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

336
SECTION II
NEUROPHARMACOLOGY
NH 2
N
H
TRYPTAMINE
5-HYDROXY-
TRYPTAMINE
(SEROTONIN)
H 3 C CH 3
N
NH 2
HO
HO
N
N
H
H
OH
5-HYDROXY-
N,N-DIMETHYL-
TRYPTAMINE
(BUFOTENINE)
HO
NH 2
5,7-DIHYDROXY-
TRYPTAMINE
N,N-DIMETHYL-
TRYPTAMINE
MELATONIN
acid tryptophan (Figure 13–2). Tryptophan is
actively transported into the brain by a carrier protein
that also transports other large neutral and
branched-chain amino acids. Levels of tryptophan in
the brain are influenced not only by its plasma concentration
but also by the plasma concentrations of
other amino acids that compete for the transporter.
Tryptophan hydroxylase, a mixed-function oxidase
that requires molecular O 2
and a reduced pteridine
cofactor for activity, is the rate-limiting enzyme in the
synthetic pathway. A brain-specific isoform of tryptophan
hydroxylase (TPH2) is entirely responsible for
the synthesis of brain 5-HT (Walther and Bader,
2003). Human genetic studies of TPH2, fueled by discoveries
of functional SNPs that alter in vitro enzymatic
activity as well as promoter SNPs that alter
expression, have focused on mood disorders, but are
so far inconclusive. Unlike tyrosine hydroxylase, tryptophan
hydroxylase is not regulated by end-product
inhibition, although regulation by phosphorylation is
common to both enzymes. Brain tryptophan hydroxylase
is not generally saturated with substrate; consequently,
the concentration of tryptophan in the brain
influences the synthesis of 5-HT.
The enzyme that converts L-5-hydroxytryptophan to 5-HT,
aromatic L-amino acid decarboxylase (AADC), is widely distributed
and has a broad substrate specificity. A long-standing debate
about whether L-5-hydroxytryptophan decarboxylase and L-dopa
decarboxylase are identical enzymes was clarified when cDNA
cloning confirmed that a single gene product decarboxylates both
N
H
H 3 CO
H 3 C CH 3
N
N
H
CH 3
H C O
N
Figure 13–1. Structures of representative indolealkylamines.
N
H
L-TRYPTOPHAN
L-5-HYDROXY-
TRYPTOPHAN
O 2
tetrahydropteridine
HO
5-HYDROXY-
TRYPTAMINE
(SEROTONIN, 5-HT)
HO
5-HYDROXYINDOLE
ACETALDEHYDE
HO
aldehyde
dehydrogenase
N
HO
vitamin B 6
H
5-HYDROXYINDOLE
ACETIC ACID
(5-HIAA)
N-ACETYL-5-HT
MELATONIN
H
O
C C
H
OH
HO
H 3 CO
NAD
N
H
N
H
N
H
N
H
C C NH 2
H H
tryptophan
hydroxylase
L-aromatic
amino acid
decarboxylase
C C NH 2
H H 5-HT
N-acetylase
aldehyde
reductase
H
5-HYDROXY-
TRYPTOPHOL
H H
O
C C NH C
H H CH3
N
H
hydroxyindole
O-methyltransferase
N
H
Figure 13–2. Synthesis and inactivation of serotonin. Enzymes
are identified in red lettering, and co-factors are shown in blue.
amino acids. 5-Hydroxytryptophan is not detected in the brain
because it is rapidly decarboxylated. The synthesized product, 5-HT,
is accumulated in secretory granules by a vesicular monoamine
transporter (VMAT2); vesicular 5-HT is released by exocytosis
from serotonergic neurons. In the nervous system, the action of
released 5-HT is terminated via neuronal uptake by a specific 5-HT
HO
H
H
COOH
COOH
C C NH 2
H H
H
MAO
H
H
O
C C
H
H
NADH
H
H
N
C C NH
H
H
H
H
C C OH
H H
O
C
CH3