Tyrosine, brain

The chemistry of the brain and central nervous system is affected by a group of substances called neurotransmitters, substances that carry messages across a synapse from one neuron to another Several of these neurotransmitters arise from l tyrosine by structural modification and decarboxylation as outlined m Figure 27 5... 

Dopamine. Dopamine (DA) (2) is an intermediate in the synthesis of NE and Epi from tyrosine. DA is localized to the basal ganglia of the brain and is involved in the regulation of motor activity and pituitary hormone release. The actions of DA are terminated by conversion to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase-A and -B (MAO-A and -B) in the neuron following reuptake, or conversion to homovanillic acid (HVA) through the sequential actions of catechol-0-methyl transferase (COMT) and MAO-A and -B in the synaptic cleft. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Fig. 2. Biosynthetic pathway for epinephrine, norepinephrine, and dopamine. The enzymes cataly2ing the reaction are (1) tyrosine hydroxylase (TH), tetrahydrobiopterin and O2 are also involved (2) dopa decarboxylase (DDC) with pyridoxal phosphate (3) dopamine-P-oxidase (DBH) with ascorbate, O2 in the adrenal medulla, brain, and peripheral nerves and (4) phenethanolamine A/-methyltransferase (PNMT) with. Cadenosylmethionine in the adrenal...

DOPA in the bloodstream can be taken up into neural tissue and into tissue devoid of tyrosine hydroxylase, thus bypassing the rate-limiting enzymatic synthetic step (35). Uptake of DOPA by the brain is the basis of the therapeutic effect of DOPA in the treatment of Parkinson s disease (a... 

BDNF (brain-derived neurotrophic factor) is a neuro-trophin, i.e. a target-derived growth factor, which is expressed in the brain predominantly in the hippocampus. It acts through its tyrosine kinase receptor, trkB,... 

Fyn is a nonreceptor tyrosine kinase related to Src that is frequently found in cell junctions. Die protein is N-myristoylated and palmitoylated and thereby becomes associated with caveolae-like membrane microdomains. Fyn can interact with a variety of other signaling molecules and control a diversity of biological processes such as T cell receptor signaling, regulation of brain function, and adhesion mediated signaling. 

Tyrosine hydroxylase (TH) is an enzyme that catalyzes the hydroxylation of tyrosine to 3,4-dihydroxypheny-lalanine in the brain and adrenal glands. TH is the rate-limiting enzyme in the biosynthesis of dopamine. This non-heme iron-dependent monoxygenase requires the presence of the cofactor tetrahydrobiopterin to maintain the metal in its ferrous state. 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

The synthesis and metabolism of DA are very similar to that of NA, even when it functions as a NT in its own right. Although both phenylalanine and tyrosine are found in the brain it is tyrosine which is the starting point for NA and DA synthesis. It appears to be transported into the brain after synthesis from phenylalanine (phenylalanine hydroxylase) in the liver rather than from phenylalanine found in the brain. Despite the fact that the concentration of tyrosine in the brain is high (5 X 10 M) very little body tyrosine (1%) is used for the synthesis of DA and NA. 

Tyrosine is converted to dopa by the cytoplasmic enzyme tyrosine hydroxylase. This is the rate-limiting step 5 x 10 M) in DA synthesis, it requires molecular O2 and Fe + as well as tetrahydropterine (BH-4) cofactor and is substrate-specific. It can be inhibited by a-methyl-p-tyrosine, which depletes the brain of both DA and NA and it is particularly important for the maintenance of DA synthesis. Since the levels of tyrosine are above the for tyrosine hydroxylase the enzyme is normally saturated and so it is not possible to increase DA levels by giving tyrosine. 

While a number of drugs, e.g. a-methyl dopa, inhibit the enzyme they have little effect on the levels of brain DA and NA, compared with inhibition of tyrosine hydroxylase and they also affect the decarboxylation of other amino acids. Some compounds, e.g. a-methyl dopa hydrazine (carbidopa) and benserazide, which do not easily enter the CNS have a useful role when given in conjunction with levodopa in the treatment of Parkinsonism (see Chapter 15) since the dopa is then preserved peripherally and so more enters the brain. 

It is possible to deplete the brain of both DA and NA by inhibiting tyrosine hydroxylase but while NA may be reduced independently by inhibiting dopamine jS-hydroxylase, the enzyme that converts DA to NA, there is no way of specifically losing DA other than by destruction of its neurons (see below). In contrast, it is easier to augment DA than NA by giving the precursor dopa because of its rapid conversion to DA and the limit imposed on its further synthesis to NA by the restriction of dopamine S-hydroxylase to the vesicles of NA terminals. The activity of the rate-limiting enzyme tyrosine hydroxylase is controlled by the cytoplasmic concentration of DA (normal end-product inhibition), presynaptic dopamine autoreceptors (in addition to their effect on release) and impulse flow, which appears to increase the affinity of tyrosine hydroxylase for its tetrahydropteridine co-factor (see below). 

Bacopoulus, NG and Bhatnager, RK (1977) Correlation between tyrosine hydroxylase activity and catecholamine concentration or turnover in brain regions. J. Neurochem. 29 631-643. 

Tyramine is produced by decarboxylation of tyrosine and is present in the CNS in higher (threefold) concentrations than m-tyramine, the hydroxylated derivative of phenylethylamine. In the periphery / -tyramine is easily hydroxylated to octopamine, which has some direct effects on ai adrenoceptors, unlike tyramine which functions by releasing NA. When tested on central neurons tyramine always produces the same effects as NA but they are slower and less marked, implying an indirect action. By contrast octopamine often produces the opposite effect to NA and it is probable that octopamine may have a functional role in the invertebrate CNS where it is found in higher concentrations (5pg/g) than in the mammalian brain (0.5ng/g). Neither tyramine nor octopamine have distinct behavioural effects, unlike phenylethylamine,... 

Non-neuronal transplants such as adrenal chromaffin cells have been tried but do not survive although some L-dopa-producing cell lines (e.g. PC 12) or glomus cells of the carotid body do produce DA in vivo and may provide the equivalent of a continuous infusion of dopa (and DA) directly into the brain. Expression of tyrosine hydroxylase to promote dopa and DA synthesis in striatal cells by direct gene transfer in vivo or in cultures for subsequent transplanting, may also be possible. (See Dunnett and Bjorklund 1999 for a review of these approaches.)... 

There is no evidence of a general overactivity in DA function in schizophrenic patients. Plasma prolactin is not reduced, so the DA inhibitory control of its release is normal there is no recorded increase in DA turnover as CSF and plasma levels of its major metabolite HVA are normal and dyskinesias, which would reflect increased DA activity, are rare. PM studies have shown no consistent increases in DA brain levels, although some reports show an increase in the left amygdala, or in the activity of enzymes involved in its synthesis (tyrosine hydroxylase) or metabolism (MAO). For a review of the neurochemistry see Reynolds (1995). 

Trulson, ME. Joe, J.C. Babb, S. and Raese, J.D. Chronic cocaine administration depletes tyrosine hydroxylase immunoreactivity in the meso-limbic dopamine system in rat brain. Brain Res Bull 19 39-45,... 

Fibiger, H.C., and McGeer, E.G. Effect of acute and chronic methamphetamine treatment on tyrosine hydroxylase activity in brain and adrenal medulla. Eur J Pharmacol 16 176-180, 1971. 

Graham, D.G. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol 14 633-643. 1978. Hotchkiss, A.J., and Gibb, J.W. Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain. J Pharmacol Exp Ther 214 257-262, 1980. 

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