 and remains protonated (–OH) at physiological pH. Due to the side chain's lack of ionization under typical conditions, tyrosine maintains an overall neutral state, exhibiting no substantial acidic or basic charge at physiological pH. Consequently, tyrosine is neutral in its standard physiological condition, neither acidic nor basic.

References

1. Amani‐Beni Z., et al., Electrochemical Quantification of Tyrosine in the Presence of Analogous Amino Acids, ChemistrySelect, 2023, 8(21): e202300493.
2. Ha C E., et al., Essentials of medical biochemistry: with clinical cases, Academic Press, 2011.
3. He Q., et al., Solubility of l-tyrosine in aqueous solutions of methanol, ethanol, n-propanol and dimethyl sulfoxide: Experimental determination and preferential solvation analysis, The Journal of Chemical Thermodynamics, 2018, 124: 123-132.
4. Hunter T. Tyrosine phosphorylation: thirty years and counting, Current opinion in cell biology, 2009, 21(2): 140-146.
5. Chakrapani A., et al., Disorders of tyrosine metabolism[M]//Inborn metabolic diseases: diagnosis and treatment. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022: 355-367.
6. Buglak A A., et al., Silver cluster interactions with tyrosine: towards amino acid detection, International Journal of Molecular Sciences, 2022, 23(2): 634.
7. Canfield C A., et al., Amino acids in the regulation of aging and aging-related diseases, Translational Medicine of Aging, 2019, 3: 70-89.
8. Tumilty L., et al., Oral tyrosine supplementation improves exercise capacity in the heat, European journal of applied physiology, 2011, 111(12): 2941-2950.
9. Mahoney C R., et al., Tyrosine supplementation mitigates working memory decrements during cold exposure, Physiology & behavior, 2007, 92(4): 575-582.
10. Li X., et al., Tyrosine supplement ameliorates murine aGVHD by modulation of gut microbiome and metabolome, EBioMedicine, 2020, 61.