Tyrosine, norepinephrine synthesis from

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). 

Pathway of epinephrine synthesis. Epinephrine and its precursor, norepinephrine, are synthesized from tyrosine. The synthesis occurs in the chromaffin cells of the adrenal medulla and in neurons of the central and peripheral nervous system. The first step, which is catalyzed by tyrosine hydroxylase, is the rate-limiting step in the pathway. 

In addition to collagen metabolism and scavenging ROS species to limit inflammation as noted above, ascorbate is required for the synthesis of norepinephrine from tyrosine, of carnitine from y-butyrobetaine whose immediate precursor is made by trimethylating lysine, for folinic acid production from folic acid. In the absence of ascorbate, the reduced activity of these processes slows nerve, energy and cardiac output, causingthe affected person to become exhausted and irritable. Scurvy is the old English word for ill-tempered. 

Figure 2.4A Norepinephrine synthesis, release and degradation. 1). Norephinephrine is synthesized from the amino acid tyrosine. Tyrosine is hydroxylated to dopa which is then carboxylated to dopamine. 2). Dopamine (empty squares) diffuses into synaptic vesicles where the enzyme dopamine P-hydroxylase hydroxylates dopamine, forming norepinephrine (solid squares).

Norepinephrine is also derived from an amino acid— tyrosine. The administration of tyrosine to rats with high blood pressure dramatically reduces blood pressure. This effect seems to be caused by the stimulation of norepinephrine synthesis in the brain. Some have conjectured that, in the future, tyrosine may be used in the treatment of behavioral disorders such tis depression. 

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... 

In addition to their well known role in protein structure, amino acids also act as precursors to a number of other important biological molecules. For example, the synthesis of haem (see also Section 5.3.1), which occurs in, among other tissues, the liver begins with glycine and succinyl-CoA. The amino acid tyrosine which maybe produced in the liver from metabolism of phenylalanine is the precursor of thyroid hormones, melanin, adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The biosynthesis of some of these signalling molecules is described in Section 4.4. 

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. 

Phenylalanine is an essential amino acid. Tyrosine is synthesized by hydroxylation of phenylalanine and therefore is not essential. However, if the hydroxylase system is deficient or absent, the tyrosine requirement must be met from the diet. These amino acids are involved in synthesis of a variety of important compounds, including thyroxine, melanin, norepinephrine, and epinephrine... 

The second impetus in this field came from the elucidation of the metabolic pathways leading to the endogenous synthesis of norepinephrine (NE) and its ultimate oxidative degradation. The availability of specific enzyme inhibitors capable of blocking (a) the ra-hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA), (b) the decarboxylation of... 

Both MAOis and TCAs have the capacity to inhibit tyrosine hydroxylase, one of the main enzymes modulating the synthesis of norepinephrine from tyrosine. Inhibition of tyrosine hydroxylase may result in a decreased concentration of norepinephrine in presynaptic storage vesicles, which will eventually lead to decreased secretion into the synaptic cleft. However, it is not yet clear if this effect is clinically significant. 

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. 

The pathway for the synthesis of serotonin from tryptophan is very similar to the pathway for the synthesis of norepinephrine from tyrosine (Fig. 48.7). The first enzyme of the pathway, tryptophan hydroxylase, uses an enzymic mechanism similar to that of tyrosine and phenylalanine hydroxylase and requires BH4 to hydroxylate the ring structure of tryptophan. The second step of the pathway is a decarboxylation reaction... 

Figure 6-2. Characteristics of transmitter synthesis, storage, release, and termination of action at cholinergic and noradrenergic nerve terminals are shown from the top downward. Circles represent transporters ACh. acetylcholine AChE. acetylcholinesterase ChAT, choline acetate transferase DOPA, dihydroxyphenylalanine NE, norepinephrine TCA, tricyclic antidepressant TH, tyrosine hydroxylase.

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. 

The accumulation of phenylalanine and its metabolites may interfere with the metabolism of other amino acids. Stein and Moore, and later Knox, showed that in phenylketonuric patients the amount of other amino acids in the plasma is decreased while phenylalanine accumulates. This interaction between the amino acids metabolism acquires particular significance in view of the mode of amino acid uptake in the brain. The investigators demonstrated that phenylalanine inhibits tyrosine uptake in the brain. Thus, in the presence of large amounts of phenylalanine, protein synthesis in the brain might be inhibited. Furthermore, because of the absence of tyrosine, the biosynthesis of well-known neuroregulators derived from tyrosine, such as norepinephrine and 3,4-dihydroxyphenylethyl-amine, could also be reduced in the brain. 

The majority of catecholamine and serotonin biosynthesis occurs within the nerve terminals by synthetic enzymes transported from the neuronal cell bodies. In all catecholamine neurons, the rate-limiting step in synthesis is conversion of tyrosine to dihydroxyphenylalanine by tyrosine hydroxylase. Dihydroxyphenylalanine is then converted to DA, norepinephrine, and epinephrine through a sequential process involving L-aromatic amino acid decarboxylase (conversion of dihydroxyphenylalanine to DA), dopamine-P-hydroxylase (conversion of DA to norepinephrine), and phenylethanol-amine-N-methyltransferase (conversion of norepinephrine to epinephrine). Cell-specific expression of these enzymes determines the main neurotransmitter for an individual catecholamine neuron. The synthesis pathway for serotonin involves a two-step process in which tryptophan hydroxylase first converts tryptophan to 5-hydroxytryptophan, which is then converted to... 

The morphology of the carotid body resembles chromaffin tissues expressing catecholamines. Now it is fairly established that carotid bodies express dopamine and norepinephrine, whereas there is no convincing evidence for epinephrine. Type I cells from a variety of species express tyrosine hydroxylase (TH) and dopamine jS hydroxylase (DBH), the enzymes responsible for the synthesis of dopamine (DA) and norepinephrine (NE), respectively (10,20,91). In addition, nerve fibers (of sensory as well as autonomic origin) and ganghon cells also show TH immunoreactivity (91). The actions of DA and NE are terminated by a reuptake mechanism involving specific transporters. However, evidence for DA and/or NE transporters in the carotid body is lacking. 

Decarboxylation. It is active in the removal of the carboxyl groups (COOH) from certain amino acids to form another compound. Decarboxylation is necessary for the synthesis of serotonin, norepinephrine, and histamine from tryptophan, tyrosine, and histidine, respectively. 

In the metabolism of tyrosine, a deficiency of vitamin C will result in the build-up and excretion of the intermediary product, P-hydroxyphenylpyruvate, as a result of inactivating the enzyme P-hydroxyphenylpyruvic acid oxidase. When large amounts of tyrosine are being metabolized, vitamin C protects the enzyme P-hydroxyphenylpyruvic acid oxidase from inactivation (rather than activates as was formerly thought), and enhances the synthesis of norepinephrine, a neurotransmitter, from tyrosine. 

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