Tyrosine catecholamine synthesis from

The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems. 

Known most famously for their part in the fight or flight response to a threat, challenge or anger, adrenaline (epinephrine) and dopamine from the adrenal medulla and noradrenaline (norepinephrine), mainly from neurones in the sympathetic nervous system are known collectively as catecholamines. Synthesis follows a relatively simple pathway starting with tyrosine (Figure 4.7). 

Corticosteroids also affect adrenomeduUary function by increasing epinephrine production the mechanism is exertion of a stimulatory action on two of the enzymes that regulate catecholamine synthesis, tyrosine hydroxylase, the rate-Umiting enzyme, and phenyl-ethanolamine Af-methyltransferase, which catalyzes the conversion of norepinephrine to epinephrine. Steroids also influence the metabolism of circulating catecholamines by inhibiting their uptake from the circulation by noimeuronal tissues (i.e., extraneuronal uptake see Chapter 9). This effect of corticoids may explain their permissive action in potentiating the hemodynamic effects of circulating catecholamines. 

Catecholamines are synthesized from the amino acid tyrosine, and serotonin from tryptophan as shown in Figure 29-2. The rate-limiting step in catecholamine biosynthesis involves conversion of tyrosine to 3,4-dihydroxyphenylalanine (L-dopa) by the enzyme, tyrosine hydroxylase. A related enzyme, tryptophan hydroxylase, catalyzes conversion of tryptophan to 5-hydroxytryptophan in the first step of serotonin synthesis. 

SYNTHESIS, STORAGE, AND RELEASE OF CATECHOLAMINES Synthesis—The steps in the synthesis of DA, NE (known outside the U.S. as noradrenaline), and Epi (known as adrenahne) are shown in Eigure 6-A. Tyrosine is sequentially 3-hydroxylated and decarboxylated to form DA. DA is 3-hydroxylated to yield NE (the transmitter in postganglionic nerves of the sympathetic branch of the ANS), which is N-methylated in chromaffin tissue to give Epi. The enzymes involved are not completely specific consequently, other endogenous substances and some drugs are also substrates. 5-hydroxytryptamine (5-HT, serotonin) can be produced from 5-hydroxy-L-tryptophan by aromatic L-amino acid decarboxylase (AAD or dopa decarboxylase). AAD also converts dopa into DA, and methyldopa to a-methyl-DA, which is converted to a-methyl-NE by dopamine /3-hydroxylase (Dj3H Table 6-4). 

A notable improvement in clinical condition has been obtained with a-methyl-tyrosine in patients suffering from phaeochromocytoma, a disease in which the s3onptomatology is directly related to the catecholamine production rate. On the other hand, the results achieved in patients with essential hypertension have been disappointing [71]. The 50-70% inhibition of catecholamine synthesis observed was apparently not sufficient in these patients to produce a fall in blood pressure. Sedation, anxiety, diarrhoea, and drug crystalluria were some of the side effects noticed with a-methyltyrosine. 

Dopamine (5-hydroxylase is a copper-containing enzyme involved in the synthesis of the catecholamines norepinephrine and epinephrine from tyrosine in the adrenal medulla and central nervous system. During hy-droxylation, the Cu+ is oxidized to Cu " reduction back... 

The turnover rate of a transmitter can be calculated from measurement of either the rate at which it is synthesised or the rate at which it is lost from the endogenous store. Transmitter synthesis can be monitored by administering [ H]- or [ " C]-labelled precursors in vivo these are eventually taken up by neurons and converted into radiolabelled product (the transmitter). The rate of accumulation of the radiolabelled transmitter can be used to estimate its synthesis rate. Obviously, the choice of precursor is determined by the rate-limiting step in the synthetic pathway for instance, when measuring catecholamine turnover, tyrosine must be used instead of /-DOPA which bypasses the rate-limiting enzyme, tyrosine hydroxylase. 

Synthesis of catecholamines from Tyr begins with hydroxylation of the Tyr ring catalyzed by tyrosine hydroxylase. 

Dopamine, a catecholamine, is synthesized in the terminals of dopaminergic neurons from tyrosine, which is transported across the blood-brain barrier by an active process (Figure 23.7). The rate-limiting step in the synthesis of dopamine is the conversion of 1-tyrosine to 1-dihydroxy-phenyta-lanine (1-dopa), catalyzed by the enzyme tyrosine hydroxylase, which is present within catechola-minergic neurons. 

Dopamine is synthesized from the amino acid tyrosine by the enzymes tyrosine hydroxylase (TH which forms L-3,4-dihydroxylphenylalanine, l-DOPA) and L-amino acid decarboxylase (AADC) in dopaminergic neurons. The mRNA expression of the TH (which is the rate-limiting enzyme in the synthesis of dopamine) is abundant throughout the human mesencephalon (Fig. 1) TH is a phenotypic marker for all catecholamines, dopamine, noradrenaline and adrenaline. Evidence for the presence of TH has been documented in the mesencephalon from at least 4.5 to 7 weeks of human fetal life... 

The first and rate-limiting step in the synthesis of these neuroffansmitters from tyrosine is the hydroxylation of the tyrosine ring by tyrosine hydroxylase, a teffahy-drobiopterin (BH4)-requiring enzyme. The product formed is dihydroxyphenylala-nine or DOPA. The phenyl ring with two adjacent OH groups is a catechol, and hence dopamine, norepinephrine, and epinephrine are called catecholamines. 

Elevated levels of phenylalanine have been shown to inhibit transport of other amino acids besides tyrosine. This might result in an imbalance of amino acids in the brain that could disrupt protein synthesis or control of the synthesis of neurotransmitters. Several enzymes, including tyrosine hydroxylase, tryptophan, and pyruvate kinase, are inhibited in vitro by phenylalanine. Irrespective of such phenomena in a patient who died with PKU, catecholamine concentration and serotonin levels were much lower than those in control brains from patients suffering mental retardation from other causes, a finding consistent with such a possible role in vivo (Ikeda et al., 1967). 

Assay of phenylalanine hydroxylase in a liver biopsy from one patient showed 20% of normal adult control values, but dihydropteridine reductase activity (Fig. 20.2) was less than 1% of normal in the liver, brain, and other tissues. This latter deficiency presents regeneration of tetrahydrobiopterin, the cofactor for the hydroxylase reaction. Since the reductase enzyme reaction regenerates the cofactor for tyrosine and tryptophan hydroxylase, catecholamine and serotonin synthesis are compromised as well. Patient studies are scanty, but in one patient dopamine and serotonin were decreased in the cerebrospinal fluid, brain, and various other tissues, while norepinephrine metabolites were normal. While phenylalanine hydroxylase activity was lower than that of adult controls, it was not determined whether this value represented significantly decreased activity in children. 

Ir-tyrosine hydroxylase (TH Joh et al., 1973), an enzyme essential for synthesis of catecholamines, has been localized in perikarya of the NOR, but not in the NPP or NLT, in early maturing male and female platyfish (Halpern-Sebold et al., 1985). Processes containing ir-TH extend dorso-caudally and ventrocaudally from NOR perikarya, but not anteriorly into the olfactory bulb. In early maturers, ir-TH can be seen in NOR perikarya only at 12 months, although ir-material is present in NOR processes at all ages from 8 to 24 months (Fig. 4 and unpublished observations). Ir-TH is not present in the NOR of late maturing males at any age. 

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