Synthesis of catecholamines
Tyrosine hydroxylation
The amino acid tyrosine is the starting material. It is taken up into
catecholaminergic nerves by an active transport system. Once inside the nerve,
an additional hydroxyl group is added to the aromatic ring of tyrosine by the
enzyme tyrosine hydroxylase. Tyrosine hydroxylation is the rate limiting step in
the synthesis of catecholamines and is subject to feedback inhibition by the end
products. This forms the catechol (dihydroxybenzene) part of the molecule
responsible for the family name. The product is dihydroxyphenylalanine (DOPA).
DOPA decarboxylation
Dihydroxyphenylalanine (DOPA) is acted upon by aromatic-L-amino acid
decarboxylase. This forms dopamine (DA), one of three naturally occurring
catecholamines. DOPA is used to treat certain diseases in which it is desired to
increased catecholaminergic transmission at certain sites.
Dopamine hydroxylation
DA in catecholaminergic nerves is taken up into synaptic vesicles and is
converted to norepinephrine (NE) by the addition of a hydroxyl group on the
carbon second (beta) from the amino group (except in a few dopaminergic
neurons). Beta hydroxylation is carried out by the enzyme
dopamine-beta-hydroxylase (DBH).
N-methylation
DBH is located in the synaptic vesicles so the final step in the synthesis of
NE occurs in the vesicle in which NE is packaged along with ATP and other
material for eventual release. In adrenal medulla cells, NE in the cytosol is
acted upon by phenylethanolamine-N-methyltransferase. This adds a methyl group
to the amino nitrogen and forms epinephrine (EPI). The addition of a methyl
group significantly alters the pharmacology of the catecholamine. Most of the
EPI formed in this process is taken into synaptic vesicles and stored for
eventual release into the blood stream. The adrenal medulla releases
catecholamines into the blood. In humans, catecholamines released from the
adrenal medulla are about 80% EPI and 20% NE. Because these catecholamines are
released into the blood and act on receptors in target tissues at some distance
these catecholamines act as circulating hormones.
In summary, synthesis of catecholamines is a multistep process. No wonder,
then, that instead of being destroyed they are 'recycled' in large part.
|
