of a further O2 molecule, maleylacetoacetate is created. Fumarylacetoacetate is created 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 by the enzyme 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. Phloretic acid is also a urinary metabolite of tyrosine in rats. Ortho- and meta-tyrosine Three structural isomers of L-tyrosine are known. In addition to the 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 (also known as , L-m-tyrosine, and m-tyr) and ortho-tyrosine (o-tyr or 2-hydroxyphenylalanine), that 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 but available synthetically) have shown application in Parkinson's disease, Alzheimer's disease and arthritis. Medical use Tyrosine is a precursor to neurotransmitters and increases plasma neurotransmitter levels (particularly dopamine and norepinephrine), but has little if any effect on mood in normal subjects. A number of studies have found tyrosine is useful during stress, cold, fatigue (in mice), prolonged work and sleep deprivation, with reductions in stress hormone levels, reductions in stress-induced weight loss seen in animal trials, and improvements in cognitive and physical performance seen in human trials. Tyrosine does not seem to have any significant effect on cognitive or physical performance in normal circumstances, but does help sustain working memory better during multitasking. Interactions It is unknown if MAOIs interact with tyrosine. Industrial synthesis L-tyrosine and its derivatives (L-DOPA, melanin, phenylpropanoids, and others) are used in pharmaceuticals, dietary supplements, and food additives. Two methods were formerly used to manufacture L-tyrosine. The first involves the extraction of the desired amino acid from protein hydrolysates using a chemical approach. The second utilizes enzymatic synthesis from phenolics, pyruvate, and ammonia through the use of tyrosine phenol-lyase. Advances in genetic engineering and the advent of industrial fermentation have shifted the synthesis of L-tyrosine to the use of engineered strains of E. coli. See also Albinism Alkaptonuria