362
chapter 17
Protein and Amino Acid Metabolism
T ry p to p h an
Q ,, te tra h y d ro b io p te rin -J
H
20
, dihydrobiopterin
T ry p to p h an -5 -h y d ro x y lase
5-H y d ro x y try p to p h an
cos'
A rom atic l -am in o acid
d e c a rb o x y la se
(pyridoxal p h o sp h a te )
H
5-H y d ro x y try p tam in e
(sero to n in )
F I G U R E 1 7 -2 5
Biosynthesis of serotonin from tryptophan.
HCL
-C H — C H — NH*
S ero to n in
1
H
A c e ty l-C o A ^ 5 -H y d ro x y try p tam in e-
C oA S H —^ N -a c e ty ltra n sfe ra se
O
-C H — C H — N H — c — C H
3
N -A cetyl-5-hydroxytryptam ine
S -A d en o sy lm eth io n in e
S -A d en o sy lh o m o cy s te in e * -^
H ydroxyindole m e th y ltra n sfe ra se
O
II
C H — O L — N H — C — C H a
M elatonin (N -acety l-5 -m eth o x y try p tam in e)
F I G U R E 1 7 -2 6
Biosynthesis of melatonin from serotonin.
adrenocorticotropic hormone (ACTH). In rats, melatonin
regulates the breeding cycle, and its secretion is increased
by exposure to light via adrenergic stimulation of the
pineal gland.
N-Acetyltransferase is activated by increased concen-
trations of cytosolic cyclic AMP and Ca2+ that is medi-
ated by the activation of adrenergic receptors of the pineal
gland. In humans, melatonin synthesis and its release fol-
lows a circadian rhythm which is stimulated by dark-
ness and inhibited by light. The blood levels of melatonin
increase by passive diffusion from the central nervous sys-
tem after the onset of darkness, reaching a peak value dur-
ing the middle of the night and declining during the second
half of the night. Melatonin secretion is also regulated en-
dogenously by signals from the suprachiasmatic nucleus.
Since melatonin’s peak concentration in plasma coincides
with sleep, exogenous administration of the hormone can
affect the circadian rhythm. Melatonin supplementation
has been used to ameliorate subjective and objective symp-
toms of jet lag caused by travel across time zones. At high
levels, melatonin promotes sleep. Short-term and long-
term biological effects of melatonin supplementation have
yet to be determined.
Serotonin is degraded to 5-hydroxyindoleacetic acid
(5-HIAA) by monoamine oxidase and aldehyde dehy-
drogenase acting in sequence. 5-HIAA is excreted in
the urine. Its excretion is markedly increased in subjects
with carcinoid tumor (found most frequently in the gas-
trointestinal tract and lungs).
Carcinoid tumors
are fre-
quently indolent and asymptomatic; however, a signifi-
cant number of these tumors can manifest as metabolic
problems. Although increased production of serotonin
is a characteristic feature of the carcinoid tumor, cells
also synthesize other substances. These include kinins,
prostaglandins, substance P, gastrin, somatostatin, corti-
cotropin, and neuron-specific enolase. Carcinoid tumor
cells are known as enterochromaffin cells because they
stain with potassium dichromate and also are known as
argentaffin cells because they take up and reduce silver
salts. The symptoms of the carcinoid tumor are due to syn-
ergistic biochemical interactions between serotonin and
the above-mentioned active metabolites. Characteristics
of the carcinoid syndrome are flushing, diarrhea, wheez-
ing, heart valve dysfunction, and pellagra. Lifestyle con-
ditions that precipitate symptoms include intake of alco-
hol or spicy foods, and strenuous exercise. The treatment
options for the carcinoid syndrome are multidisciplinary,
including lifestyle changes, inhibitors of serotonin re-
lease and serotonin receptor antagonists, somatostatin ana-
logues, hepatic artery embolization, chemotherapy, and
surgery.
