Catecholamines enzymatic methylation

Amino acid-derived hormones include the catecholamines, epinephrine and norepinephrine (qv), and the thyroid hormones, thyroxine and triiodothyronine (see Thyroid AND ANTITHYROID PREPARATIONS). Catecholamines are synthesized from the amino acid tyrosine by a series of enzymatic reactions that include hydroxylations, decarboxylations, and methylations. Thyroid hormones also are derived from tyrosine iodination of the tyrosine residues on a large protein backbone results in the production of active hormone. 

Discovery. The majority of both old and new antidepressants act by virtue of their ability to inhibit monoamine transporter mechanisms in the brain. The concept that neurotransmitters are inactivated by uptake of the released chemical into the nerve terminal from which it had been released or into adjacent cells is less than 40 years old. Before this it was generally assumed that the inactivation of norepinephrine and the other monoamine neurotransmitters after their release from nerves was likely to involve rapid enzymatic breakdown, akin to that seen with acetylcholinesterase. The degradation of monoamines by the enzyme monoamine oxidase vas known early on, and in the 1950s a second enzyme catechol-O-methyl transferase (COMT) vas discovered and was thought to play a key role in inactivating norepinephrine and other catecholamines. 

Apart from its arachidonoyl moiety, the catecholamine moiety of NADA is also likely to be subject to both enzyme-catalysed and non-enzymatic oxidation. However, to date, only the methylation ofthe 3-hydroxy-group of NADAby catechol-0-methyl transferase has been observed (Huang et al. 2002). The reaction product is significantly less active at TRPVl receptors (Huang et al. 2002), whereas its activity at CBi receptors has not been investigated. 

From tyrosine, a series of enzymatic reactions including ring hydroxyla-tion, deciurboxylation, deamination, and D-methylation are responsible for over 20 majof metabolites of neurochemical interest. All of the above metabolites retain at least an electroactive phent nudeus, and most provide enhanced detectability via vanillyl or catechol functional groups. Table III provides cyclic voltammctric data in 90% 0.1 M citrate (pH 4)/10% methanol for a series of these metabolites. Substituent effects are evident. Gener-aUy the catecholamines with their OKlihydroxyphenyl structures are easiest to oxidize, followed by vanillyl dmvatives such as normetanephrine and vanillylmandelic acid. Simple phenols such as tyrosine remain the most difficult to oxidize in this series. 

Catecholamines and their metabolites The catecholamines, adrenaline, noradrenaline, and dopamine are essential components of the central nervous system acting as neurotransmitters both within the brain and at peripheral nerves. All are synthesized in the adrenal medulla from phenylalanine or tyrosine and are metabolized by a mixture of enzymatic side chain oxidation and methylation of the hydroxy groups on the ring. If the metabolism is complete, adrenaline and noradrenaline are degraded to 4-hydroxy-3-methoxy mandelic acid (HMMA, commonly called vanillylmandelic acid - VMA), while dopamine is broken down to homovanillic acid (HVA). Urinary excretion of these metabolites and their conjugates is the major route of elimination of catecholamines from the body, although small amounts are excreted unchanged as the free catecholamines. 

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