section 32.2
Adrenal Medulla
761
more catecholamines. This cholinergic activation of tyro-
sine hydroxylase involves phosphorylation of the enzyme,
presumably by a Ca
2
+-calmodulin-dependent protein
kinase.
Synthesis of Epinephrine
Epinephrine (adrenaline) (Figure 32-7) is synthesized
from tyrosine by conversion of tyrosine to 3,4-dihydro-
xyphenylalanine (dopa) by tyrosine-3-monooxygenase
(tyrosine hydroxylase) in the cytosol. The mixed-function
oxidase
requires
molecular
oxygen
and
tetrahydro-
biopterin, which is produced from dihydrobiopterin by
NADPH-dependent dihydrofolate reductase. In the reac-
tion, tetrahydrobiopterin is oxidized to dihydrobiopterin,
which is reduced to the tetrahydro form by NADH-
dependent dihydropteridine reductase. These reactions are
similar to the hydroxylations of aromatic amino acids
(phenylalanine and tryptophan), in which an obligatory
biopterin electron donor system is used (Chapter 17).
The rate-controlling step of catecholamine synthe-
sis is the tyrosine hydroxylase reaction, for which the
catecholamines are allosteric inhibitors. The enzyme is
activated by the cAMP-dependent protein kinase phos-
phorylating system. a-N-Methyl-p-tyrosine is an inhibitor
of this enzyme and is used to block adrenergic activity in
pheochromocytoma (see below).
Dopa is decarboxylated to 2-(3,4-dihydroxyphenyl)
ethylamine (dopamine) by aromatic L-amino acid decar-
boxylase, a nonspecific cytosolic pyridoxal phosphate-
dependent enzyme also involved in formation of other
amines (e.g., 5-hydroxytryptamine).
NH3
,CH2— CH— COO
Aromatic
t-am ino acid
decarboxylase
------------------------------►
HO*
Pyridoxal phosphate
•CH2— CH2— NH3 + C 0 2
Dopa
Dopamine
Tyrosine can be decarboxylated to tyramine by aro-
matic L-amino acid decarboxylase of intestinal bacteria.
Tyramine, which is present in large amounts in certain
foods (e.g., aged cheeses, red wines), is converted by
monoamine oxidase (MAO) to the aldehyde derivatives.
However, individuals who are receiving MAO inhibitors
for the treatment of depression can accumulate high lev-
els of tyramine, causing release of norepinephrine from
sympathetic nerve endings and of epinephrine from the
adrenal medulla. This results in peripheral vasoconstric-
tion and increased cardiac output, which lead to hyperten-
sive crises that can cause headaches, palpitations, subdural
hemorrhage, stroke, or myocardial infarction.
In dopaminergic neurons, dopamine is not metabolized
further but is stored in presynaptic vesicles. In noradren-
ergic neurons and in the adrenal medulla, dopamine enters
the secretory granules and is further hydroxylated to
norepinephrine. This reaction is catalyzed by dopamine-
/3-monooxygenase,
a
copper
protein
that
requires
molecular oxygen and ascorbate or tetrahydrobiopterin.
Dopamine
•CH2— CH2— NH3+
Dopamme-0-
monooxygenase
r
\
Ascorbate.
Dehydro-
0 2
ascorbate.
H 20
Norepinephrine
Norepinephrine diffuses into the cytosol, where it
is
converted
to
epinephrine
by
méthylation
of its
amino
group.
This
reaction,
in
which
the
methyl
group
is
donated
by
S-adenosylmethionine,
is
cat-
alyzed by S-adenosyl-L-methionine:phenylethanolamine-
N-methyltransferase (PNMT). Epinephrine enters the
granules and remains there until it is released.
..
.
. .
S-adenosyl-
S-adenosyl-
.
Norepinephrine
u.
.
Epinephrine
methionine
homocysteine
Catecholamine neurotransmitters in the central ner-
vous system are synthesized in that location itself be-
cause they cannot cross the blood-brain barrier. However,
dopa readily crosses the blood-brain barrier, promoting
the catecholamine synthesis. Thus, in disorders involv-
ing deficiency of catecholamine synthesis, administra-
tion of dopa may have beneficial effects. In
Parkinson’s
disease,
in which deficiency of dopamine synthesis af-
fects nerve transmission in the substantia nigra of the
upper brain stem, administration of dopa leads to some
symptomatic relief. Parkinsonism is a chronic, progressive
disorder characterized by involuntary tremor, decreased
motor power and control, postural instability, and muscu-
lar rigidity.
Regulation of Catecholamine Secretion
Regulation o f Synthesis
Dopamine
(DA) and
norepinephrine
(NE) are allo-
steric inhibitors of tyrosine hydroxylase and regulate
catecholamine synthesis when the adrenal medulla is
quiescent (unstimulated). Continuous stimulation of the
adrenal medulla (as during prolonged stress) promotes ty-
rosine hydroxylase activity primarily because the turnover
of DA and NE is rapid. Tyrosine hydroxylase ac-
tivity is also regulated by cAMP and by choliner-
gic nerve activity. The enzyme is active when phos-
phorylated (Chapter 30). Tonic cholinergic impulses
maintain the activity of tyrosine hydroxylase, whereas
