Pathways

The tyrosine metabolism pathway describes the many ways in which tyrosine is catabolized or transformed to generate a wide variety of biologically important molecules. In particular, tyrosine can be metabolized to produce hormones such as thyroxine and triiodothyronine or it can be metabolized to produce neurotransmitters such as L-DOPA, dopamine, adrenaline, or noradrenaline. Tyrosine can also serve as a precursor of the pigment melanin and for the formation of Coenzyme Q10. Additionally, tyrosine can be catabolized all the way down into fumarate and acetoacetate. This particular pathway for tyrosine degradation starts with an alpha-ketoglutarate-dependent transamination reaction of tyrosine, which is mediated through the enzyme known as tyrosine transaminase. This process generates p-hydroxyphenylpyruvate. This aromatic acid is then acted upon by p-hydroxylphenylpyruvate-dioxygenase which generates the compound known as homogentisic acid or homogentisate (2,5-dihydroxyphenyl-1-acetate). In order to split the aromatic ring of homogentisate, a unique dioxygenase enzyme known as homogentisic acid 1,2-dioxygenase is required. Through this enzyme, maleylacetoacetate is created from the homogentisic acid precursor. The accumulation of excess homogentisic acid and its oxide (named alkapton) in the urine of afflicted individuals can lead to a condition known as alkaptonuria. This genetic condition, also known as an inborn error of metabolism or IEM, occurs if there are mutations in the homogentisic acid 1,2-dioxygenase gene. After the breakdown of homogentisate is achieved, maleylacetoacetate is then attacked by the enzyme known as maleylacetoacetate-cis-trans-isomerase, which generates fumarylacetate. This isomerase catalyzes the rotation of the carboxyl group created from the hydroxyl group via oxidation. This cis-trans-isomerase uses glutathione as a coenzyme or cofactor. The resulting product, fumarylacetoacetate, is then split into acetoactate and fumarate via the enzyme known as fumarylacetoacetate-hydrolase through the addition of a water molecule. Through this set of reactions fumarate and acetoacetate (3-ketobutyroate) are liberated. Acetoacetate is a ketone body, which is activated with succinyl-CoA, and thereafter it can be converted into acetyl-CoA, which in turn can be oxidized by the citric acid cycle (also known as the TCA cycle) or used for fatty acid synthesis. Other aspects of tyrosine metabolism include the generation of catecholamines. In this process, the enzyme known as tyrosine hydroxylase (or AAAH or TYH) catalyzes the conversion of tyrosine to L-DOPA. The L-DOPA can then be converted via the enzyme DOPA decarboxylase (DDC) to dopamine. Dopamine can then be converted to 3-methoxytyramine via the action of catechol-O-methyltransferase (COMT). Dopamine can also be converted to norepinephrine (noradrenaline) through the action of the enzyme known as dopamine beta hydroxylase (DBH). Norepinephrine can then be converted to epinephrine (adrenaline) through the action of phenyethanolamine N-methyltransferase (PNMT). Catecholamines such as L-DOPA, dopamine and methoxytyramine are produced mainly by the chromaffin cells of the adrenal medulla and by neuronal cells found in the brain. For example, dopamine, which acts as a neurotransmitter, is mostly produced in neuronal cell bodies in the ventral tegmental area and the substantia nigra while epinephrine is produced in neurons in the human brain that express PMNT. Catecholamines typically have a half-life of a few minutes in the blood. They are typically degraded via catechol-O-methyltransferases (COMT) or by deamination via monoamine oxidases (MAO). Another important aspect of tyrosine metabolism includes the production of melanin. Melanin is produced through a mechanism known as melanogenesis, a process that involves the oxidation of tyrosine followed by the polymerization of these oxidation by-products. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are three types of melanin: pheomelanin, eumelanin, and neuromelanin of which eumelanin is the most common. Melanogenesis, especially in the skin, is initiated through the exposure to UV light. Melanin is the primary pigment that determines skin color. Melanin is also found in hair and the pigmented tissue underlying the iris. The first step in the synthesis for both eumelanins and pheomelanins is the conversion of tyrosine to dopaquinone by the enzyme known as tyrosinase. The resulting dopaquinone can combine with cysteine to produce cysteinyldopa, which then polymerizes to form pheomelanin. Dopaquinone can also form lecuodopachrome, which then can be converted to dopachrome (a cyclization product) and this eventually becomes eumelanin. Tyrosine plays a critical role in the synthesis of thyroid hormones. Thyroid hormones are produced and released by the thyroid gland and include triiodothyronine (T3) and thyroxine (T4). These two hormones are responsible for regulating metabolism. Thyroxine was discovered and isolated by Edward Calvin Kendall in 1915. Thyroid hormones are produced by the follicular cells of the thyroid gland through the action of thyroperoxidase, which iodinates reactive tyrosine residues on thyroglobulin. Proteolysis of the thyroglobulin in cellular lysosomes releases the small molecule thyroid hormones. In mammals, tyrosine can be formed from dietary phenylalanine by the enzyme phenylalanine hydroxylase, found in large amounts in the liver. Phenylalanine is considered an essential amino acid, while tyrosine (which can be endogenously synthesized) is not. In plants and most microbes, tyrosine is produced via prephenate, an intermediate that is produced as part of the shikimate pathway.

The tyrosine metabolism pathway describes the many ways in which tyrosine is catabolized or transformed to generate a wide variety of biologically important molecules. In particular, tyrosine can be metabolized to produce hormones such as thyroxine and triiodothyronine or it can be metabolized to produce neurotransmitters such as L-DOPA, dopamine, adrenaline, or noradrenaline. Tyrosine can also serve as a precursor of the pigment melanin and for the formation of Coenzyme Q10. Additionally, tyrosine can be catabolized all the way down into fumarate and acetoacetate. This particular pathway for tyrosine degradation starts with an alpha-ketoglutarate-dependent transamination reaction of tyrosine, which is mediated through the enzyme known as tyrosine transaminase. This process generates p-hydroxyphenylpyruvate. This aromatic acid is then acted upon by p-hydroxylphenylpyruvate-dioxygenase which generates the compound known as homogentisic acid or homogentisate (2,5-dihydroxyphenyl-1-acetate). In order to split the aromatic ring of homogentisate, a unique dioxygenase enzyme known as homogentisic acid 1,2-dioxygenase is required. Through this enzyme, maleylacetoacetate is created from the homogentisic acid precursor. The accumulation of excess homogentisic acid and its oxide (named alkapton) in the urine of afflicted individuals can lead to a condition known as alkaptonuria. This genetic condition, also known as an inborn error of metabolism or IEM, occurs if there are mutations in the homogentisic acid 1,2-dioxygenase gene. After the breakdown of homogentisate is achieved, maleylacetoacetate is then attacked by the enzyme known as maleylacetoacetate-cis-trans-isomerase, which generates fumarylacetate. This isomerase catalyzes the rotation of the carboxyl group created from the hydroxyl group via oxidation. This cis-trans-isomerase uses glutathione as a coenzyme or cofactor. The resulting product, fumarylacetoacetate, is then split into acetoactate and fumarate via the enzyme known as fumarylacetoacetate-hydrolase through the addition of a water molecule. Through this set of reactions fumarate and acetoacetate (3-ketobutyroate) are liberated. Acetoacetate is a ketone body, which is activated with succinyl-CoA, and thereafter it can be converted into acetyl-CoA, which in turn can be oxidized by the citric acid cycle (also known as the TCA cycle) or used for fatty acid synthesis. Other aspects of tyrosine metabolism include the generation of catecholamines. In this process, the enzyme known as tyrosine hydroxylase (or AAAH or TYH) catalyzes the conversion of tyrosine to L-DOPA. The L-DOPA can then be converted via the enzyme DOPA decarboxylase (DDC) to dopamine. Dopamine can then be converted to 3-methoxytyramine via the action of catechol-O-methyltransferase (COMT). Dopamine can also be converted to norepinephrine (noradrenaline) through the action of the enzyme known as dopamine beta hydroxylase (DBH). Norepinephrine can then be converted to epinephrine (adrenaline) through the action of phenyethanolamine N-methyltransferase (PNMT). Catecholamines such as L-DOPA, dopamine and methoxytyramine are produced mainly by the chromaffin cells of the adrenal medulla and by neuronal cells found in the brain. For example, dopamine, which acts as a neurotransmitter, is mostly produced in neuronal cell bodies in the ventral tegmental area and the substantia nigra while epinephrine is produced in neurons in the human brain that express PMNT. Catecholamines typically have a half-life of a few minutes in the blood. They are typically degraded via catechol-O-methyltransferases (COMT) or by deamination via monoamine oxidases (MAO). Another important aspect of tyrosine metabolism includes the production of melanin. Melanin is produced through a mechanism known as melanogenesis, a process that involves the oxidation of tyrosine followed by the polymerization of these oxidation by-products. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are three types of melanin: pheomelanin, eumelanin, and neuromelanin of which eumelanin is the most common. Melanogenesis, especially in the skin, is initiated through the exposure to UV light. Melanin is the primary pigment that determines skin color. Melanin is also found in hair and the pigmented tissue underlying the iris. The first step in the synthesis for both eumelanins and pheomelanins is the conversion of tyrosine to dopaquinone by the enzyme known as tyrosinase. The resulting dopaquinone can combine with cysteine to produce cysteinyldopa, which then polymerizes to form pheomelanin. Dopaquinone can also form lecuodopachrome, which then can be converted to dopachrome (a cyclization product) and this eventually becomes eumelanin. Tyrosine plays a critical role in the synthesis of thyroid hormones. Thyroid hormones are produced and released by the thyroid gland and include triiodothyronine (T3) and thyroxine (T4). These two hormones are responsible for regulating metabolism. Thyroxine was discovered and isolated by Edward Calvin Kendall in 1915. Thyroid hormones are produced by the follicular cells of the thyroid gland through the action of thyroperoxidase, which iodinates reactive tyrosine residues on thyroglobulin. Proteolysis of the thyroglobulin in cellular lysosomes releases the small molecule thyroid hormones. In mammals, tyrosine can be formed from dietary phenylalanine by the enzyme phenylalanine hydroxylase, found in large amounts in the liver. Phenylalanine is considered an essential amino acid, while tyrosine (which can be endogenously synthesized) is not. In plants and most microbes, tyrosine is produced via prephenate, an intermediate that is produced as part of the shikimate pathway.

Tyrosine is produced in cells by hydroxylating (via phenylalanine hydroxylase) the essential amino acid phenylalanine. Half of the phenylalanine required goes into the production of tyrosine; if the diet is rich in tyrosine itself, the requirements for phenylalanine are reduced by about 50%. Phenylalanine hydroxylase is a mixed-function oxygenase: one atom of oxygen is incorporated into water and the other into the hydroxyl of tyrosine. The reductant is the tetrahydrofolate-related cofactor tetrahydrobiopterin, which is maintained in the reduced state by the NADH-dependent enzyme dihydropteridine reductase (DHPR). The catabolism of tyrosine starts with an α-ketoglutarate dependent transamination through the tyrosine transaminase, which generates p-hydroxyphenylpyruvate. The next oxidation step is catalyzed by p-hydroxylphenylpyruvate-dioxygenase and generates homogentisate (2,5-dihydroxyphenyl-1-acetate). In order to split the aromatic ring of homogentisate, a further dioxygenase, homogentistate-oxygenase is required. Through this reaction, maleylacetoacetate is created. Fumarylacetate is then generated by maleylacetoacetate-cis-trans-isomerase through rotation of the carboxyl group created from the hydroxyl group via oxidation. This cis-trans-isomerase contains glutathione as a coenzyme. Fumarylacetoacetate is finally split into acetoactate and fumarate via fumarylacetoacetate-hydrolase through the addition of a water molecule. Thereby fumarate (also a metabolite of the citric acid cycle) and acetoacetate (3-ketobutyroate) are liberated. Acetoacetate is a ketone body, which is activated with succinyl-CoA, and thereafter it can be converted into acetyl-CoA which in turn can be oxidized by the citric acid cycle or be used for fatty acid synthesis.

Tyrosine kinase inhibitors (TKIs) block chemical messengers (enzymes) called tyrosine kinases. Tyrosine kinases help to send growth signals in cells, so blocking them stops the cell growing and dividing. Cancer growth blockers can block one type of tyrosine kinase or more than one type. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Tyrosine kinase enzymes (TKs) can be categorized into receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases (NRTKs), and a small group of dual-specificity kinases (DSK) which can phosphorylate serine, threonine, and tyrosine residues. RTKs are transmembrane receptor that includes vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), insulin receptor (InsR) family, and the ErbB receptor family, which includes epidermal growth factor receptors (EGFR) and the human epidermal growth factor receptor-2 (HER2). NRTKs are cytoplasmic proteins that consist of nine families, including Abl, Ack, Csk, Fak, Fes/Fer, Jak, Src, Syk/Zap70, and Tec, with the addition of Brl/Sik, Rak/Frk, Rlk/Txk, and Srm, which fall outside the nine defined families. The most notable example of DSKs is the mitogen-activated protein kinase kinases (MEKs), which are principally involved in the MAP pathways. Kinase inhibitors are either irreversible or reversible. The irreversible kinase inhibitors tend to covalently bind and block the ATP site resulting in irreversible inhibition. The reversible kinase inhibitors can further subdivide into four major subtypes based on the confirmation of the binding pocket as well as the DFG motif. Different binding modes of TKIs include Type I inhibitors: competitively bind to the ATP-binding site of active TKs. The arrangement of the DFG motif in type I inhibitors has the aspartate residue facing the catalytic site of the kinase. Type II inhibitors: bind to inactive kinases, usually at the ATP-binding site. The DFG motif in type II inhibitors protrudes outward away from the ATP-binding site. Due to the outward rotation of the DFG motif, many type II inhibitors can also exploit regions adjacent to the ATP-binding site that would otherwise be inaccessible. Type III inhibitors: do not interact with the ATP-binding pocket. Type III inhibitors exclusively bind to allosteric pockets adjacent to the ATP-binding region. Type IV inhibitors: bind allosteric sites far removed from the ATP-binding pocket. Type V inhibitors: refer to a proposed subset of kinase inhibitors that exhibit multiple binding modes

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Tyrosinemia type 3, one of the three types of tyrosinemia, is a rare disorder with only a few reported cases. Tyrosinemia type 3 results from a defect in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. 4-Hydroxyphenylpyruvate dioxygenase plays a role in the catabolism of tyrosine by catalyzing the conversion of 4-hydroxyphenylpyruvate to homogentisate. A defect in this enzyme causes tyrosine and phenylalanine to accumulate in the blood resulting in increased excretion of tyrosine in the urine. Tyrosinemia type 3 symptoms include: seizures, mental retardation and intermittent ataxia (occasional loss of balance and coordination).

Tyrosinemia type 3, one of the three types of tyrosinemia, is a rare disorder with only a few reported cases. Tyrosinemia type 3 results from a defect in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. 4-Hydroxyphenylpyruvate dioxygenase plays a role in the catabolism of tyrosine by catalyzing the conversion of 4-hydroxyphenylpyruvate to homogentisate. A defect in this enzyme causes tyrosine and phenylalanine to accumulate in the blood resulting in increased excretion of tyrosine in the urine. Tyrosinemia type 3 symptoms include: seizures, mental retardation and intermittent ataxia (occasional loss of balance and coordination).