As one of the amino acids classified as non-essential, tyrosine emerges through the conversion of phenylalanine. While healthy individuals can produce sufficient quantities through metabolic processes without dietary sources, this compound serves as a crucial component in numerous biochemical and physiological functions. Our discussion explores tyrosine's metabolic mechanisms, its diverse biological roles, and the significant impact of its metabolism on immune function and various pathological conditions.
Summary of Tyrosine
Tyrosine is the amino acid that makes up proteins. Its chemical name is 2-amino-3-p-hydroxyphenylpropionic acid. According to the chemical structure of the amino acid side chain group, tyrosine belongs to an aromatic amino acid, a semi-essential amino acid and a ketogenic sugar amino acid in the human body. Its main physiological functions are four:
Synthesis of the protein
Tyrosine is one of the basic raw materials for protein synthesis. Tyrosine plays a key role in the synthesis of some enzymes and hormones. Clinically, it is also used as a raw material for amino acid infusions and amino acid composite preparations and a nutritional supplement to treat polio, tuberculosis encephalitis, hyperthyroidism and other diseases.
Service
Synthesis of thyroid hormones
Thyroid hormones are a class of hormones secreted by the thyroid gland, mainly including free T3, free T4, and thyroid-stimulating hormones that regulate thyroid hormones.
Tyrosine is the most important amino acid involved in thyroid hormone synthesis. Thyroid hormone is activated from iodine to iodinated tyrosine, and passes through mono-iodinated tyrosine, di-iodinated tyrosine, tri-iodinated tyrosine, and tetra-iodinated tyrosine in thyroid epithelial cells. It is referred to clinically as T3 and T4, and finally forms thyroid hormone. If tyrosine is lacking, it can lead to dysfunction in thyroid hormone synthesis.
Neurotransmitter synthesis
Dopamine is a substance that triggers happiness. It is a nitrogen-containing organic compound. It is a neurotransmitter produced and secreted by the hypothalamus and pituitary glands. It is synthesized by tyrosine and when it enters the body, it is sent to the brain. Neurons responsible for secreting dopamine, with the help of other enzymes, convert tyrosine into dopamine and transmit signals to other nerve cells through synapses in the brain. Dopamine is related to human lust and feelings. It conveys information of excitement and happiness and plays a key role in the brain's reward mechanism, exercise control, and emotional regulation. It can also be further converted into norepinephrine and epinephrine, which play a role in physiological processes such as the sympathetic nervous system responding to stress and regulating blood pressure.
Melanin synthesis
In melanocytes, tyrosine undergoes a series of oxidation reactions to produce melanin. When the skin is exposed to sunlight, melanocytes accelerate the synthesis of melanin and darken the skin color, thereby absorbing and scattering ultraviolet light and reducing ultraviolet damage to skin cells. If tyrosine is lacking, vitiligo and white hair are prone to occur. Therefore, people with vitiligo eating foods containing tyrosine can promote the formation of melanin and reduce the symptoms of vitiligo.
Tyrosine Biosynthesis and Catabolism
Tyrosine Biosynthesis Pathways
Tyrosine is mainly converted from phenylalanine by phenylalanine hydroxylase (PAH). This reaction converts phenylalanine to tyrosine through an oxygenation reaction while consuming oxygen and tetrahydrobiopterin (BH4) as cofactors. In some plants and bacteria, tyrosine synthesis can also be achieved through the Arogenate pathway, a pathway regulated by arogenate dehydrogenase (ADH). Unlike the phenylalanine pathway, the Aroinate pathway involves the biosynthesis of aromatic amino acids and is an important tyrosine synthesis pathway in plants and some microorganisms.
Figure 1. Tyrosine metabolism pathways.
Synthesis of dopamine
Under the action of tyrosine hydroxylase (TH), L-tyrosine is converted to L-3,4-dihydroxyphenylalanine (L-DOPA) by consuming the cofactor Tetrahydrobiopterin (BH4) and iron ions. This is the rate-limiting step in dopamine synthesis because TH is a key enzyme in this pathway. Under the action of Aromatic L-Amino Acid Decarboxylase (AADC), L-DOPA is converted into dopamine by consuming the cofactor Pyridoxal Phosphate (PLP). This process is also known as DOPA decarboxylation. Dopamine is synthesized in the cytoplasm of neurons and transported to synaptic vesicles for storage. When neurons are stimulated, dopamine is released into the synaptic gap through the synaptic vesicle transporter (VMAT2), binding to dopamine receptors, and exerting its neuroregulatory role.
Synthesis of norepinephrine and epinephrine
Dopamine, catalyzed by dopamine β-hydroxylase (DBH), adds the hydroxyl group (-OH) on the beta carbon to dopamine to produce norepinephrine. This process requires the consumption of oxygen and molecular oxygen as cofactors. Norepinephrine is mainly synthesized in vesicles in nerve endings, binds to ATP and chromogranin, and is stored in the vesicles. Under the catalysis of phenylethanolamine-N-methyltransferase (PNMT), norepinephrine methylates the adjacent amine group of norepinephrine through a methylation reaction to produce epinephrine. This step relies on S-adenosylmethionine (SAM) as a methyl donor. Adrenaline is mainly synthesized in chromaffin cells in the adrenal medulla and stored in the secretory granules of the adrenal medulla.
Degradation of catecholamine
Methylation pathway
Catechol-O-methyltransferase (COMT): COMT catalyzes the methylation of the 3-hydroxyl group of catecholamines (e.g., dopamine, norepinephrine) to produce 3-methoxy derivatives (e.g., 3-methoxytyramine). This process occurs mainly in the liver and kidneys. 3-Methoxytyramine is further oxidized by COMT to 3-methoxy-4-hydroxyphenethyl alcohol (MHPG), which is then converted to 3-methoxy-4-hydroxyphenylacetic acid (MHPA) by aldehyde dehydrogenase (ALDH) or aldehyde reductase (ADH), and is finally excreted through urine.
Oxidative deamination pathway
Monoamine Oxidase (MAO): MAO catalyzes the oxidative deamination of catecholamines to produce corresponding aldehydes (such as 3,4-dihydroxyphenylacetaldehyde, DOPAL). This process occurs mainly in nerve endings and surrounding tissues and requires the cofactor FAD. DOPAL is converted to acid or alcohol by aldehyde dehydrogenase (ALDH) or aldehyde reductase (ADH). For example, DOPAL is oxidized by ALDH to homovanillic acid (HVA), which is then excreted in urine.
The Role of Tyrosine Metabolism in Diseases and Cancer
Disorders of tyrosine metabolism play a key role in many diseases, especially in the development of cancer. Tyrosine phosphorylation is one of the important mechanisms of metabolic reprogramming in cancer cells. Studies have shown that tyrosine phosphorylation can regulate the activities of multiple metabolic enzymes, affecting glycolysis, the tricarboxylic acid cycle (Krebs cycle) and other metabolic pathways.
The Role of Tyrosine Metabolism in Cancer
In epithelial cancers such as ovarian cancer, abnormal expression of some key enzymes in tyrosine metabolism such as FAH and HGD may lead to changes in DNA damage responses, which in turn affects the proliferation and survival of cancer cells. Loss of FAH or dysfunction of HGD may lead to the accumulation of DNA damage, increasing the sensitivity of cancer cells to genotoxic drugs. In addition, the down-regulation of GSTZ1 is closely related to the development of liver cancer and tumor proliferation. Loss of GSTZ1 activates the NRF2/IGF1R signaling axis, thus affecting the survival and proliferation of tumor cells. Therefore, these key enzymes in the tyrosine metabolic pathway may become potential cancer treatment targets.
Figure 2. Tyrosine catabolism enhances genotoxic chemotherapy. (Li, J., et. al, 2023)
Tyrosine metabolism and tumor microenvironment
The heterogeneity of tyrosine metabolism in the tumor microenvironment has also attracted attention. For example, in melanoma, restricting melanin production can prevent tumor colonization in the lungs and enhance the macrophage capacity of immune cells. This suggests that tyrosine metabolism not only affects the tumor cells themselves, but also affects tumor metastasis and immune escape by regulating the tumor microenvironment.
Tyrosine metabolism and neurodegenerative diseases
Abnormal tyrosine metabolism has been associated with a variety of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Studies have shown that tyrosine metabolites such as dopamine and norepinephrine play a key role in neurotransmitter synthesis, and their abnormalities may lead to neuronal dysfunction.
Tyrosine metabolism and cardiovascular disease
Abnormal tyrosine metabolism is associated with an increased risk of cardiovascular disease. For example, high L-tyrosine levels are associated with susceptibility to type 2 diabetes, obesity and cardiovascular disease. In addition, abnormalities in the tyrosine metabolic pathway may further exacerbate the development of cardiovascular disease by affecting oxidative stress and inflammatory responses.
Relationship between tyrosine and brain-gut axis
The researchers found that tyrosine can be metabolized by the intestinal microbiota to 4EP, which is then produced by the host sulfotransferase (SULT1A1) to 4-ethylphenol sulfate (4EPS); 4EPS enters the brain of mice, affects the activation and connection of specific brain areas, and disrupts the maturation and myelination patterns of oligodendrocytes in the brain, thereby regulating brain activity and anxiety-like behavior in mice (Needham,et.al, 2022). In addition, intestinal microorganisms can indirectly affect the metabolism and utilization of tyrosine by producing short chain fatty acids (SCFAs), bile acids and other metabolites.
Tyrosine plays an important role in the brain-gut axis. It is not only a precursor of multiple neurotransmitters, but also affects brain function and behavior through the metabolic activities of intestinal microorganisms. The intestinal microbiota produces a variety of metabolites by metabolizing tyrosine and its precursor tryptophan, which can enter the brain and affect the synthesis and function of neurotransmitters. In addition, tyrosine and its metabolites play a key role in the occurrence and development of mental illness, and reasonable intake and regulation may help improve cognitive function and emotional state.
Impact of Tyrosine on the Immune System
The impact of tyrosine metabolism on the immune system is mainly reflected in its regulation of the function and differentiation of immune cells through multiple pathways, as well as its regulation of the tumor microenvironment.
Tyrosine metabolism and immune cell differentiation
Tyrosine metabolites, such as catecholamines (including epinephrine and norepinephrine), play an important role in the differentiation and function of immune cells. For example, catecholamines can affect macrophage function by regulating the expression of tyrosine hydroxylase (TH) and catecholamine receptors. Studies have shown that expression of β2-adrenergic receptors in macrophages decreases after adrenalectomy, while expression of tyrosine hydroxylase increases, possibly to compensate for the decrease in catecholamine levels. In addition, catecholamines can also affect the immune response by regulating the activity of immune cells.
Tyrosine metabolism and T cell function
Tyrosine metabolism has a significant impact on T cell function. Studies have found that tyrosine metabolic reprogramming can promote immune infiltration in the tumor microenvironment and upregulate immune checkpoint molecules on the surface of tumor cells, thereby inhibiting the activation of T cells. In addition, thyroid hormones (such as T3 and T4) affect the function of immune cells by regulating gene expression and non-gene expression mechanisms. Changes in thyroid hormone levels (such as hyperthyroidism or hypothyroidism) can also have different regulatory effects on the immune system.
Future directions for tyrosine metabolism research
The future direction of tyrosine metabolism research can be discussed from two aspects: biotechnology innovation and clinical significance and drug development.
Biotechnology innovation
Advances in metabolic engineering to optimize tyrosine production in plants and microorganisms. In recent years, metabolic engineering has made significant progress in optimizing tyrosine production in microorganisms and plants. Through strategies such as removing feedback inhibition, increasing precursor supply, blocking competitive pathways, and regulating transport, the production of L-tyrosine has been significantly improved. For example, using CRISPR/Cas9 technology to genetically edit Escherichia coli can optimize its tyrosine transport system, thereby increasing tyrosine production. CRISPR technology has broad application prospects in metabolic engineering. Using the CRISPR/Cas system, researchers can redesign the metabolic pathways of microorganisms to enhance their ability to produce specific compounds. For example, CRISPRi technology has been used to detect essential genes, enhance precursor availability, reduce carbon flux transfer, and identify positive candidate genes. In addition, CRISPR technology can also be used to build new biosynthetic pathways that enable the synthesis of simple precursors to complex molecules.
Clinical significance and drug development
Develop enzyme inhibitors or activators for the potential to treat tyrosine-related metabolic disorders or cancer. Tyrosinase is an important enzyme with a wide range of biological activities and can catalyze a variety of reactions. In recent years, the application of tyrosinase in the biomedical field has attracted widespread attention. For example, tyrosinase can be used in tumor treatment, neurodegenerative disease treatment, cardiovascular disease treatment, etc. In addition, tyrosinase can also be used for food preservation, food preservation, food processing, etc.
References
- Li, J., Zheng, C., Mai, Q., et.al. (2023). Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer. Cell metabolism, 35(11), 2044–2059.e8. https://doi.org/10.1016/j.cmet.2023.10.002
- Needham, B. D., Funabashi, M., Adame, M. D., et.al. (2022). A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature, 602(7898), 647–653. https://doi.org/10.1038/s41586-022-04396-8
