DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 8–4
Enzymes for Synthesis of Catecholamines
SUBCELLULAR COFACTOR SUBSTRATE
ENZYME OCCURRENCE DISTRIBUTION REQUIREMENT SPECIFICITY COMMENTS
Tyrosine Widespread; Cytoplasmic Tetrahydrobiopterin, Specific for Rate limiting step.
hydroxylase sympathetic O 2
, Fe 2+ L-tyrosine Inhibition can
nerves
deplete NE
Aromatic Widespread; Cytoplasmic Pyridoxal phosphate Nonspecific Inhibition does
L-amino acid sympathetic not alter tissue
decarboxylase nerves NE and Epi
appreciably
Dopamine Widespread; Synaptic vesicles Ascorbic acid, O 2
Nonspecific Inhibition can
β-hydroxylase sympathetic (contains copper) decrease NE
nerves
and Epi levels
Phenylethanolamine Largely in Cytoplasmic S-Adenosyl Nonspecific Inhibition can
N-methyltransferase adrenal gland methionine decrease
(CH 3
donor)
adrenal
E pi
/NE; regulated
by glucocorticoids
cloned, and characterized (Nagatsu, 1991). Table 8–4
summarizes some of the important characteristics of the
four enzymes. These enzymes are not completely specific;
consequently, other endogenous substances, as
well as certain drugs, are also substrates. For example,
5-hydroxytryptamine (5-HT, serotonin) can be produced
from 5-hydroxy-L-tryptophan by aromatic L-amino acid
decarboxylase (or dopa decarboxylase). Dopa decarboxylase
also converts dopa into DA (Chapter 13) and
methyldopa to α-methyldopamine, which in turn is converted
by dopamine β-hydroxylase (DβH) to methylnorepinephrine.
The hydroxylation of tyrosine by tyrosine hydroxylase (TH)
generally is regarded as the rate-limiting step in the biosynthesis of
catecholamines (Zigmond et al., 1989); this enzyme is activated following
stimulation of sympathetic nerves or the adrenal medulla.
The enzyme is a substrate for PKA, PKC, and CaM kinase; phosphorylation
is associated with increased hydroxylase activity. This is an
important acute mechanism for increasing catecholamine synthesis
in response to elevated nerve stimulation. In addition, there is a
delayed increase in TH gene expression after nerve stimulation. This
increased expression can occur at multiple levels of regulation,
including transcription, RNA processing, regulation of RNA stability,
translation, and enzyme stability (Kumer and Vrana, 1996).
These mechanisms serve to maintain the content of catecholamines
in response to increased transmitter release. In addition, TH is
subject to feedback inhibition by catechol compounds, which
allosterically modulate enzyme activity.
TH deficiency has been reported in humans and is characterized
by generalized rigidity, hypokinesia, and low cerebrospinal
fluid (CSF) levels of NE and DA metabolites homovanillic
acid and 3-methoxy-4-hydroxyphenylethylene glycol (Wevers
et al., 1999). TH knockout is embryonically lethal in mice, presumably
because the loss of catecholamines results in altered cardiac
function. Interestingly, residual levels of DA are present in
these mice. It has been suggested that tyrosinase may be an alternate
source for catecholamines, although tyrosinase-derived catecholamines
are clearly not sufficient for survival (Carson and
Robertson, 2002).
DβH deficiency in humans is characterized by orthostatic
hypotension, ptosis of the eyelids, retrograde ejaculation, and elevated
plasma levels of dopamine. In the case of DβH-deficient mice,
there is ~90% embryonic mortality (Carson and Robertson, 2002).
Our understanding of the cellular sites and mechanisms of
synthesis, storage, and release of catecholamines derives from studies
of sympathetically innervated organs and the adrenal medulla.
Nearly all the NE content of innervated organs is confined to the
postganglionic sympathetic fibers; it disappears within a few days
after section of the nerves. In the adrenal medulla, catecholamines
are stored in chromaffin granules (Aunis, 1998). These vesicles contain
extremely high concentrations of catecholamines (~21% dry
weight), ascorbic acid, and ATP, as well as specific proteins such as
chromogranins, DβH, and peptides including enkephalin and neuropeptide
Y. Vasostatin-1, the N-terminal fragment of chromogranin
A, has been found to have antibacterial and antifungal activity
(Lugardon et al., 2000), as have other chromogranin A fragments
such as chromofungin, vasostatin II, prochromacin, and chromacins
I and II (Taupenot et al., 2003). Two types of storage vesicles are
found in sympathetic nerve terminals: large dense-core vesicles