Human Endogenous Natural Products
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the central and peripheral nervous systems. In the TAAR1 variant, the syntheses of
β-PEA and TYR occur in dopaminergic terminals. Unlike dopamine, which is stored
within synaptic vesicles, trace amines readily diffuse across the plasma membranes.
It is known already that the organic cation transporter OCT2 plays a role in the reuptake of trace amines into the presynaptic terminals, while the postsynaptic importer
of trace amines is still unknown. Since TAAR1 is located predominantly in the cytoplasm, both pre- and postsynaptic effects are plausible. The heterodimerization of
TAAR1 with the dopamine D2 receptor D2R may trigger translocation of TAAR1
onto the cytoplasmic membrane, which subsequently promotes biased D2R signaling
through the Gi cascade instead of the arrestin pathway. Unlike D2R, TAAR1 does not
interact with D1. Dopamine and its metabolites also play multiple roles in the TAAR1
pathway. Dopamine itself activates presynaptic D2R and inhibits the synthesis of
PEA/TYR via the Gi signal transduction pathway. An extracellular catechol-Omethyl transferase transforms dopamine into a trace amine, 3-methoxytyramine (3MT), which activates both pre- and postsynaptic TAAR1 as the archetypal trace
amines (Fig. 3). Nutrient-induced hormone secretion is also regulated by TAAR1 in
the peripheral nervous system, and this could be developed as a novel therapeutic
target for diabetes and obesity [4].
2.2 Steroid Natural Products
Besides the endogenous amines, steroids are also a family of endogenous secondary
metabolites. The most important chemicals in this family are the steroid hormones,
which regulate a number of physiological and developmental processes from birth
to death. The biosynthesis of steroid hormones starts from the cleavage of cholesterol by P450scc to form pregnenolone, the last common intermediate of steroid
hormone biosynthesis. The 3-dehydrogenation of pregnenolone yields progesterone,
which can be transformed further to aldosterone. Progesterone can also undergo 17hydroxylation to form 17-hydroxyprogesterone, which is the progenitor of cortisone
and cortisol. The C-17–C-20 lysis of pregnenolone gives dehydroepiandrosterone,
which is the common intermediate of androstane-type and estrane-type steroids.
The 3-dehydrogenation and 17-dehydrogenation of dehydroepiandrosterone yields
testosterone as the final product via androstenedione or androstenediol. Further
demethylation of testosterone or androstenedione gives estradiol or estrone. Testosterone is also the precursor of 5α-steroid hormones such as dihydrotestosterone
and androsterone. The majority of their biosynthetic enzymes are either cytochrome
P450s (CYPs) or hydroxysteroid dehydrogenases (HSDs), and some transformations
are not strictly order-dependent, because of the promiscuity of these enzymes. Moreoverever, human P450c17 does not prefer 17-hydroxylprogesterone and the C-17–
C-20 lysis of 17-hydroxylpregnenolone is the preferred pathway to androstane-type
steroids in human beings [5] (Fig. 4).
Steroid hormones are important in homeostasis. Cortisone and cortisol are glucocorticoids that inhibit inflammation and dehydration while increasing blood sugar.
317
the central and peripheral nervous systems. In the TAAR1 variant, the syntheses of
β-PEA and TYR occur in dopaminergic terminals. Unlike dopamine, which is stored
within synaptic vesicles, trace amines readily diffuse across the plasma membranes.
It is known already that the organic cation transporter OCT2 plays a role in the reuptake of trace amines into the presynaptic terminals, while the postsynaptic importer
of trace amines is still unknown. Since TAAR1 is located predominantly in the cytoplasm, both pre- and postsynaptic effects are plausible. The heterodimerization of
TAAR1 with the dopamine D2 receptor D2R may trigger translocation of TAAR1
onto the cytoplasmic membrane, which subsequently promotes biased D2R signaling
through the Gi cascade instead of the arrestin pathway. Unlike D2R, TAAR1 does not
interact with D1. Dopamine and its metabolites also play multiple roles in the TAAR1
pathway. Dopamine itself activates presynaptic D2R and inhibits the synthesis of
PEA/TYR via the Gi signal transduction pathway. An extracellular catechol-Omethyl transferase transforms dopamine into a trace amine, 3-methoxytyramine (3MT), which activates both pre- and postsynaptic TAAR1 as the archetypal trace
amines (Fig. 3). Nutrient-induced hormone secretion is also regulated by TAAR1 in
the peripheral nervous system, and this could be developed as a novel therapeutic
target for diabetes and obesity [4].
2.2 Steroid Natural Products
Besides the endogenous amines, steroids are also a family of endogenous secondary
metabolites. The most important chemicals in this family are the steroid hormones,
which regulate a number of physiological and developmental processes from birth
to death. The biosynthesis of steroid hormones starts from the cleavage of cholesterol by P450scc to form pregnenolone, the last common intermediate of steroid
hormone biosynthesis. The 3-dehydrogenation of pregnenolone yields progesterone,
which can be transformed further to aldosterone. Progesterone can also undergo 17hydroxylation to form 17-hydroxyprogesterone, which is the progenitor of cortisone
and cortisol. The C-17–C-20 lysis of pregnenolone gives dehydroepiandrosterone,
which is the common intermediate of androstane-type and estrane-type steroids.
The 3-dehydrogenation and 17-dehydrogenation of dehydroepiandrosterone yields
testosterone as the final product via androstenedione or androstenediol. Further
demethylation of testosterone or androstenedione gives estradiol or estrone. Testosterone is also the precursor of 5α-steroid hormones such as dihydrotestosterone
and androsterone. The majority of their biosynthetic enzymes are either cytochrome
P450s (CYPs) or hydroxysteroid dehydrogenases (HSDs), and some transformations
are not strictly order-dependent, because of the promiscuity of these enzymes. Moreoverever, human P450c17 does not prefer 17-hydroxylprogesterone and the C-17–
C-20 lysis of 17-hydroxylpregnenolone is the preferred pathway to androstane-type
steroids in human beings [5] (Fig. 4).
Steroid hormones are important in homeostasis. Cortisone and cortisol are glucocorticoids that inhibit inflammation and dehydration while increasing blood sugar.