640
16 Sterols and Steroids
C19 steroids. Plasma proteins from sharks, rays
and lampreys bind C2b C18 and C19 steroids with
the same low affinity, and the blood of the common hagfish Myxine contains no steroid-binding
proteins of any sort. Transcortin-like proteins are
apparently widely distributed from the bony fish
onwards. There are, however, large differences in
amino acid composition and molecular mass
between, for example, human and chicken transcortins. CBG, like other plasma proteins, is secreted by the liver but the corresponding human
mRNA is also found in the lung, testis and
kidney. Human CBG consists of a polypeptide
chain of 383 amino acids and five oligosaccharides, which make up about 23 % of the molecular
mass of 58 kDa. The amino acid sequence shows
no similarity to other steroid-binding proteins but
does exhibit significant homology to alantitrypsin and other serpins [44].
Sex hormone-binding globulin has been found
in many mammals, but is absent from rodents,
elephants and the birds. Reptiles possess SHBG
and, in fact, have separate androgen- and
oestrogen-specific proteins. SHBG-like proteins
have also been detected in various amphibians
and teleosts [102]. The SHBG of the mammals
is a dimer of two identical polypeptides of
367-373 amino acids with three carbohydrate
chains, although it binds only one steroid molecule [45, 126]. At least in the N-terminal region,
it shows sequence similarity to the similar-sized
androgen-binding protein (ABP) from mammalian testis; the function of ABP appears to be to
concentrate androgens and thereby amplify their
effects on spermatogenesis and sperm maturation
[41, 57]. A similar protein is found in the testis of
the spiny dogfish Squalus acanthias [73]. The
steroid-binding protein from rat prostate apparently functions in a feedback mechanism to regulate androgen activity; it is a tetramer of four different polypeptides that both bind to, and are
induced by, androgen. This protein shows significant sequence homology to the uteroglobin from
the uterus and lung of the rabbit; this is a homodimer of about 16 kDa that is both induced by
and binds to progesterone. The 91 co dons of the
gene sequences of the pre-uteroglobins of the
rabbit and of the hare Lepus capensis have five
synonymous substitutions, suggesting that the
two species separated about 4 million years ago;
there are also six amino acid-exchanging substitutions, which suggests an unusually high rate of
evolution [72].
16.3.3 Corticosteroids
Only in the mammals are steroid-producing and
catecholamine-producing (chromaffine) cells of
the adrenal gland organized into the cortex and
medulla of a compact organ; in the birds, reptiles
and amphibians they are mixed together in various ways, and in fish they form two separate
organs. The corticosteroids carry a side-chain of
two C atoms on C-17, and these can be substituted with hydroxy or oxo groups. Additional
oxygens on C-3, C-ll, C-17 or C-18 result in a
large number of related steroids, most of which
are inactive metabolic products. Due to the large
number of polar groups, the corticosteroids are
quite soluble in water. All biologically active corticosteroids influence both the carbohydrate and
the mineral balance, but as one function usually
predominates a distinction may be drawn between glucocorticoids and mineral corticoids. The
glucocorticoids all have a hydroxy or oxo group at
C-ll (for the formula see Fig. 16.10), whereas the
ll-deoxysteroids act as mineral corticoids. One
exception to this rule is aldosterone, in which the
ll-hydroxy group forms a semi-acetal, together
with the aldehyde group on C-18; this is unique to
this molecule (Fig. 16.11a). The glucocorticoids
stimulate the synthesis of various enzymes of gluconeogenesis, resulting in glycogen storage. The
mineral corticoids act primarily on ion transport
via the ATPases of the cell membrane, and regulate the excretion of sodium and calcium in the
distal tubules of the kidney [39, 74]. The spectrum of corticosteroids varies between the different vertebrate groups. Cortisol predominates in
most mammals. Only in the case of the rat,
mouse and rabbit is there almost no cortisol but
only corticosterone. However, exogenous cortisol
is still highly active in these species. Birds appear
to completely lack cortisol, and corticosterone
predominates in the reptiles and the amphibians.
Cortisol is, however, the main corticosteroid of
the teleosts. Aldosterone appears to be absent
from the agnathans, elasmobranch and teleosts,
but is present in the dipnoans and all tetrapods.
In the teleosts cortisol also regulates sodium
uptake by the gills. In the birds, reptiles and
amphibians, aldosterone and also corticosterone
appear to be involved in regulation of the mineral
balance; both act, to some extent, antagonistically. From this it is clear that the classification into
glucocorticoids and mineral corticoids is only
strictly observed in the mammals [39, 74].
16 Sterols and Steroids
C19 steroids. Plasma proteins from sharks, rays
and lampreys bind C2b C18 and C19 steroids with
the same low affinity, and the blood of the common hagfish Myxine contains no steroid-binding
proteins of any sort. Transcortin-like proteins are
apparently widely distributed from the bony fish
onwards. There are, however, large differences in
amino acid composition and molecular mass
between, for example, human and chicken transcortins. CBG, like other plasma proteins, is secreted by the liver but the corresponding human
mRNA is also found in the lung, testis and
kidney. Human CBG consists of a polypeptide
chain of 383 amino acids and five oligosaccharides, which make up about 23 % of the molecular
mass of 58 kDa. The amino acid sequence shows
no similarity to other steroid-binding proteins but
does exhibit significant homology to alantitrypsin and other serpins [44].
Sex hormone-binding globulin has been found
in many mammals, but is absent from rodents,
elephants and the birds. Reptiles possess SHBG
and, in fact, have separate androgen- and
oestrogen-specific proteins. SHBG-like proteins
have also been detected in various amphibians
and teleosts [102]. The SHBG of the mammals
is a dimer of two identical polypeptides of
367-373 amino acids with three carbohydrate
chains, although it binds only one steroid molecule [45, 126]. At least in the N-terminal region,
it shows sequence similarity to the similar-sized
androgen-binding protein (ABP) from mammalian testis; the function of ABP appears to be to
concentrate androgens and thereby amplify their
effects on spermatogenesis and sperm maturation
[41, 57]. A similar protein is found in the testis of
the spiny dogfish Squalus acanthias [73]. The
steroid-binding protein from rat prostate apparently functions in a feedback mechanism to regulate androgen activity; it is a tetramer of four different polypeptides that both bind to, and are
induced by, androgen. This protein shows significant sequence homology to the uteroglobin from
the uterus and lung of the rabbit; this is a homodimer of about 16 kDa that is both induced by
and binds to progesterone. The 91 co dons of the
gene sequences of the pre-uteroglobins of the
rabbit and of the hare Lepus capensis have five
synonymous substitutions, suggesting that the
two species separated about 4 million years ago;
there are also six amino acid-exchanging substitutions, which suggests an unusually high rate of
evolution [72].
16.3.3 Corticosteroids
Only in the mammals are steroid-producing and
catecholamine-producing (chromaffine) cells of
the adrenal gland organized into the cortex and
medulla of a compact organ; in the birds, reptiles
and amphibians they are mixed together in various ways, and in fish they form two separate
organs. The corticosteroids carry a side-chain of
two C atoms on C-17, and these can be substituted with hydroxy or oxo groups. Additional
oxygens on C-3, C-ll, C-17 or C-18 result in a
large number of related steroids, most of which
are inactive metabolic products. Due to the large
number of polar groups, the corticosteroids are
quite soluble in water. All biologically active corticosteroids influence both the carbohydrate and
the mineral balance, but as one function usually
predominates a distinction may be drawn between glucocorticoids and mineral corticoids. The
glucocorticoids all have a hydroxy or oxo group at
C-ll (for the formula see Fig. 16.10), whereas the
ll-deoxysteroids act as mineral corticoids. One
exception to this rule is aldosterone, in which the
ll-hydroxy group forms a semi-acetal, together
with the aldehyde group on C-18; this is unique to
this molecule (Fig. 16.11a). The glucocorticoids
stimulate the synthesis of various enzymes of gluconeogenesis, resulting in glycogen storage. The
mineral corticoids act primarily on ion transport
via the ATPases of the cell membrane, and regulate the excretion of sodium and calcium in the
distal tubules of the kidney [39, 74]. The spectrum of corticosteroids varies between the different vertebrate groups. Cortisol predominates in
most mammals. Only in the case of the rat,
mouse and rabbit is there almost no cortisol but
only corticosterone. However, exogenous cortisol
is still highly active in these species. Birds appear
to completely lack cortisol, and corticosterone
predominates in the reptiles and the amphibians.
Cortisol is, however, the main corticosteroid of
the teleosts. Aldosterone appears to be absent
from the agnathans, elasmobranch and teleosts,
but is present in the dipnoans and all tetrapods.
In the teleosts cortisol also regulates sodium
uptake by the gills. In the birds, reptiles and
amphibians, aldosterone and also corticosterone
appear to be involved in regulation of the mineral
balance; both act, to some extent, antagonistically. From this it is clear that the classification into
glucocorticoids and mineral corticoids is only
strictly observed in the mammals [39, 74].