Catecholamine synthesis

Catecholamine biosynthesis begins with the uptake of the amino acid tyrosine into the sympathetic neuronal cytoplasm, and conversion to DOPA by tyrosine hydroxylase. This enzyme is highly localized to the adrenal medulla, sympathetic nerves, and central adrenergic and dopaminergic nerves. Tyrosine hydroxylase activity is subject to feedback inhibition by its products DOPA, NE, and DA, and is the rate-limiting step in catecholamine synthesis the enzyme can be blocked by the competitive inhibitor a-methyl-/)-tyrosine (31). 

Nagatsu T, Stjarne L (1998) Catecholamine synthesis and release. Adv Pharmacol 42 1-14... 

Neff, NH and Costa, E (1966) The influence of monoamine oxidase inhibition on catecholamine synthesis. Life Sci. 5 951-959. 

The concentration of catecholamines within nerve terminals remains relatively constant. Despite the marked fluctuations in the activity of catecholamine-containing neurons, efficient regulatory mechanisms modulate the rate of synthesis of catecholamines [ 11 ]. A long-term process affecting catecholamine synthesis involves alterations in the amounts of TH and DBH present in nerve terminals. When sympathetic neuronal activity is increased for a prolonged period of time, the amounts of mRNA coding for TH and DBH are increased in the neuronal perikarya. DDC does not appear to be modulated by this process. The newly synthesized enzyme molecules are then transported down the axon to the nerve terminals. 

In addition, two mechanisms operative at the level of the nerve terminal play important roles in the short-term modulation of catecholamine synthesis and are responsive to momentary changes in neuronal activity [12]. TH, the rate-limiting enzyme in the synthesis pathway, is... 

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). 

Prioux-Guyonneau M, Mocaer-Cretet E, Cohen Y, Jacquot C. (1984). Evidence for an activating effect of tabernanthine on rat brain catecholamine synthesis and elimination. Experientia. 40(12) 1388-89. Prohovnik I, Arnold SE, Smith G, Lucas LR. (1997). Physostigmine reversal of scopolamine-induced hypofrontality. Cereb Blood Flow Metab. 17(2) 220-28. 

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. 

Drugs have been developed which specifically inhibit the L-aromatic amino acid decarboxylase step in catecholamine synthesis and thereby lead to a reduction in catecholamine concentration. Carbidopa and benserazide are examples of decarboxylase inhibitors which are used clinically to... 

Decarboxylation of dopa yields dopamine, an important transmitter in the CNS. In dopaminergic neurons, catecholamine synthesis stops at this point. 

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. 

Liu M, Yanagihara N, Toyohira Y, Tsutsui M, Ueno S, Shinohara Y. 2007c. Dual effects of daidzein, a soy isoflavone, on catecholamine synthesis and secretion in cultured bovine adrenal medullary cells. Endocrinology 148 5348-5354. 

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). 

Muscle-derived differentiation factor (MDF) induces tyrosine hydroxylase expression in a variety of central nervous system neurons, including those of striatum, cerebellum, and cortex. Normally, i.e., without MDF, these neurons do not express this enzyme of catecholamine synthesis. Further in vitro studies revealed that MDF enhances TH-mRNA 40-fold in fetal mesencephalic neurons. In vivo studies, employing infusion of partially isolated MDF, reported this molecule to enhance tyrosine hydroxylase activity in dopamine-depleted striata of 6-OHDA-lesioned animals. Furthermore, an increase of striatal dopamine concentrations and a partial compensation of rotational asymmetry were observed. In contrast, dopaminergic parameters were not affected by administration of MDF in control animals, suggesting that adult dopaminergic neurons may regain sensitivity toward differentiation factors after lesion. 

Cosentino M, Marino F, Bombelli R, Ferrari M, Lecchini S, Frigo G (1999) Endogenous catecholamine synthesis, metabolism, storage and uptake in human neutrophils. Life Sci. 64 975-981. 

Musso NR, Brenci S, Setti M, Indiveri F, Lotti G (1996) Catecholamine content and in vitro catecholamine synthesis in peripheral human lymphocytes. J. Clin. Endocrinol. Metab. 81 3553-3557. 

McCann UD, Penetar DM, Belenky G. Panic attacks in healthy volunteers treated with a catecholamine synthesis inhibitor. Biol Psychiatry 1991 30(4) 413-6. 

Metirosine (a-methyl-p-t5n osine) is a competitive inhibitor of the eruyme tyrosine hydroxylase, which converts t5U-osine to dopa as dopa is further converted to noradrenaline and adrenaline they are similarly depleted by metirosine. It is used as an adjuvant (with phenoxybenzamine) to treat phaeo-chromocytomas that caimot be removed surgically. Catecholamine synthesis is reduced by up to 80% over 3 days. It also readily penetrates the CNS and depletes brain noradrenaline and dopamine causing reserpine-like side effects (see above). Hence, in patients whose life expectancy is threatened more by tumour invasion than by mild or moderate hypertension, the need for the drug should be weighed carefully. 

Metirosine (a-methyltyrosine) has been used with some success to block catecholamine synthesis in malignant phaeochromocytomas. 

DOPA decarboxylase Conversion of EXDPA to dopamine, in the pathway of catecholamine synthesis... 

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