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tyrosine

Friday 29 October 2004

Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 amino acids that are used by cells to synthesize proteins. Tyrosine has a polar side group. Tyrosine is a non-essential amino acid and is found in casein.

The word "tyrosine" is from the Greek tyros, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese.

Functions

Aside from being a proteogenic amino acid, tyrosine has a special role by virtue of the phenol functionality. It occurs in proteins that are part of signal transduction processes.

It functions as a receiver of phosphate groups that are transferred by way of protein kinases (so-called receptor tyrosine kinases).

Phosphorylation of the hydroxyl group changes the activity of the target protein.

Biosynthesis

In plants and most microorganisms, the tyrosine is produced via prephenate, an intermediate on the shikimate pathway. Prephenate is oxidatively decarboxylated with retention of the hydroxyl group to give p-hydroxyphenylpyruvate, which is transaminated using glutamate as the nitrogen source to give tyrosine and α-ketoglutarate.

Mammals synthesize tyrosine from the essential amino acid phenylalanine (phe), which is derived from food. The conversion of phe to tyr is catalyzed by the enzyme phenylalanine hydroxylase, a monooxygenase.

This enzyme catalyzes the reaction causing the addition of an hydroxyl group to the end of the 6-carbon aromatic ring of phenylalanine, such that it becomes tyrosine.

Metabolism

- Phosphorylation and sulphation

Some of the tyrosine residues can be tagged with a phosphate group (phosphorylated) by protein kinases. (In its phosphorylated state, it is referred to as phosphotyrosine).

Tyrosine phosphorylation is considered to be one of the key steps in signal transduction and regulation of enzymatic activity.

Phosphotyrosine can be detected through specific antibodies. Tyrosine residues may also be modified by the addition of a sulfate group, a process known as tyrosine sulfation.

Tyrosine sulfation is catalyzed by tyrosylprotein sulfotransferase (TPST). Like the phosphotyrosine antibodies mentioned above, antibodies have recently been described that specifically detect sulfotyrosine.

- Precursor to hormones

In the adrenal gland, tyrosine is converted to levodopa by the enzyme tyrosine hydroxylase (TH). TH is also the rate-limiting enzyme involved in the synthesis of the catecholamine hormones dopamine, norepinephrine (noradrenaline), and epinephrine.

The thyroid hormones triiodothyronine (T3) and thyroxine (T4) in the colloid of the thyroid also are derived from tyrosine.

- Precursor to alkaloids

In Papaver somniferum, the opium poppy, tyrosine is used to produce the alkaloid morphine.

- Precursor to pigments

Tyrosine is also the precursor to the pigment melanin.

Degradation

The decomposition of L-tyrosine (syn. para-hydroxyphenylalanine) begins with an α-ketoglutarate dependent transamination through the tyrosine transaminase to para-hydroxyphenylpyruvate. The positional description para, abbreviated p, mean that the hydroxyl group and side chain on the phenyl ring are across from each other.

The next oxidation step catalyzes by p-hydroxylphenylpyruvate-dioxygenase and splitting off CO2 homogentisate (2,5-dihydroxyphenyl-1-acetate).

In order to split the aromatic ring of homogentisate, a further dioxygenase, homogentistate-oxygenase is required. Thereby, through the incorporation of a further O2 molecule, maleylacetoacetate is created.

Fumarylacetate is created 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 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.

Ortho- and meta-tyrosine

Three isomers of tyrosine are known. In addition to common amino acid L-tyrosine which is the para isomer (para-tyr, p-tyr or 4-hydroxyphenylalanine) there are two additional regioisomers, namely meta-tyrosine (m-tyr or 3-hydroxyphenylalanine or L-m-tyrosine) and ortho-tyrosine (o-tyr or 2-hydroxyphenylalanine) which occur in nature.

The m-tyr and o-tyr isomers, which are rare, arise through non-enzymatic free-radical hydroxylation of phenylalanine under conditions of oxidative stress.

m-Tyrosine and analogues (rare in nature and therefore available synthetically) have shown application in Parkinson Disease, Alzheimer disease and arthritis.