581-584 amino acids corresponding to a molecular mass of about 66 kDa. The long, strung-out
molecule has dimensions of 4 X 14 nm and is
subdivided into three domains which, despite
similarities in structure, appear to have differences in function [36, 92]. The significant
sequence homology between the three domains
indicates that albumin arose by the triplication of
a polypeptide of about 190 amino acids. Of
physiological importance is the binding capacity
of albumin for organic anions like gall pigments,
steroid and thyroid hormones, fatty acids and
drugs. A high-affinity fatty-acid-binding site is
found in domain III; evolutionary rudiments in
the form of low-affinity fatty-acid-binding sites
are detectable in domains I and II. The binding
site for bilirubin lies on domain II and that for
indole on domain 1. There is a marked speciesspecifity in the binding properties of the albumins. For example, bilirubin binds much more
strongly to human and chicken albumin than to
bovine or rabbit albumin; frog albumin, in contrast to the others, cannot bind tryptophan. Albumin, like almost all other plasma proteins, is synthesized in the liver. The prepro-albumin formed
initially has an N-terminus which bears a signal
sequence of 24 amino acids as well as a Propeptide of 5-6 amino acids; pro-albumin has
been isolated from the liver of various mammals
and birds.
Serum albumin belongs to the proteins that
show a high rate of evolution (see Table 4.12,
p. 161). This fact, and the ease with which albumin can be isolated, makes it especially suitable
for immunological studies of relationships by the
method of microcomplement fixation (p.151).
Such investigations have now been carried out on
many hundreds of vertebrate species. Positive
immunological cross-reactions between serum
albumins, corresponding to sequence differences
of not more than 40 % , are only obtained
between vertebrates of the same class; one exception is the positive reaction between the alligator
and the chicken. Thus, an albumin comparison is
suitable, above all, for clarifying relationships at
the level of the family or order. Multiple albumins
are known from the polyploid species of the
genus Xenopus (see Table 4.6, p. 126): tetraploid
species have two, octaploid species two or three
and the dodecaploid X. ruwezoriensis three albumins, which apparently can differ significantly in
size and sequence. The peptide cleavage patterns
are species specific; thus, it is seen that the tetraploid species X. andrei possesses two fraseri and
one vestitus albumin and is actually an allopoly5.2 Serum Albumin and a-Fetoprotein
187
ploid that arose by hybridization of these latter
two species [90]. Genetic variants of serum albumins are known from man and several vertebrates. There are human and rat "analbumin" individuals whose blood plasma, however, still contains
5-25 fLg albumin/ml. Although this is a 1000 times
less than the normal concentration, it should not
be concluded that serum albumin is dispensable.
The heritable analbumin in one rat line is the
result of a failure to transcribe exon H because of
a 7-bp deletion in the preceding intron [228].
The predominant plasma protein of all mammalian embryos is a-fetoprotein, which on electrophoregrams, appears in the region of the ac
globulins, but belongs to the same super-family as
the serum albumins. In humans, the maximal
concentration of ca. 3 mg/ml is reached in the
13th week of embryo development; in adults it is
found at only ng/ml concentrations, except in
cases of liver regeneration or liver tumours when
higher values are recorded. The a-fetoprotein is
apparently not just a passive plasma protein but
has various immunological and growth-regulating
functions [170]. The amino acid sequences,
obtained from cDNA or gene sequences, of
human, rat and mouse fetoproteins agree to
about 35 % with those of the albumins. The rate
of evolution of the a-fetoproteins is even higher
than that of the albumins and is comparable with
the rates for the pseudo genes [86]. In contrast to
the non-glycosylated albumins, a-fetoprotein carries at least two oligosaccharide chains. Serum
albumin and a-fetoprotein are each encoded by
single genes which lie close to each other on the
same chromosome. Both genes consist of 15
exons; exons 3-14 are subdivided into three similar sets of four exons, each of which makes up a
domain. In mammalian foetuses, the afetoprotein is made in the yolk-sac, the liver and
the gut wall. This tissue-specific expression is controlled in the mouse by three enhancer sequences
in the 5' flanking gene region [183]. Artificial
"minigenes" with enhancer I are expressed only
in the gut cells, those with enhancer II in the liver
and yolk-sac, and those with enhancer III in the
yolk-sac and the gut [94]. Small amounts of
mature albumin and a-fetoprotein mRNAs are
also detectable in rat kidney and pancreas [184].
In the neighbourhood of these two genes is a
further gene of similar structure which encodes
the very important vitamin D-binding protein
(DBP) of the blood plasma; this is also known as
group specific component (Gc). Serum albumin,
a-fetoprotein and DBP belong to the same superfamily; they have about 20 % identical amino
molecule has dimensions of 4 X 14 nm and is
subdivided into three domains which, despite
similarities in structure, appear to have differences in function [36, 92]. The significant
sequence homology between the three domains
indicates that albumin arose by the triplication of
a polypeptide of about 190 amino acids. Of
physiological importance is the binding capacity
of albumin for organic anions like gall pigments,
steroid and thyroid hormones, fatty acids and
drugs. A high-affinity fatty-acid-binding site is
found in domain III; evolutionary rudiments in
the form of low-affinity fatty-acid-binding sites
are detectable in domains I and II. The binding
site for bilirubin lies on domain II and that for
indole on domain 1. There is a marked speciesspecifity in the binding properties of the albumins. For example, bilirubin binds much more
strongly to human and chicken albumin than to
bovine or rabbit albumin; frog albumin, in contrast to the others, cannot bind tryptophan. Albumin, like almost all other plasma proteins, is synthesized in the liver. The prepro-albumin formed
initially has an N-terminus which bears a signal
sequence of 24 amino acids as well as a Propeptide of 5-6 amino acids; pro-albumin has
been isolated from the liver of various mammals
and birds.
Serum albumin belongs to the proteins that
show a high rate of evolution (see Table 4.12,
p. 161). This fact, and the ease with which albumin can be isolated, makes it especially suitable
for immunological studies of relationships by the
method of microcomplement fixation (p.151).
Such investigations have now been carried out on
many hundreds of vertebrate species. Positive
immunological cross-reactions between serum
albumins, corresponding to sequence differences
of not more than 40 % , are only obtained
between vertebrates of the same class; one exception is the positive reaction between the alligator
and the chicken. Thus, an albumin comparison is
suitable, above all, for clarifying relationships at
the level of the family or order. Multiple albumins
are known from the polyploid species of the
genus Xenopus (see Table 4.6, p. 126): tetraploid
species have two, octaploid species two or three
and the dodecaploid X. ruwezoriensis three albumins, which apparently can differ significantly in
size and sequence. The peptide cleavage patterns
are species specific; thus, it is seen that the tetraploid species X. andrei possesses two fraseri and
one vestitus albumin and is actually an allopoly5.2 Serum Albumin and a-Fetoprotein
187
ploid that arose by hybridization of these latter
two species [90]. Genetic variants of serum albumins are known from man and several vertebrates. There are human and rat "analbumin" individuals whose blood plasma, however, still contains
5-25 fLg albumin/ml. Although this is a 1000 times
less than the normal concentration, it should not
be concluded that serum albumin is dispensable.
The heritable analbumin in one rat line is the
result of a failure to transcribe exon H because of
a 7-bp deletion in the preceding intron [228].
The predominant plasma protein of all mammalian embryos is a-fetoprotein, which on electrophoregrams, appears in the region of the ac
globulins, but belongs to the same super-family as
the serum albumins. In humans, the maximal
concentration of ca. 3 mg/ml is reached in the
13th week of embryo development; in adults it is
found at only ng/ml concentrations, except in
cases of liver regeneration or liver tumours when
higher values are recorded. The a-fetoprotein is
apparently not just a passive plasma protein but
has various immunological and growth-regulating
functions [170]. The amino acid sequences,
obtained from cDNA or gene sequences, of
human, rat and mouse fetoproteins agree to
about 35 % with those of the albumins. The rate
of evolution of the a-fetoproteins is even higher
than that of the albumins and is comparable with
the rates for the pseudo genes [86]. In contrast to
the non-glycosylated albumins, a-fetoprotein carries at least two oligosaccharide chains. Serum
albumin and a-fetoprotein are each encoded by
single genes which lie close to each other on the
same chromosome. Both genes consist of 15
exons; exons 3-14 are subdivided into three similar sets of four exons, each of which makes up a
domain. In mammalian foetuses, the afetoprotein is made in the yolk-sac, the liver and
the gut wall. This tissue-specific expression is controlled in the mouse by three enhancer sequences
in the 5' flanking gene region [183]. Artificial
"minigenes" with enhancer I are expressed only
in the gut cells, those with enhancer II in the liver
and yolk-sac, and those with enhancer III in the
yolk-sac and the gut [94]. Small amounts of
mature albumin and a-fetoprotein mRNAs are
also detectable in rat kidney and pancreas [184].
In the neighbourhood of these two genes is a
further gene of similar structure which encodes
the very important vitamin D-binding protein
(DBP) of the blood plasma; this is also known as
group specific component (Gc). Serum albumin,
a-fetoprotein and DBP belong to the same superfamily; they have about 20 % identical amino