188
5 Plasma Proteins, Yolk Proteins and Metal-Binding Proteins
acids and the same periodicity of structure with 15
exons and 3 mutually homologous protein
domains. It has been calculated from sequence
comparisons that the separation of DBP occurred
560-600 million years ago, and the separation of
albumin and a~fetoprotein about 280 million
years ago, i.e. shortly after the separation of the
reptiles from the amphibians. Accordingly, one
should find larval a-fetoprotein in the reptiles but
not in the fish or amphibians; up to now this
hypothesis has only been tested in Xenopus tadpoles, where a-fetoprotein is, in fact, not present
[92]. A further protein, fetuin, is found in the foetal plasma of the ungulates (cattle, sheep, goats,
pigs) at concentrations up to 5 mg/ml but it is
only present in trace amounts in adult animals.
Immunological analysis has demonstrated the
presence of fetuin in all mammals tested. In
sheep and bovine embryos, fetuin is also found at
high concentrations in the cerebral cortex, and it
is detectable immunologically in trace amounts in
the brains of human embryos. In the latter case,
significantly greater amounts are found of the
azHS glycoprotein, which has 70 % amino acids
in common with fetuin [66].
5.3 Plasma Proteins with Special Binding
and Transport Functions
Plasma proteins are involved in many ways in the
transport activities of the blood. Relatively nonspecific binding of organic anions to serum albumin occurs in vertebrate blood, and, in addition,
there are specific plasma proteins binding iron
(transferrin), copper (caeruloplasmin), haemoglobin (haptoglobin), haem (haemopexin), thyroxin (thyroxin-binding protein), steroid hormone (transcortin), vitamin B (transcobalamin)
and lipids (lipoproteins). Corresponding transport proteins are also present in the invertebrates, although these have been less thoroughly
investigated, e.g. the juvenile hormone and
ecdysone-binding proteins of the insects, and the
lipoproteins of various arthropods.
5.3.1 Transferrin
Free Fe3+ ions cannot exceed a concentration of
ca. 10- 17 mo1/1 in neutral solution without forming
insoluble ferric oxide. In vertebrates, which exhibit a very intensive iron metabolism in connection
with haemoglobin synthesis, iron is transported
between the sites of resorption, storage, use and
elimination by specific transport proteins. The
most important are the serum transferrins; these
are glycoproteins of 65-85 kDa which are red in
an iron-saturated condition (I.'max = 470 nm).
Under normal physiological conditions they are,
for example in humans, up to only 30 % saturated, and thus only 3-5 mg of iron, which represents 1/1000th of the total body iron, is found dissolved in the blood plasma. In female birds, more
than 50 % of the serum iron is bound to vitellogenino Each transferrin molecule can bind two iron
atoms. This process is unique in so far as one
bicarbonate is bound per iron. The affinity of
transferrin for iron is extraordinarily high and
varies very little between different mammalian
species [271].
The transferrins also have antimicrobial activity, denying microorganisms essential iron by virtue of their high affinity. The uptake of iron, e.g.
into haemoglobin-synthesizing reticulocytes,
occurs via receptor-mediated endocytosis at
coated pits. The primary structure of human
transferrin receptors has been determined from
the mRNA sequence. It is a dimeric transmembrane protein with two polypeptides of 90 kDa
and three N-bound oligosaccharide chains, as
well as phosphoric acid and fatty acid residues.
Of the 760 amino acids in each chain, the first 62
form the cytoplasmic region, the following 26 the
transmembrane part, and the remaining 672
make up the extracellular domain [254]. The
binding of transferrin to the receptor is not species specific, but it is, to a limited extent, group
specific. Thus, the receptors of higher mammals
(placentals) bind transferrin of other Placentalia
but not that of pouched animals (marsupials),
birds or amphibians [148].
There are three types of vertebrate transferrin:
in addition to serum transferrin (siderophilin),
which is found in all vertebrates, there is the ovotransferrin (conalbumin) of bird eggs, and lactotransferrin (lactoferrin), which occurs in the milk
of all mammals and also in tears and leukocytes.
Ovo- and lactotransferrin are probably mostly
antimicrobial in function. The three transferrins
comprise a protein super-family. The ca. 700amino-acid-Iong polypeptide chain of human lacto transferrin shows about 59 % agreement with
human serum transferrin and about 49 % with
chicken ovotransferrin. The serum transferrin and
ovotransferrin of the chicken differ only in the
carbohydrate components and not in the amino
acid sequence. Whilst human and bovine milk
transferrins differ markedly from those of the
5 Plasma Proteins, Yolk Proteins and Metal-Binding Proteins
acids and the same periodicity of structure with 15
exons and 3 mutually homologous protein
domains. It has been calculated from sequence
comparisons that the separation of DBP occurred
560-600 million years ago, and the separation of
albumin and a~fetoprotein about 280 million
years ago, i.e. shortly after the separation of the
reptiles from the amphibians. Accordingly, one
should find larval a-fetoprotein in the reptiles but
not in the fish or amphibians; up to now this
hypothesis has only been tested in Xenopus tadpoles, where a-fetoprotein is, in fact, not present
[92]. A further protein, fetuin, is found in the foetal plasma of the ungulates (cattle, sheep, goats,
pigs) at concentrations up to 5 mg/ml but it is
only present in trace amounts in adult animals.
Immunological analysis has demonstrated the
presence of fetuin in all mammals tested. In
sheep and bovine embryos, fetuin is also found at
high concentrations in the cerebral cortex, and it
is detectable immunologically in trace amounts in
the brains of human embryos. In the latter case,
significantly greater amounts are found of the
azHS glycoprotein, which has 70 % amino acids
in common with fetuin [66].
5.3 Plasma Proteins with Special Binding
and Transport Functions
Plasma proteins are involved in many ways in the
transport activities of the blood. Relatively nonspecific binding of organic anions to serum albumin occurs in vertebrate blood, and, in addition,
there are specific plasma proteins binding iron
(transferrin), copper (caeruloplasmin), haemoglobin (haptoglobin), haem (haemopexin), thyroxin (thyroxin-binding protein), steroid hormone (transcortin), vitamin B (transcobalamin)
and lipids (lipoproteins). Corresponding transport proteins are also present in the invertebrates, although these have been less thoroughly
investigated, e.g. the juvenile hormone and
ecdysone-binding proteins of the insects, and the
lipoproteins of various arthropods.
5.3.1 Transferrin
Free Fe3+ ions cannot exceed a concentration of
ca. 10- 17 mo1/1 in neutral solution without forming
insoluble ferric oxide. In vertebrates, which exhibit a very intensive iron metabolism in connection
with haemoglobin synthesis, iron is transported
between the sites of resorption, storage, use and
elimination by specific transport proteins. The
most important are the serum transferrins; these
are glycoproteins of 65-85 kDa which are red in
an iron-saturated condition (I.'max = 470 nm).
Under normal physiological conditions they are,
for example in humans, up to only 30 % saturated, and thus only 3-5 mg of iron, which represents 1/1000th of the total body iron, is found dissolved in the blood plasma. In female birds, more
than 50 % of the serum iron is bound to vitellogenino Each transferrin molecule can bind two iron
atoms. This process is unique in so far as one
bicarbonate is bound per iron. The affinity of
transferrin for iron is extraordinarily high and
varies very little between different mammalian
species [271].
The transferrins also have antimicrobial activity, denying microorganisms essential iron by virtue of their high affinity. The uptake of iron, e.g.
into haemoglobin-synthesizing reticulocytes,
occurs via receptor-mediated endocytosis at
coated pits. The primary structure of human
transferrin receptors has been determined from
the mRNA sequence. It is a dimeric transmembrane protein with two polypeptides of 90 kDa
and three N-bound oligosaccharide chains, as
well as phosphoric acid and fatty acid residues.
Of the 760 amino acids in each chain, the first 62
form the cytoplasmic region, the following 26 the
transmembrane part, and the remaining 672
make up the extracellular domain [254]. The
binding of transferrin to the receptor is not species specific, but it is, to a limited extent, group
specific. Thus, the receptors of higher mammals
(placentals) bind transferrin of other Placentalia
but not that of pouched animals (marsupials),
birds or amphibians [148].
There are three types of vertebrate transferrin:
in addition to serum transferrin (siderophilin),
which is found in all vertebrates, there is the ovotransferrin (conalbumin) of bird eggs, and lactotransferrin (lactoferrin), which occurs in the milk
of all mammals and also in tears and leukocytes.
Ovo- and lactotransferrin are probably mostly
antimicrobial in function. The three transferrins
comprise a protein super-family. The ca. 700amino-acid-Iong polypeptide chain of human lacto transferrin shows about 59 % agreement with
human serum transferrin and about 49 % with
chicken ovotransferrin. The serum transferrin and
ovotransferrin of the chicken differ only in the
carbohydrate components and not in the amino
acid sequence. Whilst human and bovine milk
transferrins differ markedly from those of the