Tyrosine

The tyrosine (abbreviated in Spanish as Tir or Y, and Tyr or Y in English) is one of the twenty amino acids that make up proteins. It is classified as a non-essential amino acid in mammals since its synthesis occurs from the hydroxylation of another amino acid: phenylalanine. This is considered so as long as the diet of mammals contains an adequate supply of phenylalanine. Therefore the amino acid phenylalanine is essential.

Like all amino acids, it is made up of a central alpha carbon (Cα) linked to a hydrogen atom (-H), a carboxyl group (-COOH), an amino group (-NH2) and a side chain. In tyrosine, the side chain is a phenolic group.

The word tyrosine comes from the Greek tyros, which means cheese. It is so named because this amino acid was discovered by a German chemist named Justus von Liebig from the protein casein, which is found in cheese.

Three different isomers of the amino acid tyrosine are known: para-tyrosine, meta-tyrosine and ortho-tyrosine. Although the best known and studied form is para-tyrosine or also called L-tyrosine.

Properties

Tyrosine.

In general, the properties of amino acids are due to the nature of their side chain, their reactivity, and the conformation of the protein chains they form. The same thing happens in tyrosine.

Tyrosine is a crystal-forming solid that is generally off-white in color, although it can also be colorless. It is considered a polar and protonatable amino acid. Although it is normally classified as a hydrophobic amino acid because of its aromatic ring, it should be noted that it also contains a hydroxyl group. It is normally uncharged, although at very basic pH it is negatively charged.

Regarding its solubility, we know that it is soluble in water and slightly soluble in alcohol. We also know its insolubility in ether.

This is an optically active molecule, which means it rotates the plane of polarized light. Like most amino acids (all except glycine) it has an asymmetry at the alpha carbon so that it cannot superimpose itself on its mirror image. It is said to have chirality.

The isoelectric point of this amino acid is at 5.7. The isoelectric point is the pH at which protonation has the same extent as deprotonation.

Regarding the melting point of tyrosine, it acquires different values depending on the type of heating. When tyrosine is heated rapidly and in a closed tube, it melts and decomposes at approximately 342°C. By contrast, heating tyrosine slowly melts at 290°C.

The mass of the tyrosine side chain is close to 163.1 Daltons and the average occurrence of this amino acid in proteins is 3.5%.

This amino acid absorbs ultraviolet light. The efficiency in the absorption of light energy is related to its molar extinction coefficient. The most common absorbance is at a wavelength between 260 and 300 nm, due to its side chain. Although it is known that at high pH (when the tyrosine side chain has a pKa = 10) the absorbance of tyrosine shifts towards higher wavelengths (towards red). For the solubilization of tyrosine with water, heating to approximately 40º is required to achieve solubilization.

Biosynthesis

Tyrosine synthesis can occur in two different ways. In mammals it is obtained from the hydroxylation of phenylalanine, while in some microorganisms it is obtained directly from profenate. The fact that tyrosine is a precursor of catecholamines (dopamine, adrenaline and norepinephrine), melanin and thyroxine influences its synthesis. This is because the production of tyrosine is regulated by the demand for these molecules.

Mammals: Hydroxylation of phenylalanine

In mammals, tyrosine is synthesized from a process of hydroxylation of the essential amino acid phenylalanine. The enzyme phenylalanine hydroxylase is involved in this reaction, which requires a cofactor called tetrahydropterin. This reaction is irreversible since the synthesis of phenylalanine from tyrosine is not possible.

Microorganisms

In microorganisms, the process for obtaining tyrosine is as follows:

1. Condensation of phosphoenolpiruvate (an intermediary of glucolysis) with the eritrosa 4-phosphate (an intermediate of the pathway of the pentase phosphate). This reaction gives rise to an open seven-carbon glow.
2. Oxidation of the glucid that had formed. It loses its phosphorylic group and forms a 3-dehydrochinate ring.
3. Dehydration of that molecule to obtain 3-dehydrosiquimate.
4. Reduction of 3-dehydrosiquimate to siquimate by NADPH action.
5. Sichymato phosphorylation by ATP to form 3-phosphate siquimate.
6. Condensation of the 3-phosphate sichymato with a phosphoenolpiruvate molecule to give rise to 5-enolpiruvil-inermediary. This last molecule loses its phosphorylic group and becomes corismate. Corismate is the common precursor of the three aromatic amino acids.
7. Conversion of corismate to prefenato, the immediate precursor of the aromatic rings of phenylalanine amino acids and thyrosine. This conversion takes place through the action of a mutase.
8. Oxidative descarboxylation of prefanato to obtain p-hydroxyphenylpiruvate.
9. Transamination to get tyrosine

Tyrosine metabolism

Tyrosine metabolism produces two molecules: fumarate and acetoacetate. It has the following stages:

1. Transamination of thyrosine to p-hydroxyphenylpiruvate through the action of an enzyme called thyrosine aminotransferase.
2. Production of homogentisic acid from p-hydroxyphenylpiruvate. This step takes place from a complex reaction that includes descarboxylation, oxidation, lateral carbonated chain migration and hydroxylation.
3. Aromatic ring excision of homogentisic acid using the enzyme homogentisate oxidase to obtain maleilacetoacetato.
4. Isomerización de la forma cis a la forma trans mediante una respuesta cataalizada por la maleilacetoacetato isomerasa, que da lugar a fumarilacetato.
5. Excision to smoke and acetoacetate.

Fumarate can be used to produce energy in the Krebs cycle (or tricarboxylic acid cycle) or for gluconeogenesis. Acetoacetate can be used for lipid synthesis or for energy production in the form of acetyl CoA.

Tyrosine as a precursor

Amino acids are the units from which peptides and proteins are obtained. But they also act as precursors to many other smaller molecules, but which perform important and highly varied biological functions. In the case of tyrosine, it is a precursor of thyroid hormones, catecholamines (adrenaline, dopamine, norepinephrine) and melanin.

Catecholamines

A part of the acetoacetate and fumarate metabolized from tyrosine that has not been used for protein synthesis is used to obtain catecholamines through the following steps:

1. Tyrosine hydroxylation from an enzyme called hydroxylase thyrosine, which also requires biopterin as cofactor. Dihydroxyphenylanine is obtained, better known as DOPA.
2. Descarboxylation of the DOPA through the DOPA descarboxilasa, giving rise to dopamine (a neurotransmitter).
3. Dopamine hydroxylation in noradrenaline through a hydroxylation reaction where dopamine β-hydroxylase acts.
4. In the adrenal marrow, noradrenaline becomes adrenaline.

Catecholamines are known for their regulation of moods. It has been observed that at low levels of catecholamines people tend to suffer from anxiety and depression.

Melanin

Melanin is a pigment that gives color to hair and skin. It also protects from ultraviolet radiation. The conversion of tyrosine to melanin requires the participation of tyrosinase, a catalytic protein that is characterized by containing copper. The process can be seen in the diagram:

Thyroid Hormones: Triiodothyronine and Thyroxine

The basic hormones of the thyroid gland are thyroxine (T4) and its active cellular form: triiodothyronine (T3). The amino acid tyrosine is involved in the process of formation of these hormones necessary for the body. The synthesis process is as follows:

1. Captation and concentration of iodine. The iodine we ingest with the diet is almost all directed to the thyroid gland. Once there, it enters into the ionized form (I-) into the basal membrane thanks to the action of a conveyor protein called NIS (Natrium-Iodide Symporter).
2. The iodine comes out of the iodine through the apical membrane by helping another protein called pendrine.
3. iodine is oxidized by the thyperoxidase enzyme (TPO).
4. The same enzyme, TPO, incorporates iodine into amino acid thyrosine to form 3-monoiodothyrosine (MIT) or diiodothyrosine (DIT).
5. The thyperoxidase enzyme (TPO), also allows the union of two diiodothyrosine to form the thyroxine hormone. For the formation of the triiodothyronine hormone it is necessary to bind a MIT molecule with a DIT molecule, also through the catalysis of the TPO enzyme.

When they are synthesized, the hormones end up in the bloodstream where they are transported to the tissues where they perform their function.

Diseases related to tyrosine metabolism

Tyrosinemias

It consists of an accumulation and/or excretion of tyrosine and its metabolites as a consequence of the absence or deficiency of the enzyme tyrosine aminotransferase. There are several types: hepatorenal or type I tyrosinemia and oculocutaneous or type II tyrosinemia. Both diseases are autosomal recessive. Type I is a dysfunction of the renal tubules, rickets and polyneuropathy. It is caused by a lack of fumarylacetoacetate hydrolase. Accumulation of fumarylacetoacetate and maleylacetate leads to DNA alkylation and tumor generation. Type II produces eye and skin lesions. In addition to mental retardation.

Alkaptonuria

It is a disease suffered by people who have a deficiency in homogentisate oxidase, which excretes almost all the tyrosine they ingest in its form of homogentisic acid through the urine. In the first years of life, the only consequence of the disease is a dark color of urine. But as the pigments formed in the oxidation of homogentisate accumulate in bone and connective tissue, ochronosis can occur. It is also an autosomal recessive disease. It is also inhibited due to symptomatic heterolytic glycolysis that originates in HIV carriers.

Albinism

It consists of a genetic condition that is characterized by the fact that the skin and hair are little or not at all pigmented. It is produced by the lack of an enzyme called tyrosinase which acts in the process of melanin formation from tyrosine. The lack of pigments in the skin makes albinos more sensitive to solar radiation. This can manifest as skin burns and/or carcinomas. In addition, the lack of pigmentation in the eyes contributes to photophobia.

Parkinson's

This is a disease that usually affects the population over 60 years of age, although it has also been observed in younger populations. It consists of tremors that gradually interfere with the motor function of various muscle groups. The defect that causes this disease is the progressive loss of dopaminergic neurons present in an area of the brain called substantia nigra and in the locus coeruleus of the brain. It is related to the amino acid tyrosine since its hydroxylation transforms it into DOPA, which in turn becomes the neurotransmitter dopamine through carboxylation.

Tyrosine Phosphorylation

Tyrosine can undergo phosphorylation at its hydroxyl group (-OH) due to the action of numerous enzymes of the tyrosine kinase type. These enzymes are involved in signal transduction and in the regulation of enzyme activity since it is known that the phosphorylation of tyrosine residues has the ability to activate or inhibit enzymes and receptors.

Tyrosine Sulfation

The amino acid can also be sulfated. This is a post-translational modification that only occurs in those proteins that pass through the Golgi apparatus and that are going to be secreted abroad or that have an extracellular domain. The enzyme that is responsible for catalyzing the sulfation process is called proteintyrosyl sulfotransferase, which is found in the membrane of the Golgi apparatus with its active site facing the lumen of this compartment. The sulfate group donor in this reaction is 3'phosphoadenosine-5'-phosphosulfate. Sulfation is a modification that affects the biological activities of neuropeptides, the process of proteolysis of precursor proteins, and the intracellular transport of secretory proteins. Fundamentally it would reinforce protein-protein interactions. Gastrin and cholecystokinin are known to have a sulfated tyrosine, which greatly increases the potency of both hormones.

Tyrosine as therapy

Tyrosine is used therapeutically in some cases of depression and stress. It is also used in schizophrenic patients, since it has been seen that in these people the transport of tyrosine in skin fibroblasts is more reduced.