Norepinephrine epinephrine synthesis

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. 

Although the adrenal medulla is the major site of epinephrine synthesis, it is also synthesized in a few neurons that use epinephrine as a neurotransmitter. These neurons contain the above pathway for norepinephrine synthesis and in addition contain the enzyme that ffansfers a methyl group from SAM to norepinephrine to form epinephrine. Thus, epinephrine synthesis is dependent on the presence of adequate levels of B12 and folate (see Chapter 40). 

The synthesis of DPE was described by Nohta et al. [411]. After the usual clean-up by alumina adsorption, cation exchange column chromatography or other suitable procedure [412], 150 fil of the sample solution (adjusted to pH 6.0-6.5) are mixed with 10 fil of a 20 mM solution of potassium ferricyanide and 150 1 of acetonitrile. Subsequently, 50 fA of the DPE solution (21.2 mg ml in 0.1 M HCl) are added and the reaction mixture is allowed to stand at 37 °C for 40 min. After cooling to room temperature, 100 /A aliquots are injected onto the column. Fluorescence intensity is recorded at 485 nm after excitation at 345 nm. Procedures for the determination of norepinephrine, epinephrine and dopamine in plasma [412] and urine [413] were reported. 

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Eig. 1) similar to the original pubHshed route of synthesis (6). Eriedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone [99-45-6] which on catalytic reduction yields (+)-epinephrine [329-65-7]. Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

PNMT catalyzes the N-methylation of norepinephrine to form epinephrine in the epinephrine-forming cells of the adrenal medulla. Since PNMT is soluble, it is assumed that norepinephrine-to-epinephrine conversion occurs in the cytoplasm. The synthesis of PNMT is induced by glucocorticoid hormones that reach the medulla via the intra-adrenal portal system. This special system provides for a 100-fold steroid concentration gradient over systemic arterial blood, and this high intra-adrenal concentration appears to be necessary for the induction of PNMT. 

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... 

As previously mentioned, the cells of the adrenal medulla are considered modified sympathetic postganglionic neurons. Instead of a neurotransmitter, these cells release hormones into the blood. Approximately 20% of the hormonal output of the adrenal medulla is norepinephrine. The remaining 80% is epinephrine (EPI). Unlike true postganglionic neurons in the sympathetic system, the adrenal medulla contains an enzyme that methylates norepinephrine to form epinephrine. The synthesis of epinephrine, also known as adrenalin, is enhanced under conditions of stress. These two hormones released by the adrenal medulla are collectively referred to as the catecholamines. 

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). 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

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. 

Several of the neurotransmitters are small-molecule amines such as dopamine, serotonin, epinephrine, and norepinephrine. These neurotransmitters are synthesized in the cytoplasm of the axon terminal and subsequently transported into and stored within the synaptic vesicles. The amino acids glycine and glutamic acid are normal constituents of proteins and are present in abundance in the axons. These are also stored in synaptic vesicles. Each electrical impulse that arrives at the presynaptic side of a synapse will cause only a small minority of the synaptic vesicles to fuse with the plasma membrane and discharge their contents. The remaining synaptic vesicles remain, waiting for subsequent electrical impulses. At the same time, neurotransmitter synthesis continues, as does their storage in synaptic vesicles. This tends to restore the full complement of amine neurotransmitters at the axon terminal. 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

The adrenal medulla synthesizes two catecholamine hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Figure 1.8). The ultimate biosynthetic precursor of both is the amino acid tyrosine. Subsequent to their synthesis, these hormones are stored in intracellular vesicles, and are released via exocytosis upon stimulation of the producer cells by neurons of the sympathetic nervous system. The catecholamine hormones induce their characteristic biological effects by binding to one of two classes of receptors, the a- and )S-adrenergic receptors. These receptors respond differently (often oppositely) to the catecholamines. 

In noradrenergic neurons, the end product is norepinephrine. In the adrenal medulla, the synthesis is carried one step further by the enzyme phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine. The human adrenal medulla contains approximately four times as much epinephrine as norepinephrine. The absence of this enzyme in noradrenergic neurons accounts for the absence of significant amounts of epinephrine in noradrenergic neurons. The structures of these compounds are shown in Figure 9.4. 

The neuronal transport system is the most important mechanism for removing norepinephrine. Any norepinephrine or epinephrine in the circulation will equilibrate with the junctional extracellular fluid and thus become accessible both to the receptors and to neuronal transport. Thus, neuronal transport is also an important mechanism for limiting the effect and duration of action of norepinephrine or epinephrine, whether these are released from the adrenal medulla or are administered as drugs. Neuronal uptake is primarily a mechanism for removing norepinephrine rather than conserving it. Under most circumstances, synthesis of new norepinephrine is quite capable of keeping up with the needs of transmission, even in the complete absence of neuronal reuptake. 

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. 

Pheochromocytoma is sometimes treated with metyrosine (cx-methyltyrosine), the -methyl analog of tyrosine. This agent is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine, norepinephrine, and epinephrine (see Figure 6-5). Metyrosine is especially useful in symptomatic patients with inoperable or metastatic pheochromocytoma. Because it has access to the central nervous system, metyrosine can cause extrapyramidal effects due to reduced dopamine levels. 

Tyrosine hydroxylase FIGRRQSL Synthesis of l-DOPA, dopamine, norepinephrine, and epinephrine... 

Regardless of the untested merits of the above work, methylation as a first step in the deactivation of noradrenaline in the body is just as plausible as is the evidence that methylation is the final step in the synthesis of adrenaline. The evidence for and against this route of synthesis has been discussed previously in this review. Tainter etal. (155) reported that in dogs under phenobarbital anesthesia Z-arterenol had a pressor activity 1.7 times that of Z-epinephrine. In this sense then, methylation might be considered a process of inactivation. However, they found in contrast that the acute toxicity of Z-epinephrine (LDso) was about four times that of Z-norepinephrine (114) 155). 

Metyrosine (Demser). Metyrosine inhibits the enzyme initiating catecholamine synthesis (epinephrine, norepinephrine) this drug is used to diminish catecholamine stores prior to removal of a catecholamine-producing tumor (pheochromocytoma). 

Hormone synthesis and release can be initiated by both extrinsic and intrinsic factors.2 Extrinsic factors include various environmental stimuli such as pain, temperature, light, and smell. Intrinsic stimuli include various humoral and neural factors. For instance, release of a hormone can be initiated by other hormones. These occurrences are particularly typical of the anterior pituitary hormones, which are controlled by releasing hormones from the hypothalamus. Hormonal release can be influenced by neural input a primary example is the sympathetic neural control of epinephrine and norepinephrine release from the adrenal medulla. Other intrinsic factors that affect hormone release are the levels of ions and metabolites within the body. For instance, parathyroid hormone release is governed directly by the calcium concentration in the bloodstream, and the release of... 

Adrenergic neurons (Figure 6-4) also transport a precursor molecule into the nerve ending, then synthesize the catecholamine transmitter, and finally store it in membrane-bound vesicles, but—as indicated in Figure 6-5—the synthesis of the catecholamine transmitters is more complex than that of acetylcholine. In most sympathetic postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, norepinephrine is further converted to epinephrine. Conversely, synthesis terminates with dopamine in the dopaminergic neurons of the central nervous system. Several important processes in these nerve terminals are potential sites of... 

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